Tobacco Cessation and Substance Abuse Treatment in Women’s Healthcare

3. Physiology of EtOH, Opiate, Hypnotics, and Stimulants Receptors

Byron C. Calhoun 

(1)

Department of Obstetrics and Gynecology, West Virginia University-Charleston, Charleston, WV, USA

Byron C. Calhoun

Email: Byron.calhoun@camc.org

Keywords

AlcoholOpioidBenzodiazepinesStimulantsReceptors and physiology

Pharmacokinetics

Pharmacokinetics involves the amount of time it takes for drugs to develop concentrations in blood and tissue (brain). Drug concentrations in blood and other tissues are influenced the absorption, distribution, metabolism, and elimination of the drug. A drug’s pharmacologic effects are directly related to the amount of the free or unbound drug concentration at its sit of action.

Absorption entails the process of the drug movement from the site of drug delivery to the site of action. Psychoactive drugs may be taken orally (ethanol, amphetamine, barbiturates, opiates), intranasally (glue, solvents, amyl nitrate, cocaine, heroin), via smoking (nicotine, marijuana, freebase cocaine), intravenously (heroin, cocaine, methamphetamine), transdermally (fentanyl and nicotine patches), and subcutaneous injection. Drug concentrations vary by time over the various routes of administration. The more rapidly the psychoactive drug is delivered to the site of action in the brain, the greater is its mood-altering and reinforcing effects. The most rapid achieved and highest peak concentrations are achieved from the pulmonary and intravenous routes.

Bioavailability consists of the fraction of unchanged drug that reaches the systemic circulation after administration by various routes. The bioavailability factor (F) adjusts for the portion of administered dose that is able to enter the bloodstream in unchanged form. For example, the amount of drug available after intravenous administration is equal to 100 % (F = 1.0). Bioavailability depends on the drug’s site-specific membrane permeability, activity of the receptors, and the first-pass metabolism. First-pass metabolism represents the metabolism that takes place before the drug reaches the bloodstream and occurs most completely for lipid-soluble drugs like morphine, methylphenidate, and desipramine. This effect significantly reduces bioavailability of the drugs. An example is morphine which requires double the dose when administered orally compared to intravenous administration. First-pass metabolism is not important for intravenous, sublingual, intramuscular, subcutaneous, and transdermal routes due to the entry directly into the blood stream.

Oral administration absorption is influenced by several phenomena: pharmaceutical properties of the drug, the pH of the gastric contents, gastric emptying time (distribution to small intestines for absorption), intestinal transit time (i.e., drugs absorbed in small intestine absorb faster with faster transit time), integrity of intestinal epithelium, and the presence of food [1]. Smoked and inhaled drugs completely bypass the venous system and have most rapid rate of delivery. Absorption of the inhaled drugs depends on the physical characteristics of the drug, especially the drugs’ volatility, particle size, and lipid solubility [2]. Drugs that are inhaled have essentially unlimited access to the vascularity through the interface of the surface of the alveoli with the central pulmonary vessels. Due to the rapid flow of the cardiac output, smoked, and freebase drugs rapidly enter the brain.

All drugs must pass through cell membranes for absorption . Passive diffusion favors lipid-soluble and uncharged molecules. Others have decreased absorption due to the effects of the reverse transporter of P-glycoprotein. This reverse transporter actually pumps drugs from the gut epithelium back into the gut itself thereby decreasing absorption. Other food and drug interactions change the first-pass phenomenon. Grapefruit juice and other foods that either inhibit or induce intestinal wall CY3A4 or P-glycoprotein may lead to altered bioavailability of drugs that are substrates for this cytochrome [34]. The class of monoamine oxidase inhibitors (MAOIs ) such as phenelzine and tranylcypromine inhibit monoamine oxidase-A in the intestinal wall and liver. This inhibition diminishes the first-pass metabolism of tyramine that is present in cheese, wines, and various other foods. When tyramine, an indirect acting sympathomimetic amine, reaches the blood stream, it can produce increased release of norepinephrine from the sympathetic postganglionic neurons which may result in severe pressor response and hypertensive crisis.

Increasing gastric emptying time may help to increase a more rapid drug effect without any change in bioavailability. Gastric emptying may be increased by drinking at least 200 mL of water and staying upright. Delay of gastric emptying , and, hence later and lower peaks of drug concentrations, include food, heavy exercise, recumbency, and drugs that slow gastric emptying (narcotics and anticholinergic drugs).

Distribution

Distribution is influenced b organ perfusion, organ size, binding of the drugs within the blood and tissues, and permeability of the tissue membranes [5]. The majority of psychoactive drugs enter the brain because of high lipid solubility. The blood–brain barrier restricts entry by non-lipid-soluble drugs into the brain by diffusion. The brain’s capillaries prevent the entry of molecules less than 25,000 Da due to the lack of fenestrations in the capillaries. Without fenestrations, the drugs must pass through the two membranes of the endothelial cells by passive diffusion. This barrier limits access by numerous drugs to the brain, spinal cord, and all areas of the subarachnoid membrane, except the floor of the hypothalamus.

Some compounds have active transport systems. These active transport systems enable glucose, amino acids, amines, purines, nucleosides, and organic acids to enter the brain [6]. The distribution of drugs to all parts of the body consists of the volume of distribution (Vd). The volume does consist of a quantifiable physical equivalent, but rather, the amount of serum, plasma, or blood that would be required for all the drug in the body. Vd can be thought of the amount of drug in the body (D = dose) divided by the concentration of drug (C) in the plasma. Drugs with a small volume of distribution are found mostly in the intravascular space of about 5 L. Drugs that are tightly bound to plasma proteins, or have a high molecular weight (large proteins, dextran, and others) may have a volume of distribution up to 50,000 L.

Protein-binding affects the free and active drug concentration. Proteins generally have characteristics of capacity (amount of bind space) and affinity (tightness of binding). For example, albumin is a high-capacity, low-affinity-binding protein unlike a specific transport protein such as transcortin which is a low capacity, high-affinity protein. Acidic drugs usually bind to albumin, the most abundant plasma protein. Examples include barbiturates, benzodiazepines, and phenytoin. Basic drugs like methadone bind to alpha1-acid glycoprotein, and others such as amitriptyline and nortriptyline bind to lipoproteins. There are binding sites that are competitive, and drugs with a higher binding site affinity can displace a drug with a lower binding site affinity. It may also be stereospecific (for one stereoisomer of a compound). Drugs that are greater than 90 % bound are considered highly protein bound, and reduced protein binding for highly protein bound drugs can lead to large increases in drug effect.

The rate of blood flow delivered to specific organs and tissues affects drug distribution . Well-perfused tissues may receive large quantities of drug provided that the drug can cross the membranes or other cell barriers between the plasma and tissue. In contrast, poorly perfused tissues, such as fat, receive and release drug at a slow rate. This explains why concentrations of drugs may be maintained long after the concentration in plasma has begun to decrease. An example is anesthetics.

Clearance of drugs is usually described as elimination. Elimination consists of the disappearance of the parent drug and/or its active molecule from the bloodstream or body. This may occur by either metabolism and/or excretion. Excretion is removing a compound from the body without chemically altering the compound. Drugs may be excreted through urine, feces, exhaled through the lungs, or secreted in sweat or salivary glands. The term clearance (CI) represents the theoretical volume of blood or plasma that is completely cleared of a given drug over a specific period of time. Factors that determine liver clearance are hepatic blood flow, the fraction of drug that is unbound, and the drug’s intrinsic clearance. If the intrinsic clearance of the unbound drug is small, then the metabolic capacity (intrinsic clearance) of the liver, rather than hepatic blood flow, becomes the major determinant of hepatic clearance. In that case, the functionality of the hepatic enzymes determines drug clearance. If the intrinsic clearance of an unbound drug is very large, blood flow to the liver becomes rate limiting. Metabolic capacity determines drug clearance in most cases.

The majority of drugs have first-order elimination kinetics: the fraction or percentage of the total amount of drug present is removed at one time is constant and independent of dosage. After drug administration of a drug with first-order kinetics , concentrations of the drug show an exponential decline of drug concentration. The slope of the decay line is the elimination constant ke1 which is the percent of drug cleared per unit time (i.e., percent/h). The half-life (t 1/2) of a drug is the amount of time it takes for a drug concentration to decrease by half. One half-life represents a 50 % change, and a 2, 3, 4, and 5 half-lives represent 75, 87.5, 93.7, and 96.8 % changes. The time to reach steady state depends upon the duration of the half-life, whereas the amount of drug in the body at steady state will depend upon the frequency of the drug administration and its dose. With drugs with dose-dependent (first-order) disposition and elimination characteristics, 5 half-lives is a reasonable estimate of the time to reach steady state for the given drug. For example, if the concentration at 2 h postdose is 100 μg/mL, and the concentration at 4 h postdose is 50 μg/mL, the t 1/2 is 2 h.

Drug metabolism is the process of chemical modification of drugs and other chemicals by the body, generally into less active and more hydrophilic compounds. These chemical modifications/reactions are generally performed by enzymatic systems, such as the cytochrome P450 enzyme system. Lipophilic drugs are generally transformed to more hydrophilic/polar products that are inactive or nontoxic, and active metabolites need to be considered when assessing a drug’s activity. In certain cases, the administered drug is intentionally designed to be a pharmacologically inactive prodrug that is converted in vivo to a pharmacologically active molecule. One example is levodopa which, after crossing the blood–brain barrier, is converted in the basal ganglia to dopamine.

Drugs may be metabolized by Phase I/or Phase II reactions . Phase I reactions are nonsynthetic reactions in which the drug is chemically altered and oxidized. For example, a drug may be demethylated. Examples of Phase I reactions include the oxidation of phenobarbital, amphetamine, meperidine, and codeine by microsomal enzymes. Phase II reactions are synthetic reactions in which the drug is conjugated with another moiety, such as glucuronide or sulfate. Examples of synthetic reactions include glucuronidation of morphine and meprobamate and acetylation of clonazepam and mescaline, which produce a compounds more polar than the parent drugs in order to facilitate metabolism. Cytochrome P450 enzymes are most commonly involved and exist in the gut, liver, and brain. The gut and liver enzymes are the best studied. Oxidations can take place by cytochromic P450-dependent and cytochrome P450-independent mechanisms. Cytochrome P450-dependent oxidations include aromatic (phenytoin, amphetamine) and aliphatic (pentobarbital, meprobamate) hydroxylations, epoxidation, and oxidative dealkylation (morphine, caffeine, codeine), deamination (amphetamine), desulfurization (thiopental), and dechlorination. Cytochrome P450-independent oxidations include dehydrogenations (ethanol); azo, nitro, and carbonyl reductions (methadone, naloxone); and ester and amide hydrolysis [7].

The other family of enzymes identified in the metabolism of drugs is the CYP group. This family of enzymes is involved in the metabolism of dietary and environmental compounds and medications. These enzymes are involved in a large number of endogenous functions (as in bile acids). CYPs that metabolize drugs operate in a large and fluid substrate-binding sites contribute to the slow catalytic rates. One particular CYP (CYP3A4) is responsible for metabolizing more than 50 % of clinically prescribed drugs.

Pharmacogenetics

Pharmacogenetics represents the study of the relationship between genetic variations and drug disposition and responses. It necessarily entails the clarification of cytochrome and other drug-metabolizing enzyme polymorphisms (different enzyme genetic subtypes), the degree of expression of polymorphisms, and the functional significance of expression. Understanding polymorphisms of expression may help explain individual differences in drug response by individuals. Genetic variability in drug-metabolizing enzymes may affect drug bioavailability and clearance [811]. Single nucleotide polymorphisms (SNPs) may alter CYP activity. One example is CYP2D6 which metabolizes codeine to morphine is one of the best elucidated of the drug metabolic enzymes. There are 48 mutations and 50 alleles that have been identified. The genotype and enzyme activity are linked to patient ethnicity which may vary from no gene/no enzyme activity (6 % of Caucasians) to two copies of a fully active gene (36 % of Ethiopians). Individuals may be genotyped for 2D6 enzyme function with classification as poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers [12]. Poor metabolizers do not receive adequate analgesia due to the inability to metabolize codeine into its active metabolite of morphine. Ultrarapid metabolizers metabolize codeine into morphine producing rare but life-threatening morphine intoxication. Even infants of mothers who are ultrarapid metabolizers may receive morphine overdoses if breastfed after the mother receives codeine postpartum [1314].

Further evaluation of other enzyme subgroups have found other genetic drug interactions. CYP2B6 has an allele for the *4 allele with higher conversion of bupropion to the active and longer lasting metabolite, hydroxybupropion with subsequent toxicity. Other alleles were noted to have less enzyme present and less activity. These poor metabolizers necessitated an increase dosage to improve smoking cessation with bupropion [15]. The enzyme of CYP3A4 has several SNPs. The prediction of the activity of f CYP3A4 is complex and not directly related to the genotype [12]. Several opioids, including methadone and buprenorphine utilize the CYP3A4 enzyme pathway. Methadone is metabolized primarily by the CYP3A4 enzyme with further actions by CYP2B6, 2C19, 3A4, and CYP2D6 [416]. Known inhibitors of CYP3A4 enzymes include erythromycin, diltiazem, ketoconazole, and saquinavir slow the metabolism of methadone and increase methadone levels. Inducers of CYP3A4 such as carbamazepine, phenobarbital, efavirenz, and St. John’s wort speed the metabolism of methadone and decrease methadone levels. Due to these variations in effects, it is necessary to know potential interactions, make pertinent clinical observations, and tailor medication regimens and dosages to optimize therapy and minimize possible toxicities.

Genetic differences in drug metabolism may influence the risk of addiction with protective effects with individuals who experience adverse drug reactions at lower drug levels. The alleles of ADH1B2-His47Arg of alcohol dehydrogenase 1B and ALDH-Glu487Lys allele of aldehyde dehydrogenase 2 alone or together can lead to flushing, nausea, and headache as a result of the accumulation of acetaldehyde when alcohol is consumed. Either allele leads to a reduction in the risk of alcoholism, with addictive protective effects when the same person carries both alleles. Individuals of South Asian descent are apt to carry both alleles, whereas those with Jewish descent often have the Arg47 allele. Heterozygous carriers of ALDH2 Lys487 have low levels of ALDH2 enzyme activity, whereas ALDH2 Lys487/Lys487 homozygous individuals are nearly completely protected from alcoholism [17]. Further, slow nicotine metabolism by CYP2D6 seems to have a protective effect against nicotine addiction [18]. This also allows for increased ability to obtain nicotine abstinence.

Most drug metabolism occurs in the liver as well as lungs, GI tract, skin, and kidneys. Several P450 cytochromes have been shown to catalyze the metabolism of neurosteroids as well as psychoactive drugs such as neuroleptics and antidepressants. Alcohol produces a three- to fivefold increase in the level of P450 and induces CYP2C, CYP2E1, and CYP4A [19]. Brain CYP2D6 will demethylate 3,4-methylenedioxy-N-methylamphetamine (MDMA-ecstasy) creating the toxic metabolite N-methyl-a-methyldopamine. Brain CYP2D6 may also O-demethylate paramethoxyamphetamine, a synthetic psychostimulant and hallucinogen into the toxic compound 4-hydroxyamphetamine [20]. CYP2B6 metabolizes cocaine, phencyclidine, and some amphetamines. Both CYP2B6 and CYP2D6 are also induced by nicotine.

Pharmacodynamics

Pharmacodynamics is the study of the dose-response of a drug. This consists of the biochemical and physiological effects of the drugs on the body and how the body responds to maintain homeostasis. Drug dose may be plotted on a logarithmic scale which allows for mathematical manipulation of different dosages. The maximal effect of a drug is known as Emax. Efficacy is the extent of functional change imparted to a receptor. Efficacy is determined by the type of receptor and its effects on the body. Potency, however, is determined by the affinity of the receptor for the drug. It is the amount of drug needed to produce the given effect. Concentration of the drug needed to produce 50 % maximal effect occurs at EC50. The more potent the drug, the smaller the dose required to achieve maximal effect.

Receptor binding may also be calculated with a log description noted that 50 % of a drug bound to receptors is Kd Maximum receptor binding is noted as Bmax. Utilizing this information drug dosing may be calculated to understand the effects of the drug at different doses. This allows for the calculation in experiments of the median effective dose (ED50), median toxic dose (TD50), and median lethal dose (LD50). The therapeutic index of a drug is calculated as the ratio of the (TD50) to the (ED50).

Receptors

Receptors contain two functional domains: ligand-binding sites and an effector or signaling area. Receptors are grouped according to four common types: ligand-gated ion channels, G protein-coupled receptor signaling, receptors with intrinsic enzymatic activity (guanylate cyclase, serine/threonine kinase, tyrosine kinase activity, tyrosine phosphatases), and receptors regulating nuclear transcription.

Ligand-gated ion channel receptors selectively gate the flow of ions through channels into the cell. Each one of these multisubunit proteins spans the plasma membrane several times forming a pore. Binding of these units enables them to control channel opening and closing. Excitatory neurotransmitters (acetylcholine and glutamate) result in a net inward current of cations like sodium, calcium, and potassium, which depolarizes the cell and increases generation of action potentials. Inhibitory neurotransmitters (GABA and glycine) result in net inward flux of anions like chloride which hyperpolarize the cell and decrease the generation of action potentials.

G proteins are coupled to what are commonly called serpentine receptors since they traverse the cell membrane an average of seven times. They posses an extracellular amino (N) terminal and an intracellular carboxyl (C) terminal. Drugs bind to the G protein receptors in the extracellular fluid and change the conformation of the receptor to activate the G protein. They may exist as dimmers or even large complexes. Dimerization may influence ligand preferences and/or regulate the affinity and specificity of the complex for G protein. Examples of G protein receptors include muscarinic acetylcholinergic receptors, receptors for adrenergic amines, serotonin receptors, and peptide hormone receptors. G proteins modify the activity of regulatory proteins and/or ion channels, which alter the activity of intracellular second messengers that enable the signal transduction and amplification. Cells of different tissues may have different G protein-dependent responses to the same initial ligand (norepinephrine, acetylcholine, serotonin).

Second messenger systems include the cyclic adenosine monophosphate (cAMP) (by means of Gs and G1), cyclic guanosine monophosphate (cGMP), and phosphoinositides. Beta-adrenergic amines, glucagon, histamine, serotonin, and other hormones act on Gs to increase adenylyl cyclase and then increase the second messenger cAMP, while 2-adrenergic amines, muscarinic acetylcholine, opioids, serotonin, and others act on Gi1, Gi2, and Gi3 to decrease adenylyl cyclase and then decrease cAMP. cAMP stimulates specific cAMP-dependent protein kinases that are differentially expressed in various tissues. When cAMP binds the regulatory dimer (D) of the kinase, two catalytic (C) chains are released which diffuse through the cytoplasm and nucleus, transferring phosphate from adenosine triphosphate(ATP) to other specific enzymes and substrate proteins.

G protein receptors may rapidly decrease their effects by reversible and rapid desensitization. When agonists induce conformational changes in the receptor, the receptor binds and activates a family of G protein-coupled receptor kinases (GRKs). The activated GRK then phosphorylates serine residues in the receptor’s carboxy terminal tail, increasing the affinity for beta-arrestin, which in turn diminishes the receptor’s to interact with Gs reducing the effects of adenylyl cyclase and the agonist response.

Desensitization may be homologous or heterologous. Homologous desensitization demonstrates feedback to the receptor molecule itself, and, heterologous desensitization extends to the action of all the receptors that share a common signaling pathway. Heterologous desensitization may affect one or more downstream proteins that participate in signaling from other receptors as well. Agonists may also induce endocytosis and membrane trafficking of receptors. Endocytosis may result in either the receptor recycling through the plasma membrane with continued cellular responsiveness or cause the receptor trafficking to lysosomes such that the causes down-regulation and decreased cellular response. Increased endocytosis and recycling of opiate receptors has been shown to have continued morphine analgesia with reduced tolerance and dependence [21].

Receptors with intrinsic enzyme activity consist of extracellular growth factor or hormone-binding domains connected to the cytoplasmic enzyme domain by a hydrophobic segment that crosses the plasma membrane’s lipid bilayer. The cytoplasmic enzyme domain may be a tyrosine kinase, a serine/threonine kinase, or a guanylate cyclase that starts the signaling sequence. Drugs may target the agonist-binding sites or the enzymatic activity of the receptor.

Receptors that regulate nuclear transcription are soluble DNA-binding proteins that bypass the plasma membrane to reach their intracellular targets. Examples include: the steroid family of androgens, progesterone, glucocorticoid, and mineralocorticoid receptors, thyroid/retinoid family of receptors (thyroid, vitamin D, retinoic acid), and orphan receptor family. Since these actions require synthesis of new proteins, they have a relatively slow onset and action.

Mechanisms of Action

Drugs of abuse usually activate the mesolimbic system by interacting with ion channel receptors, binding to Gio-coupled receptors, or interfering with monoamine transporters [22]. Substances utilizing the first two mechanisms usually inhibit GABA inhibitory interneurons resulting in the net release of dopamine. Drugs that act indirectly or directly upon ion channel receptors can additionally increase dopamine in the nucleus accumbens and ventral tegmental areas (VTAs). Drugs that interfere with monoamine transporters block the reuptake or stimulate nonvesicular release of dopamine, causing an accumulation of dopamine in target structures. Nicotine, benzodiazepines, phencyclidine, and ketamine work through the ionotropic receptors. Nicotine activates the nicotinic acetylcholine receptor, and the benzodiazepines are modulators of GABAA receptors, potassium inwardly rectifying or G protein activated inwardly, rectifying potassium channels (Kir3/GIRK), glycine receptors, N-methyl-D-aspartate (NMDA) receptors, and 5-HT receptors. Alcohol also inhibits ENT1, the equilibrium producing nucleoside transporter for adenosine reuptake, resulting in adenosine accumulation, stimulation of adenosine A2 receptors, and enhanced cAMP response to element-binding (CREB) protein signaling. Neither phencyclidine nor ketamine is physically addictive or associated with withdrawal but may lead to long-lasting psychosis due to noncompetitive antagonism of the NMDA receptor. With inhalants, nitric oxide acts on NMDA receptors while the fuel addictives enhance GABAA receptor function.

Opioids, cannabinoids, gamma-hydroxybutyric acid, and the hallucinogens all exert their action through Gio. The mu, kappa, and deltoid receptors all inhibit adenylyl cyclase but produce different neuronal effects. Mu opioid agonists inhibit GABA inhibition of dopamine with the net release of mesolimbic dopamine, reinforcement, and euphoria. However, kappa agonists inhibit dopamine neurons and induce dysphoria. Cannabinoids cause presynaptic inhibition. The lipid-soluble neurotransmitters 2-arachidonoyl glycerol and anandamide bind to CB1 receptors to induce retrograde signaling from post- to presynaptic neurons where they may inhibit the release of either glutamate or GABA. Hallucinogens like LSD, mescaline, and psilocybin neither stimulate dopamine release nor cause addiction. These drugs act through 5-HT2A receptor which couples to Gq proteins and inositol triphosphate (IP3) and leads to intracellular calcium release. Hallucinogens by enhancing excitatory afferent input from the thalamus and increasing glutamate release in the cortex. Cocaine, amphetamine, methamphetamine, and ecstasy bind to transporters of biogenic amines. Cocaine inhibits the dopamine transporter, decreasing dopamine clearance from the synaptic cleft and causing an increase in extracellular dopamine. Amphetamine competitively inhibits dopamine transport at the dopamine transporter and interferes with the vesicular monoamine transporter to lessen the storage of dopamine in the synaptic vesicles. As cytoplasmic dopamine increases, there is reversal of the dopamine transporter, increasing the nonvesicular release of dopamine and further increasing extracellular dopamine. Ecstasy or MDMA is similar to amphetamine and causes release of biogenic amines by reversing the serotonin and other transporters.

G protein-coupled receptors may exist in multiple conformational states that include active, inactive, partially active, and selectively active. Drugs may bind at these sites as well. The affinity of the drug for the receptor will determine how much effect the drug has on the patient. Full agonists have a higher affinity for the active conformation and drive the equilibrium toward the active state. Partial agonists bind to the receptor with only moderate affinity for the active than for the inactive receptor. Even at saturation levels, partial agonists do no enable a full biologic response. An example is buprenorphine as a highly potent mu receptor agonist. It has a high affinity for the mu receptor and actually will displace morphine, methadone and other full opiate agonists from receptors. However, since it is not a full agonist, increases in dosages do not increase pharmacologic effects. Thus, higher doses of buprenorphine may be given without respiratory depression.

Antagonists have no effect upon response when used alone. They bind with equal affinity to the active and inactive conformations to prevent an agonist from inducing a response [23]. Inverse agonists have preferential affinity for inactive receptor conformations when otherwise the equilibrium would be shifted toward an active receptor. They, therefore, produce an effect opposite to those of an agonist. An example of this is a GABA-gated chloride ion channel agonist. This produces an inhibition of hyperpolarizing postsynaptic potentials. Their activity produce a range of sedative, anxiolytic, and anticonvulsant effects. The barbiturates and benzodiazepines both act at the GABA receptor. Benzodiazepines increase the frequency of the GABA-mediated chloride ion channel opening, and barbiturates increase the duration of the openings [24].

Tolerance and sensitization reflect changes in the way the body responds to a drug when it is used repeatedly. Tolerance is the reduction in response to a drug after its repeated administration. Tolerance shifts the dose-response curve to the right, requiring higher doses than the initial dose to achieve the same effect. Sensitization means that there is an increased drug response after its repeated administration. Repeated doses cause a greater effect after the initial dose. Some examples include cocaine which has its euphoria tolerance occur more rapidly than the cardiovascular effects. This may lead to massive overdoses of drugs to try an obtain the “rush” leading to toxic overdose effects.

Tolerance may occur by several mechanisms. Pharmacokinetic tolerance develops due to increased metabolism of a drug after repeated exposure with less of the drug being available in the bloodstream. For instance, microsomal ethanol-metabolizing enzymes, may be activated with prolonged ethanol exposure. Pharmacodynamic tolerance refers to the adaptive changes in receptor density, efficiency of receptor coupling, and/or signal transduction pathways that occur after repeated drug exposure. Learned tolerance refers to a reduction in the effects of a drug because of compensatory mechanisms that are learned. This may be seen in roofers and workers who are able to maintain their balance in the face of alcohol abuse. Conditioned tolerance is a subset of learned tolerance that occurs when a specific environment cues to drug administration. In fact, so powerful is the effect that the drug’s action may be experienced before the drug is taken [25]. Cross-tolerance develops when the tolerance to repeated use of a specific drug in a given category is generalized to other drugs in same structural category. The cross-tolerance that occurs between alcohol, barbiturates, and benzodiazepines may be used to provide weaning of a patient during drug detoxification. Physical dependence is a state that develops as a result of the adaptation produced by the resetting homeostatic mechanisms after repeated drug use. Physical dependence can arise from many sources, addictive and nonaddictive.

Alcohol

Alcohol is the chemical name for a group of related compounds that contains a hydroxyl group (–OH) bound to a carbon atom. The form consumed by humans is ethyl alcohol or ethanol consisting of two carbons and a single hydroxyl group (written as C2H2OH or C6H6O). This class of substances includes beer, wines, and distilled spirits. A standard alcohol drink is defined as one that contains 0.6 fluid ounces of alcohol. This is the amount of alcohol in a 12 oz can of beer, 5 oz of wine, or 1.5 oz of distilled spirits (40 % ethanol by volume). Alcohol is a small, water-soluble molecule is rapidly and efficiently absorbed into the bloodstream from the stomach, small intestine, and colon. Rate of absorption depends on the gastric emptying time and can be delayed by the presence of food in the small intestine. Once in the bloodstream, alcohol is rapidly distributed throughout the body and gains access to all tissues, including the fetus in the pregnant. The relationship between alcohol intake and blood levels is weight dependent. Gender is important with women showing a 20–25 % higher blood alcohol level than men with the same amount of alcohol ingested. Most of alcohol is metabolized by enzymes with a small amount excreted through the lungs as vapor. In the liver, alcohol is broken down by ADH and mixed function oxidases of P4500IIE1 (CYP2E1). Levels of CYP2E1 may be increased in chronic drinkers. ADH converts alcohol to acetaldehyde, which may be converted to acetate by the actions of acetaldehyde dehydrogenase. The rate of alcohol metabolism by ADH is relatively constant, as the enzyme is saturated at low blood alcohol levels and exhibits zero-order kinetics (constant amount oxidized per unit of time). Alcohol metabolism is proportional to body weight (and liver weight) and averages approximately 1 oz of pure alcohol per 3 h in adults. There are no effective “alcohol antagonists” that will reverse intoxicating effects of alcohol. Naloxone , the opiate antagonist, has been tested for its ability to reverse alcohol-induced coma but appears ineffective [26]. Several gamma-aminobutyric acidA (GABAA) receptor antagonists have also been evaluated including flumazenil (Anexate) and metadoxine (pyridoxal L-2-pyrrolidone-5-carboxylate) appears to increase clearance of alcohol and speed recovery [27].

Alcohol acts acutely as a central nervous system (CNS) depressant. During the initial phase when blood alcohol levels are rising, a period of disinhibition often occurs and signs of behavioral arousal are common. These include relief of anxiety, increased talkativeness, feelings of confidence and euphoria, and enhanced assertiveness. As the drinking continues, there are impairments in judgment and reaction time, increased emotional outbursts, and ataxia. At higher blood levels, alcohol acts as a sedative and hypnotic, although the quality of sleep may be reduced after alcohol intake. In patients with sleep apnea, alcohol increases the severity and frequency of episodes. It may also potentiate the sedative–hypnotic properties of benzodiazepines and barbiturates. Alcohol also enhances the sedative effects of antihistamines and the liver toxic effects of acetaminophen and the gastric irritation effects of NSAIDs increasing the risk of gastritis and upper GI bleeding.

Alcohol effects the reward pathway by enhancing the release of dopamine from the midbrain dopaminergic projections that regulate neurotransmission within the limbic and cortical circuits that regulate motivated behavior [28]. The dopamine (DA) neurons involved in this action reside in the midbrain VTA and project to discrete areas of the brain, including the nucleus accumbens, olfactory tubercle, frontal cortex, amygdale, and septal/Hippocampal areas. These regions are thought to be involved in translating emotion and perception into action through the activation of motor pathways; thus, they may be important in initiating and sustaining drug-seeking behavior. Lesions or inactivation of these discrete brain areas in animals can reduce both the acquisition of drug seeking and its reinstatement following long periods of abstinence.

The initial reinforcing action of alcohol appears to involve the excitation of VTA dopamine neurons. Initially, alcohol enhances the firing rate of the midbrain DA neurons. Chronic exposure to alcohol leads to alternations in the excitability of these neurons in the absence of alcohol that may persist for significant periods of time. Electrophysiologic studies have demonstrated enhanced efficiency of glutamatergic signaling in neurons following exposure to alcohol and other drugs of abuse [2931]. Human studies with selective pharmacologic agents found neurotransmitters like GABA, serotonin, and opiates mediate the rewarding and craving of alcohol addiction. Imaging studies are now being done to identify changes in brain activation during exposure to alcohol or alcohol-related cues between control and alcohol-dependent subjects [3233].

Psychostimulants like cocaine, amphetamines, or opiates like heroin and morphine all produce their primary effects by binding to specific protein receptors expressed on brain neurons. By contrast, alcohol interacts with a wide variety of targets including both lipids and proteins. Alcohol’s acute depressant action on neuronal excitability results from its influence on the function of inhibitory ion channels while it blocks the activity of excitatory receptors.

Alcohol usually potentiates GABAA and glycine receptor function . However, the subset of GABAA-rho receptors are inhibited by alcohol. Both the gamma-GABAA and delta-GABA receptors are acutely sensitive to low levels of alcohol. Both of these GABA receptors contain the alpha-4, beta, and delta subunit receptors instead of the gamma receptors and appear to be affected by only 5–10 mM of alcohol consistent with only a single drink [34]. Further evidence has also been found to demonstrate the effects of alcohol’s effects on the presynaptic release of GABA instead of the GABA receptors. The amygdala appears to show affects on the release of GABA from the postsynaptic regions rather than the GABA receptors [35].

The major excitatory neurotransmitter is glutamate which has three major subtypes of ion channels that activate the brain. These ion channels are AMPA, kainate, and NMDA receptors. AMPA is alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid. The ion channels control the majority of the fast excitatory synaptic transmissions in the brain and critical mediators of most of the types of synaptic plasticity involved in learning and memory. NMDA receptors need both glutamate and glycine for activation and are extremely calcium permeable. The AMPA and kainate receptors, however, only need glutamate to function. NMDA receptors are inhibited by alcohol, nitrous oxide, anesthetics, and volatile solvents like toluene [36]. NMDA receptors have sensitivity to varying concentrations of alcohol. AMPA and kainate receptors have a more selective ethanol receptor sensitivity. The NMDA receptors are antagonized by alcohol concentrations at 10–100 mM and are associated with intoxication and sedation. NMDA demonstrates regional differences most likely due to differential expression of GluN1 and GluN2 NMDA subunits [3738]. The blocking of excitatory NMDA signals appears to be critical the intoxicating and sedative effects of effects of alcohol. Inhibition of NMDA receptors in the prefrontal cortex likely contributes to the cognitive and judgment errors with alcohol intoxication [39]. Long-term alcohol use may also affect NMDA receptors in the medial and orbital cortical areas which are necessary for adapting behavior to changing environment. The NMDA receptors are also important in the regulation of dopamine release in the mesolimbic region of the nucleus accumbens.

The 5-HT3 receptors are ligand-gated ion channels activated by serotonin. Studies show that 5-HT3 receptor antagonists block the ability to discriminate alcohol from saline which may explain the subjective effects of alcohol.

Acetylcholine activates a group of ligand-gated ion channels expressed in brain neurons that are similar to the nicotinic receptors found at the neuromuscular junctions [40]. Alcohol appears to have both inhibitory and excitatory effects on acetylcholine receptors. These effects seem to be related to the various subunits of nicotine. The alpha-beta subunits appear potentiated by ethanol and the alpha subunits (alpha-7) are inhibited by ethanol. It is known that nicotinic receptors are expressed by neurons in the VTA, nucleus accumbens, and prefrontal cortex where they assist in the excitability of the neurons.

ATP-gated ion channels release ATP into the synapses where it exerts its influence on the ATP-gated channels of the 2PX family [41]. The actions on the P2X receptors is subtype specific. The PX2 and P2X4 receptors are inhibited by alcohol and the PsX3 receptors are facilitated.

Potassium and calcium-selective ion channels regulated by calcium and those by G proteins (SK and BK channels) are directly and indirectly affected by alcohol. Potassium channels inhibit excitatory glutamatergic transmissions by hyperpolarizing the membrane. BK channel activity is activated by alcohol and this is thought to inhibit the release of vasopressin from the neurohypophysial terminal and result in diuresis. SK channels do not appear to be inhibited by ethanol but their expression and localization in Hippocampal neurons are changed by chronic alcohol usage. This may be part of the cause of the ethanol withdrawal excitability. Alterations in T-type calcium channels in thalamic neurons caused by alcohol use may cause sleep problems seen in ethanol-dependent individuals.

Adenosine functions as a significant inhibitory neurotransmitter in the brain and as a possible endogenous antiepileptic due to its ability to inhibit neuronal function. Alcohol inhibits the function of nucleoside transporters leading to increased intracellular adenosine levels.

Increases in the activity of the mesolimbic projecting dopamine neurons are important in reinforcing the effects of alcohol abuse. Alcohol increases the firing of dopamine neurons that a found in the VTA causing increased dopamine release in the nucleus accumbens [42].

Endogenous opioids (endorphins and enkephalins) along with other neuropeptides have been linked to ethanol addiction. Alcohol increases blood levels of beta-endorphins in humans [43].

Endocannabinoids (EC) appear to be a significant actor in alcohol use [44]. ECs are lipid-derived molecules that activate receptors (CB1, CB2) and also bind THC the psychoactive part of marijuana. ECs regulate the GABAergic and glutamatergic synaptic transmission and are synthesized during periods of significant neuronal depolarization.

Nonalcohol Sedative Hypnotics

Sedative–hypnotic drugs are a diverse group of drugs that suppress CNS activity. They are most commonly used as anxiolytics, hypnotics, anticonvulsants, muscle relaxants, and anesthesia inducing agents. This includes benzodiazepines, nonbenzodiazepines hypnotics, barbiturates, and other compounds. The basic structure of the benzodiazepines is the 1,4-benzodiazepine nucleus. Alterations of the structure change the efficacy, potency, and other properties of the different drugs. Substitutions on the benzodiazepine ring structure have produced: (a) the triazole group: alprazolam, triazolam, and estazolam; (b) 2-keto group: diazepam, flurazepam, and clorazepate; (c) the 2-aminogroup: chlordiazepoxide; (d) the 3-hydroxy group: lorazepam, oxazepam, and temazepam; (e) the trifluoroethyl group: quazepam; (f) the imidazole group: midazolam; and (g) the 7-nitrogroup: nitrazepam and clonazepam. There are four other nonbenzodiazepine hypnotics that also have hypnotic effects due to the gamma-aminobutyric acid (GABAA) receptors. These include: (a) zopiclone, a cyclopyrrolone; (b) eszopiclone, a stereoselective isomer zopiclone; (c) zaleplon, a pyrazolopyrimidine; and (d) zolpidem, an imidazopyridine [4547]. All these drugs operate at the gamma-butyric acid receptors but not exactly like benzodiazepines.

Benzodiazepines including alprazolam, lorazepam, and diazepam are very common psychiatric medications. Most benzodiazepines have hepatic metabolism involving oxidative reactions mediated by the cytochrome P450 (CYP450) enzymes. Oxidative metabolism involves N-dealkylation or aliphatic hydroxylation. The VYP3A4 enzyme controls the oxidative metabolism of many of the benzodiazepines and is active in the biotransformation of the nonbenzodiazepine sedative–hypnotics: eszopiclone, zaleplon, and zolpidem. A number of the benzodiazepines are converted into active metabolites like desmethyldiazepam that have long half-lives. The final common pathway usually involves conjugation of the parent drug or the metabolites with glucuronide. The drugs or metabolites that undergo glucuronidation have a hydroxyl group attached. Those with parent drugs, like lorazepam and oxazepam, with direct glucuronidation have less drug interaction and reduced clearance with impaired liver function when compared to other benzodiazepines.

The other nonbenzodiazepine hypnotics appear to have unique metabolic pathways for their metabolism. Zolpidem is metabolized by CYP3A4, CYP2C9, and CYP29 into inactive metabolites by hydroxylation [48]. Aldehyde dehydrogenase appears to have a major part in the metabolism of zaleplon. Zaleplon converts to the metabolite of 5-oxozaleplon with urinary excretion. Zopiclone converts to a decarboxylated metabolite via an esterase and is excreted through the lungs. It is also converted by CYP3A4 into an active metabolite zopiclone N-oxide and an inactive metabolite of N-desmethylzopiclone.

Benzodiazepines and abuse appears complex. The quick onset of action appears to produce euphoria. The onset of action after oral administration is influenced by the formulation of the drug, the intrinsic activity, lipid solubility, protein binding, and rate of entry into the brain. It is thought that greater lipid solubility enhances uptake in the brain with diazepam more rapidly entering the brain than lorazepam. However, the pharmacokinetics may not predict abuse. Certain medications, such as clonazepam, are rapidly absorbed and quickly reach high plasma levels, yet do not produce the euphoria sought by abusing individuals when compared to lorazepam. Lower abuse potential follows the need to convert prodrugs into active metabolites in the liver. An example is formation of desmeythldiazepam from halazepam which is much less likely to be abused compared to diazepam.

The benzodiazepines and the benzodiazepine receptor agonists exert their effects via the allosteric modulation of the GABAA receptors. The inhibitory effects of the GABA receptors by the benzodiazepines is the reason these medications are sedative, anticonvulsants, hypnotic, and amnesia producing. GABAA receptors are a hetropentameric protein scaffolding surrounded by a central chloride channel [49]. The receptors may be activated by direct agonists like muscimol, which leads to an influx of chloride ions, or, indirectly by drugs such as the benzodiazepines which enhance GABA binding to the receptor with increased frequency of opening the chloride channel. There are five subunits have several subtypes (alpha, beta, gamma, delta, epsilon, rho, and pi) which each have a specific amino acid sequence. There are also multiple subtypes in each category that inhabit various regions of the brain. Benzodiazepines bind primarily the gamma-2 and alpha subunits. Alpha-1 subunits are found in the frontal, cortex, and other cortical areas, globus pallidus, hippocampus substantia nigra, and cerebellum. GABAA of the alpha-5 subunit are seen in the limbic regions [50]. Receptors with the alpha-1, alpha-2, alpha-3, and alpha-5 subunits all react to the benzodiazepines. The alpha-5 receptor operates extrasynaptically and regulates the tonic GABAergic currents while the other three are found in the synapse and modulate the GABA rapid-phase currents. The alpha-4 and alpha-6 receptors cause a lack of sensitivity to the benzodiazepines.

The alpha-1 receptors control the sedative–hypnotic effects of the benzodiazepines [51]. There is also evidence to support this subunit may be the source of the ataxia with benzodiazepines and zolpidem. Antianxiety receptors include the alpha-2 and alpha-3 subunits [52]. The alpha-2 and alpha-3 subunits may also be involved in the muscle relaxation and reward aspects of benzodiazepines.

Barbiturates possess pharmacodynamic properties of the benzodiazepines. At lower concentrations, the barbiturates modulate GABAA receptors with allosteric modification. At the higher concentrations, barbiturates are direct GABAA agonists that open the chloride channels. Barbiturates appear to reduce excitatory neurotransmission by inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and also inhibit neurotransmitter release by blocking voltage-sensitive calcium channels. The nonbarbiturate hypnotics as positive modulators of the effects of GABA agonists on GABAA receptors. They act very similarly to the benzodiazepines producing sedative–hypnotic, anxiolytic, myorelaxation, and anticonvulsant effects. They appear to have less amnestic effects and less tolerance. Differences in the binding affinities for different GABAAreceptor subtypes are reflected in the potency of the positive GABAA receptor modulators to enhance the GABA-mediated currents.

Serious drug interaction occurs with the use of sedative–hypnotics and alcohol. Benzodiazepines that are metabolized through the CYP3A4 pathway may have adverse effects by other drugs. Some inhibitors include ketoconazole, itraconazole, macrolide antibiotics (EES), fluoxetine, nefazodone, and cimetidine. Combined contraceptives may alter the metabolism of substrates of CYP1A2, CYP3A4, and CYP2C19. Inducers of P450, such as rifampin, may increased clearance of the nonbarbiturate hypnotics with decreased plasma levels. Barbiturates in particular are extremely dangerous when take with alcohol or used in high doses due to CNS depression. Barbiturates may induce their own metabolism with reduced therapeutic effects (CYP2B6, CYP2C9, CYP3A4).

The sedative–hypnotics have three characteristics in the production of addiction: hedonic effects, tolerance, and withdrawal syndrome. Hedonistic effects with the benzodiazepines not commons since they do not produce euphoria unless used with other drugs. Tolerance is most commonly seen when the medications are used as hypnotics but less commonly for anxiety. The withdrawal from benzodiazepines may be significant and even seizures may occur. The GABAA receptors appear to decrease in responsiveness in the development of tolerance. There may also be alteration in the receptor subtypes with chronic exposure that alters responsiveness. The glutamatergic system may also have a major role in the benzodiazepine withdrawal by the upregulation of Hippocampal AMPA receptors and the conductance of APMA-controlled neurons.

Benzodiazepines have definite abuse potential and those with the most likelihood are flunitrazepam, diazepam, alprazolam, and lorazepam. The lowest likelihood are clonazepam, chlordiazepoxide, halazepam, prazepam, quazepam, and oxazepam. Much of this is related to rapidity of onset with a feeling of well-being, relief of anxiety, and relaxation.

Opioids

There are three types of opioid receptors found in the nervous system : mu, kappa, and delta. The usual opioid analgesics act mostly as agonists or partial agonists at mu receptors. Heroin and most of the compounds derived from opium and man-made analogs act at the opioid receptors as agonists. The three natural endogenous opioids also act as agonists: beta-endorphins, enkephalins, and dynorphins. There is some selectivity for the receptor classes The beta-endorphins have a high affinity fro mu and delta receptors with lower affinity for kappa receptors. The dynorphins, however, have a selectivity for kappa receptors over the mu and delta receptors. The mu receptor appears to be the most clinically relevant of the three. Beta-endorphin is produced in the anterior pituitary from proopiomelanocortin. It is further produced in the CNS and the periphery. The mu receptors control both the analgesic and pleasurable effects of opioid compounds. The also modulate effects in the hypothalamic-pituitary-adrenal (HPA) axis, immune, gastrointestinal, and pulmonary regions.

The opioids include all the compounds, natural, and synthetic that are related to opium poppies and endogenous opioid neuropeptides.

Heroin is a synthetically manufactured natural opioid alkaloid morphine. Due to the rapidity of onset and short half-life, heroin is a classic and popular drug for abuse. It is a Schedule I drug with no therapeutic use. Heroin is a prodrug that is not active itself. Heroin is rapidly deacetylated to 6-monoacetyl morphine and morphine which are active at the mu receptors. Heroin is a prodrug that is more water soluble and potent than morphine. It is synthesized from morphine by acetylation at the 3 and 6 positions and metabolized in humans to active opioid compounds initially by deacetylation to the 6-monoacetylmorphine (6-MAM), and then by further deacetylation to morphine. Heroin has an average ½ life in humans of about 3 min and IV administration; the half-life of the metabolite 6-acetylmorphine is about 30 min in humans. Any use of heroin by the intranasal, IM, or IV routes produce peak blood levels within about 5 min but intranasal has about half the relative potency of IV or IM routes.

Morphine is a natural product of the opium poppy Papaver somniferum. Morphine is an alkaloid compound that belongs to the class of drugs called the phenanthrenes. This also includes codeine and thebaine. Synthetic modifications of the chemical structure of morphine at the 3, 6, and 17 positions produce other synthetic compounds including morphine-6-glucuronide (M6G). Related drugs include hydrocodone (Vicodin), oxycodone (OxyContin), hydromorphone (Dilaudid), and heroin. Synthetic compounds also include antagonists like naloxone (Narcan), naltrexone (Trexan), nalmefene (Revix) along with partial agonists like buprenorphine (subutex) and naloxone/buprenorphine (suboxone) [53]. Morphine is mostly selective for MOP-r receptors and is biotransformed mostly by hepatic glucuronidation to the major inactive metabolite morphine-3-glucuronide (M3G) and the biologic M6G compound [55]. The pharmacokinetics or morphine and metabolites vary depending on the route of administration. Its oral bioavailability varies from 35 to 75 % with the plasma half-life of 2–3.5 h with the analgesic effect half-life of 4–6 h which reduces accumulation. It mostly cleared in the liver with the enterohepatic cycling with oral administration. Adjustment for renal disease is needed due to the clearance by the kidneys.

Oxycodone is used usually for moderate pain and popular for abuse when crushed and taken intranasally or IV. It is a semisynthetic compound derived from thebaine with agonist activity mostly at the mu receptors. It is pharmacologically similar to morphine as has a 1:2 equivalency to morphine. Onset of action begins 1 h after oral administration with the sustained release lasting for about 12 h and a plasma half-life for the immediate release of 3–4 h. Plasma levels stabilize within 24 h with oral bioavailability from 60 to 87 % with 45 % protein bound. Oxycodone is chiefly metabolized in the liver with the remainder processed in the kidneys. The two major metabolites are oxymorphone which is also a potent analgesic and noroxycodone which is weaker. Protein binding and lipophilicity is similar to morphine with a longer half-life and greater bioavailability. It is metabolized mostly by the cytochrome CYP2D6 enzyme.

Codeine is methyl morphine, with a methyl substitution on the phenolic hydroxyl group of morphine. It is more lipophilic than morphine and crosses the blood–brain barrier more rapidly. Also, has a large first-pass phenomenon in the liver with greater bioavailability then morphine but is less potent. A small portion is metabolized to morphine by the cytochrome 2D6 system [53]. Codeine has a high oral-parental effect due to its low first-pass metabolism in the liver. Its metabolites are mostly inactive and excreted in the urine with 10 % demethylated by the CYP2D6 enzyme pathway to morphine. Morphine is responsible for the analgesic effects since codeine has a low activity for the opioid receptors. Genetic variations in the enzyme systems may cause a lower production of M6G with accumulation of the active metabolites in patients with poor renal clearance.

Meperidine is phenylpiperidine and has several forms. It is rarely used longer than 48 h or doses greater than 600 mg/day due to its toxicity. It is active in CNS and bowel. If used with MAOIs, it may produce a serotonergic effect with clonus, hyperreflexia, hyperthermia, and agitation. Onset of the analgesic effects begin after oral ingestion in about 15 min with the peak in 1–2 h with a duration of 1½–3 h [53]. The medication is absorbed by all routes but less reliable by IM routes. It is mostly metabolized in the liver with a half-life of about 3 h. Liver disease leads to increased half-life and bioavailability of meperidine and normeperidine. Sixty percent of the drug is excreted protein bound.

Pentazocine is available in oral and parenteral formulas. It is one of the first agonist–antagonist medications. It is a weak antagonist or partial agonist with a plateau effect at the mu and kappa receptors. Peak effect is ½–1 h with given orally and its duration of action is 3–6 h. Sixty percent is protein bound, and it is metabolized by the liver in the oxidative and glucuronide conjugation with a large first-pass effect. Oral bioavailability is about 10 % except with cirrhosis it may increase to 60–70 %. Half-life is about 2–3 h with small amounts excreted unchanged in the urine.

Hydromorphone is a potent opioid analgesic than morphine and is used for moderate to severe pain. It is excreted by the kidneys. It is available by IV, oral, and rectal routes. It is five times more potent per milligram than morphine orally and 8.5 times more potent when given IV. It is shorter acting than morphine. It has an oral bioavailability of 30–40 % with an analgesic onset after 10–20 min with a peak in 30–60 min with effects lasting for 3–5 h. The oral parenteral ratio is 5:1 with an equivalency of 1.5 mg of hydrocodone to 10 mg of morphine.

Hydrocodone is a mild pain reliever and often combined with acetaminophen. Hydrocodone has a half-life of 2–4 h with a peak efficacy at ½–1 h. Its duration of action is 3–4 h. It may show up in urine drug testing with codeine use since about 11 % of codeine is metabolized to hydrocodone therefore giving a false-positive testing.

Methadone is a synthetic long-acting full mu opioid agonist active by oral and parenteral routes. Its primary use is in heroin addiction as a substitute medication. The l®-methadone enantiomer has up to 50 times more analgesic activity and the potential for respiratory depression than the d(S)-enantiomer. Both forms have modest NMDA receptor antagonism. Methadone has a diphenylheptylamine structure and is a racemic mix of both d(S)- and l(R)-methadone. Both the enantiomers are weak NMDA receptor antagonists and therefore retards and attenuates the development of opioid tolerance. It meets the two most important criteria for use with addictions: high systemic bioavailability (>90 %) with oral administration and long half-life with long-term administration. Oral methadone is rapidly absorbed bur has delayed onset of action with peak plasma levels at 2–4 h and sustained over a 24 h time frame. Further, the mean terminal half-life of racemic d,l-methadone is about 24 h and the l-enantiomer with a half-life of 36 h. Chronic administration accumulates methadone in the liver and levels remain constant due to the slow release of unmetabolized drug into the bloodstream with more than 90 % plasma protein bound. Due to the long half-life, the medication must be increased slowly by 10 mg every 4–7 days (initial dosing 20–40 mg/day). Some patients are rapid metabolizers with increased clearance by the P450-enzyme or p-glycoprotein-related transporter systems. Levels of methadone generally peak at 3–8 h after administration. Methadone is biotransformed in the liver by the cytochrome P450-related enzymes (CYP3A4 in the majority and to a lesser extent the CYP2B6, CYP2D6, and CYP1A2 systems) [56]. It is biotransformed into the two N-demethylated biologically inactive metabolites that then undergo further oxidative metabolism. It is excreted in almost equal amounts in the urine and feces. It patients with renal disease, the drug may be cleared entirely by the GI route. Severe liver disease may cause decreased methadone levels due to decreased storage. Use of medications that alter the cytochrome P450 enzyme system must be used with caution. This includes rifampin, rifabutin, carbamazepine, phenytoin, and phenobarbital. Also, consumption of more than four drinks in a day have been shown to alter methadone levels.

Levo-alpha-acetylmethadol (LAAM) is a synthetic, longer acting form (48 h) of methadone that is orally effective. LAAM has had problems with prolonged QT interval and torsade de pointes and is no longer available in the USA.

Buprenorphine alone and combined with naloxone was approved in 2002 by the FDA as a sublingual treatment for heroin and opioid addiction and rescheduled to a Schedule III medication. Buprenorphine is an MOP-r-directed partial agonist and also a partial kappa agonist. It structurally a oripavine with a C7 side chain with a tert-butyl group. Norbuprenorphine is the major metabolite with activity at the MOP-r receptors as well. Buprenorphine is metabolized to norbuprenorphine due to dealkylation in the cytochrome P450-related enzyme 3A4 system which buprenorphine is a weak inhibitor [57]. The drug undergoes rapid first pass in the liver with sublingual bioavailability of 50–60 %. There have been several deaths reported with buprenorphine and benzodiazepines. It also has some weak kappa opioid receptor activity. Due to ceiling effects of the drug, doses greater than 32 mg sublingually do not have any further effects on the mu MOP-r receptors. It has a long half-life of 24–48 h because of its slow dissociation from the MOP-r receptors. IV dosing has a plasma half-life of 3–5 h. Oral administration is not very effective due to its first-pass phenomenon.

Opioids generally are abused as agonists of the MOP-receptors (mu-encoded receptors at OPRM1 receptor gene) [54]. MOP-r are G protein-coupled 7-transmembrane domain receptors. They are coupled to Gi and Goproteins and result in acute downstream decrease in adenylate cyclase activity. The MOP-r receptors are widely found in the CNS, and their effects are mediated in different areas of the CNS. Therapeutic analgesic effects are found in the dorsal spinal column and thalamus while respiratory depression is found in the brainstem. The receptors are also active in the locus ceruleus and other centers to produce physiologic dependence and withdrawal. The abuse and addiction effects are thought to be found in the ventral and dorsal striatal areas with effects on the dopaminergic mesocorticolimbic and nigrostriatal systems.

Cocaine, Amphetamines, stimulants

Stimulants include the naturally occurring plant alkaloids including cocaine, ephedra, and khat as well as the synthetic compounds like amphetamines and methylphenidate. Most of these stimulants are modifications of the basic phenethylamine structure which is similar to endogenous catecholamine neurotransmitters norepinephrine and dopamine. The stimulant all have similar psychological and physiologic characteristics.

Cocaine

Cocaine is an alkaloid with a tropane ester structure similar to scopolamine and other plant alkaloids. The compound is found in the leaves of the Erythoxylum coca. The leaves contain approximately 0.2–1 % cocaine and several other tropane alkaloids of unknown activity. Cocaine has two stereoisomers: (−)-cocaine and (+)-cocaine which has less affinity for the dopamine transporter and is relatively inactive due to rapid metabolism by butyrylcholinesterase.

Ephedra

Ephedrine and pseudoephedrine are naturally occurring alkaloids with phenethylamine chemical structure and are found in several of the Ephedraceae plant species. It is prepared from the dried young branches of the plants. It then is taken as a capsule, tincture, liquid extract, or tea. Synthetic ephedrine and pseudoephedrine are also available for consumption. The ephedra alkaloids have the same range of psychological and physiological effects that cocaine and amphetamines do. These compounds have been linked to severe cardiovascular and CNS problems and, thus, their ban in the USA in 2006.

Khat

This is the common name for any preparations of the Catha edulis plant native to East Africa and in the southern Arabian peninsula. Fresh khat leaves contain two stimulant alkaloids with phenethylamine chemical structure: cathinone (1–3 %) and cathine (norpseudoephedrine). Pure cathinone is a Schedule I substance and cathine is a Schedule IV substance. Cathinone has action and potency similar to amphetamines [58]. Potent synthetic cathinones include mephedrone, methylone, and 3,4-methylenedioxypyrovalerone which are sold as “bath salts.”

Synthetic Stimulants

There are over a dozen synthetic stimulant medications legally available in the USA by either prescription or over the counter. Most of the medications are variations from the basic phenethylamine structure. All legal stimulants are sold as tablets, capsules, or in the liquid form. The extend release formulations are used for the treatment of attention deficit disorder (ADD). Also methylphenidate may be used a transdermal patch. Amphetamine is available as a prodrug lisdexamfetamine which is a d-amphetamine with the amino acid L-lysine. Active drug is formed when the lysine is hydrolyzed off in the intestines and liver. This allows for longer duration of action and reduced abuse potential. Some OTC medications have aerosolized forms for use as decongestants. Amphetamines are usually abused by the oral or IV route. Also, the pure crystallized methamphetamine may be used intranasally, or smoked, like cocaine. Illicit “meth labs” make methamphetamine by reducing ephedrine or pseudoephedrine. Stimulants with the phenylisopropylamine structure (amphetamine, methamphetamine, ephedrine, pseudoephedrine, and phenylpropanolamine) have a chiral, or stereoisomeric, center a the alpha-carbon atom and exist in two or more stereoisomeric forms that have differing pharmacodynamic and pharmacokinetic properties. The d- or S-(+) isomer has 3–5 times the CNSA activity and about 1/3 the half-life of the l- or R (−) isomer. The l-isomers have more peripheral alpha-adrenergic activity. For instance, d-methamphetamine is a strong CNS stimulant while l-methamphetamine has uses as a decongestant (as in a nasal inhaler). Methylphenidate has four stereoisomers with the d-threo as the active drug.

Pharmacokinetics

Route of administration greatly effects the pharmacokinetics of the stimulants. Smoked stimulants (cocaine/amphetamine) are quickly absorbed and reach the brain in 6–8 s. The onset and peak are within minutes of administration. The redistribution of the stimulant from the brain leads to a rapid decline in effects. IV administration has peak brain uptake in 4–7 min based on the positron emission tomography (PET ) scans with radiolabeled cocaine [59]. The highest levels of cocaine are found in the striatum (Caudate, putamen, and nucleus accumbens) and the lowest in the orbital cortex and cerebellum. Clearance to the half-peak levels in the brain takes 17–30 min and is most rapidly cleared from the orbital cortex, thalamus, and cerebellum with slowest clearing in the striatum. The rapid decline in the levels is described as a “crash” by users. Intranasal and oral stimulants have a slower absorption and slower onset of effect (30–45 min), a longer peak effect, and a more gradual decline from peak levels. The peak intensity with oral use relates to the peak cocaine plasma concentration which is generally about half that of intranasal cocaine. Cocaine is well absorbed in mucous membranes, intact skin, or even passive inhalation of aerosolized particles of smoked cocaine. Stimulants may enter most tissues. Cocaine rapidly distributes to the heart, kidney, adrenal glands, and liver. In concert with blood and urine, cocaine and its hydrolytic metabolites, amphetamines, phentermine, and ephedrine and its analogs may be found in hair, sweat, saliva, nails, and breast milk. They also cross the placenta and are found in the umbilical cord blood, amniotic fluid, and meconium.

Metabolism of cocaine is 95 % by hydrolysis of ester bonds to benzoylecgonine (primary urinary metabolite) and ecgonine methyl ester by the action of the carboxylesterases in the liver and butyrylcholinesterase in the liver, plasma, brain, lung, and other tissues [6062]. The remaining 5 % of cocaine is N-demethylated to norcocaine by the CYP3A4 isozyme of the liver cytochrome P450 microsomal enzyme system. Norcocaine has similar action to cocaine and is hepatotoxic. Amphetamines are metabolized in three separate pathways: deamination to inactive metabolite, oxidation to norephedrine and other active metabolites, and parahydroxylation to active metabolites. Most stimulants and their metabolites are eliminated in the urine. Benzoylecgonine is the highest level metabolite found in the urine and may be present for several days after last use.

Mechanism of Action of Stimulants

All stimulants act to enhance the extracellular concentration of the monoamine neurotransmitters (dopamine, norepinephrine, and serotonin) in the central and peripheral nervous system. Stimulants act by disrupting the function of the plasma membrane transport system. Usually, the monoamine transporters control the uptake or reuptake of the previously released neurotransmitters from the extracellular space back into the nerve cells. These transporters are found not just at synapses but also on cell bodies, dendrites, and axons. Stimulant drugs fall into two classes based on their molecular mechanism of action: transporter blockers and transporter substrates. Transporter blockers include cocaine and methylphenidate that bind to the extracellular face of transporters and inhibit the uptake of previously released monoamine neurotransmitters. Transport blockers are often called uptake or reuptake blockers. Transporter substrates include amphetamine and phentermine. These drugs bind to transporters, move into the cell neuronal cytoplasm with sodium ions, and trigger the release of monoamines by reversing the normal direction of transporter flux. Inside the neuronal cytoplasm the transporters interact with vesicular monoamine transporters (VMAT) to move monoamines into the cytoplasm increasing the concentration available for release. Thus, these drugs are styled as releasers.

The potent stimulants such as cocaine and amphetamine act at the dopamine and norepinephrine transporters. Weaker stimulants such as (−)-ephedrine and its isomers target norepinephrine transporters. Stimulant drugs may also have other ancillary actions. Cocaine blocks the sodium channels and amphetamine inhibits monoamine oxidase.

Stimulants act centrally by activating the mesocorticolimbic dopamine system [63]. The pathway is thought to involve the cell bodies in the VTA that send axonal projections to the prefrontal cortex, nucleus accumbens, and amygdala. The mesocorticolimbic dopamine neurons are included in the cortical-striatal-pallidal system that is responsible for adaptive behavioral responses. The nucleus accumbens is the center critical to the circuitry receiving stimulatory glutamate afferents from the hippocampus, amygdala, and frontal cortex. The primary cell is the GABA-containing spiny neuron that has direct synaptic contact from the dopamine and glutamate neurons. The spiny neurons send efferent projections to several target areas including pallidal structures in the substantia nigra pars reticulata that modulates tonic suppression of motor nuclei. Activation of the GABAergic spiny neurons recruit motor behaviors by inhibiting the pallidal output (via disinhibition). The spiny neurons include two types based upon their affinity for dopamine receptors: low-affinity D1 dopamine receptors and high-affinity dopamine D2receptors. The spiny neurons respond to glutamate and the dopamine receptors differentially modulate the response to the glutamate. In general, the D1 dopamine receptors increase the excitability of the spiny neurons and the D2receptors inhibit the spiny neurons. Thus, behaviors are either executed (D1 dopamine receptors) or suppressed (D2 receptors). Natural responses to stimulation modulate discrete subpopulations of spiny neurons for normal response and behavior. Stimulants induce a sustained elevation in the extracellular dopamine and excite spiny neurons to drive aberrant behaviors.

Cocaine, amphetamines, methylphenidate, and modafinil all enhance dopamine transmission by acting on the dopamine transporters. The administration of cocaine or amphetamines increases the brain extracellular dopamine concentrations in the striatum and the nucleus accumbens. There is also an increased in the D1 receptors in the striatum and also increased sensitivity in the nucleus accumbens. The euphoria or “high” associated with stimulants appears related to the action of the time and intensity of the stimulants in the brain with dopamine transporter occupancy and with the extracellular dopamine release in the striatum [64]. Even presentation of cues related to consumption of stimulants has been documented to enhance release of dopamine in the striatum. In vivo human studies of the brain with PET scanning show that cocaine users have decreased dopamine D2 receptor binding in the striatum and frontal cortex while having normal levels of dopamine transporter binding [64]. Amphetamine users, in contrast, demonstrate increased D1 receptors in the nucleus accumbens and decreased dopamine transporter density in the nucleus accumbens, striatum, and prefrontal cortex.

Cocaine, amphetamines, methylphenidate, phentermine, and ephedrine increase norepinephrine neurotransmission acting on the norepinephrine transporters. The majority of the stimulants appear to have lesser effects on the serotonin transporters with the exception of cocaine. It blocks uptake at the transporters for serotonin, dopamine, and norepinephrine at equal potency. Cocaine increases extracellular serotonin concentrations in the nucleus accumbens and VTA thereby reducing the action of the serotonin neurons in the dorsal raphe.

Endogenous opiate receptors in the brain (endorphins, enkephalins) are influenced by stimulants. Cocaine users show increased mu opiate receptor binding with PET scanning. Postmortem fatal cocaine overdoses also demonstrate kappa opiate receptor binding in the limbic area [65].

Cocaine or amphetamine both increase release of glutamate in the VTA, nucleus accumbens, dorsal striatum, ventral pallidum, septum, and cerebellum. Several of the glutamate receptors are important in the reinforcement of cocaine. Blocking NMDA in the nucleus accumbens decreases cocaine reinforcement along with reduction of mGluR5 receptor activity. Stimulation of the presynaptic mGluR2 receptors reduces cocaine reinforcement but reduction of the mGluR2 activity actually enhances reinforcement. Chronic use of cocaine may decrease nonsynaptic extracellular glutamate. Withdrawal from chronic cocaine use decreases the membrane excitability in GABA-containing spiny neurons which then induces a persistent upregulation of AMPA-glutamate receptors on the spiny neurons. This makes the spiny neurons more receptive to glutamate input from the cortex and other regions.

Cocaine and methamphetamine block neuronal nicotinic acetylcholine (Ach) receptors and cocaine also blocks the muscarinic Ach receptors in the brain and cardiac myocytes [66]. The stimulants cause Ach release in the striatum, nucleus accumbens, medial thalamus, and interpeduncular nucleus. Cocaine used chronically down-regulates the brain cholinergic systems and methamphetamine upregulates the cholinergic system.

Further research needs to be accomplished to further understand the complex and interdependent nature of the effects on receptors of addictive drugs on the brain and other organ systems.

References

1.

Stepensky D. Prediction of drug disposition on the basis of its chemical structure. Clin Pharmacokinet. 2013;52:415–31.CrossRefPubMed

2.

Johnson F, Setnik B. Morphine sulfate and naltrexone hydrochloride extended-release capsules: naltrexone release, pharmacodynamics, and tolerability. Pain Physician. 2011;14(4):391–406.PubMed

3.

Won CS, Oberlies NH, Paine MF. Mechanisms underlying food-drug interactions: inhibition of intestinal metabolism and transport. Pharmacol Ther. 2012;136:186–201.CrossRefPubMedPubMedCentral

4.

Hermann R, von Richter O. Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. Planta Med. 2012;78(13):1458–77.CrossRefPubMed

5.

Rowland M, Tozer TN. Clinical pharmacokinetics concepts and applicants. 3rd ed. Baltimore: Lippincott Williams and Wilkins; 1995.

6.

Geier EG, Schlessinger A, Fran H, et al. Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1. Proc Natl Acad Sci U S A. 2013;110(14):5480–5.CrossRefPubMedPubMedCentral

7.

Ince I, Knibbe CA, Danhof M, et al. Development changes in the expression and function of cytochrome P450 3A isoforms: evidence from in vitro and in vivo investigations. Clin Pharmacokinet. 2013;52(5):215–33.CrossRef

8.

Daly AK. Genetic polymorphisms affecting drug metabolism: recent advances and clinical aspects. Adv Pharmacol. 2012;63:137–67.CrossRefPubMed

9.

Meyer MR, Maurer HH. Absorption, distribution, metabolism, and excretion pharmacogenomics of drugs of abuse. Pharmacogenomics. 2011;12(2):215–33.CrossRefPubMed

10.

Mroziewicz M, Tyndale RF. Pharmacogenetics: a tool for identifying genetic factors in drug dependence and response to treatment. Addict Sci Clin Pract. 2010;5(2):17–29.PubMedPubMedCentral

11.

Sturgess JE, George TP, Kennedy JL, et al. Pharmacogenetics of alcohol, nicotine and drug addiction treatments. Addict Biol. 2011;16(3):357–76.CrossRefPubMed

12.

Daly AK, Brockmoller J, Broly F, et al. Nomenclature for human CYP2D6 alleles. Pharmacogenomics. 1996;6(3):193–201.CrossRef

13.

Kelly LE, Madadi P. Is there a role for therapeutic drug monitoring with codeine? Ther Drug Monit. 2012;34(3):249–56.CrossRefPubMed

14.

Madadi P, Avard D, Koren G. Pharmacogenetics of opioids for the treatment of acute maternal pain during pregnancy and lactation. Curr Drug Metab. 2012;13(6):721–7.CrossRefPubMed

15.

Zhu AZX, Cox LS, Nollen N, et al. CYP2B6 and bupropion’s smoking-cessation pharmacology: the role of hydroxypropion. Clin Pharmacol Ther. 2012;92(6):771–7.CrossRefPubMedPubMedCentral

16.

Hung CC, Chiou MH. huang BH, et al. Impact of genetic polymorphisms in ABCB1, CYP2B6, OPRM1, ANKK1, and DRD2 genes on methadone therapy in Han Chinese patients. Pharmacogenomics. 2011;12(11):1525–33.CrossRefPubMed

17.

Tian JN, Ho IK, Tsou HH, et al. UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients. Pharmacogenomics. 2012;13(8):879–88.CrossRefPubMed

18.

Chenowith MJ, O’Loughlin J, Sylvestre MP, et al. CYP2A6 slow nicotine metabolism is associated with increased quitting b adolescent smokers. Pharmacogenet Genomics. 2013;23(4):232–5.CrossRef

19.

Dutheil F, Beaune P, Loriot MA. Xenobiotic metabolizing enzymes in the central nervous system: contribution of cytochrome P450 enzymes in normal and pathological human brain. Biochimie. 2008;90(3):708–14.CrossRef

20.

Hedlund E, Gustafsson JA, Warner M. Cytochrome P450 in the brain: a review. Curr Drug Metab. 2001;2(3):245–63.CrossRefPubMed

21.

Kim JA, Bartlett S, He L, et al. Morphine induced receptor endocytosis in a novel knockin mouse reduces tolerance and dependence. Curr Biol. 2008;18(2):129–35.CrossRefPubMedPubMedCentral

22.

Eiden LE, Weihe E. VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci. 2011;1216:86–98.CrossRefPubMedPubMedCentral

23.

Gilchrist A. Modulating G, protein-coupled receptors: from traditional pharmacology to allosterics. Trends Pharmacol Sci. 2007;28(8):431–7.CrossRefPubMed

24.

Trevor AJ, Way WL. Sedative-hypnotic drugs. In: Katzung BG, editor. Basic and clinical pharmacology. 8th ed. New York: Lange Medical Books/McGraw-Hill; 2001. p. 364–81.

25.

O’Brien CP. Drug addictions and drug abuse. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman and Gilman’s the pharmacologic basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 621–42.

26.

Garces JM, de la Torre R, Gutierrez J, et al. Clinical effectiveness of naloxone in acute ethanol intoxication. Rev Clin Esp. 1993;193:431.PubMed

27.

Vonghia L, Leggio L, Ferrulli A, et al. Acute alcohol intoxication. Eur J Intern Med. 2008;19:561.CrossRefPubMed

28.

Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2009;35:217.CrossRefPubMedCentral

29.

Saal D, Dong Y, Bonci A, et al. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003;37:577.CrossRefPubMed

30.

Beckley JT, Evins CE, Fedarovich H, et al. Medical prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons. J Neurosci. 2013;33:804.CrossRefPubMedPubMedCentral

31.

Wang J, Lanfranco MF, Gibb SL, et al. Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J Neurosci. 2010;30:10187.CrossRefPubMedPubMedCentral

32.

Sinha R, Li CS. Imaging stress-and cue-induced drug and alcohol craving; association with relapse and clinical implications. Drug Alcohol Rev. 2007;26:25.CrossRefPubMed

33.

Myrick H, Anton RF, Li X, et al. Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving. Neuropsychopharmacology. 2004;29:393.CrossRefPubMed

34.

Wallner M, Hancher HJ, Olsen RW. Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans. Proc Natl Acad Sci U S A. 2003;100:15218.CrossRefPubMedPubMedCentral

35.

Roberto M, Madamba SG, Moore SD, et al. Ethanol increases GABergic transmission at both pre- and postsynaptic sites in rat central amygdale neurons. Proc Natl Acad Sci U S A. 2003;100:2053.CrossRefPubMedPubMedCentral

36.

Beckley JT, Joodward JJ. The abused inhalant toluene differentially modulates excitatory and inhibitory synaptic transmission in deep-layer neurons of the medial prefrontal cortex. Neuropsychopharmacology. 2011;36:1531.CrossRefPubMedPubMedCentral

37.

Jin C, Smothers CT, Woodward JJ. Enhanced ethanol inhibitions of recombinant N-methyl-D-aspartate receptors by magnesium: role of NR3A subunits. Alcohol Clin Exp Res. 2008;32:1059.CrossRefPubMedPubMedCentral

38.

Jin C, Woodward JJ. Effects of 8 different NR1 splice variants on the ethanol inhibition of recombinant NMDA receptors. Alcohol Clin Exp Res. 2006;30:673.CrossRefPubMed

39.

Tu Y, Kroener S, Abernathy K, et al. Ethanol inhibits persistent activity in prefrontal cortical neurons. J Neurosci. 2007;27:4765.CrossRefPubMedPubMedCentral

40.

Dani J, Betrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007;4:699.CrossRef

41.

Khakh BS, North RA. Neuromodulation by extracellular ATP and P2X receptors in the CNS. Neuron. 2012;76:51.CrossRefPubMedPubMedCentral

42.

Brodie MS, Pesold C, Appel SB. Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res. 1999;23:1848.CrossRefPubMed

43.

Oswald LM, Wand GS. Opioids and alcoholism. Physiol Behav. 2004;81:339.CrossRefPubMed

44.

Pava MJ, Woodward JJ. A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research. Alcohol. 2012;46:185.CrossRefPubMedPubMedCentral

45.

Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hyposedatives: zaleplon, zolpidem, and zopiclone. Clin Pharmacokinet. 2004;43(4):227–38.CrossRefPubMed

46.

Fleck MW. Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone. J Pharmacol Exp Ther. 2002;302(2):612–8.CrossRefPubMed

47.

Sanna E, Busonero F, Talani G, et al. Comparison of the effects of zaleplon, zolpidem, and triazolam at various GABA(A) receptor subtypes. Eur J Pharmacol. 2002;451(2):103–10.CrossRefPubMed

48.

Mandrioli R, Mercolini L, Raggi MA. Metabolism of benzodiazepine and non-benzodiazepine anxiolytic-hypnotic drugs: an analytical point of view. Curr Drug Metab. 2010;11(9):815–29.CrossRefPubMed

49.

Beanarroch EE. GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology. 2007;68(8):612–4.CrossRef

50.

Lingford-Hughes A, Hume SP, Feeney A, et al. Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro154513 positron emission tomography. J Cereb Blood Flow Metab. 2002;22(7):878–89.CrossRefPubMed

51.

McKernan RM, Rosaahl TW, Reynolds DS, et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha 1 subtype. Nat Neurol. 2000;3(6):587–92.CrossRef

52.

Dias R, Shepard WF, Fradley RL, et al. Evidence for a significant role of alpha 3-containing GABA-A receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci. 2005;25(46):10682–8.CrossRefPubMed

53.

Gutstein H, Akil H. Opioid analgesics. In: Brunton L, Lazo L, Parker K, editors. Goodman and Gillman’s the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2005. p. 547–90.

54.

Raynor K, Kong H, Mestek A, et al. Characterization of the cloned human mu opioid receptor. J Pharmacol Exp Ther. 1995;272:423–8.PubMed

55.

Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain. 2002;18:S1–13.CrossRef

56.

Ferrari A, Coccia CP, Bertolini A, et al. Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004;50:551–9.CrossRefPubMed

57.

Kobayashi K, Yamamoteo T, Chiba K, et al. Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3a4. Drug Metab Dispos. 1998;26:818–21.PubMed

58.

Fleckenstein AE, Gibb JW, Hanson GR. Differential effects of stimulants on monoaminergic transporters: pharmacological consequences and implications for neurotoxicity. Eur J Pharmacol. 2000;406:1–13.CrossRefPubMed

59.

Telang FW, Volkow ND, Levy A, et al. Distribution of tracer levels of cocaine in the human brain as assessed with averaged [11C] cocaine images. Synapse. 1993;31:290–6.CrossRef

60.

Cone EJ. Pharmacokinetics and pharmacodynamics of cocaine. J Anal Toxicol. 1995;19:459–78.CrossRefPubMed

61.

Warner A, Norman AB. Mechanisms of cocaine hydrolysis and metabolism in vitro and in vivo: a clarification. Ther Drug Monit. 2000;22:266–70.CrossRefPubMed

62.

Maurer HH, Sauer C, Theobald DS. Toxicokinetics of drugs of abuse: current knowledge of the isozymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. Ther Drug Monit. 2006;28:447–53.CrossRefPubMed

63.

Feltenstein MW. The neurocircuitry of addiction: an overview. Br J Pharmacol. 2008;154:261–74.CrossRefPubMedPubMedCentral

64.

Volkow ND, Fowler JS, Wang GJ, et al. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology. 2009;56 Suppl 1:3–8.CrossRefPubMedPubMedCentral

65.

Staley JK, Rothman RB, Rice KC, et al. K2 opioid receptors in limbic area of the human brain are upregulated by cocaine in fatal overdose victims. J Neurosci. 1997;17:8225–33.

66.

Williams MJ, Adinoff B. The role of acetylcholine in cocaine addiction. Neuropsychopharmacology. 2008;33:1779–97.CrossRefPubMedPubMedCentral