Pharmacology - An Illustrated Review

7. Neuropharmacological Principles

7.1 General Features of Central Neurotransmitters

Most drugs that act on the central nervous system (CNS), except perhaps general anesthetics and ethanol, have specific effects on certain neurotransmitter systems, some of which have been discussed in the previous unit. They can be classified according to their action at a given synapse as excitatory (generally depolarizing), inhibitory (generally hyperpolarizing), or modulatory (conditional). Modulatory actions explain why a given neurotransmitter does not necessarily produce the same effect at all sites; for example, norepinephrine relaxes bronchial smooth muscle but increases contraction of the heart.

Synaptic plasticity

Neurons are not static, and, in addition to the primary responses to drugs, they undergo several longer-term synaptic changes in response to drugs. These changes may include receptor downregulation, receptor upregulation, and changes in intracellular signal transduction processes. Currently, synaptic plasticity is not exploited as a mechanism of drug action, but it is a definite result of drug use, especially long-term use, and may contribute to the clinical development of tolerance and dependence.


7.2 Specific Central Neurotransmitters

This section discusses neurotransmitters that specifically act on the CNS. The effects of these and other CNS neurotransmitters, as well as their receptors, are summarized in Fig. 7.1.


Dopamine is also discussed on page 57.


There are five types of dopamine receptors located on postsynaptic cells and as autoreceptors on dopamine neurons. Termed D1 to D5, these are G-protein coupled receptors (Fig. 7.2).

Pathways and Functions

The major relevant functions of dopamine are correlated with the three major dopaminergic tracts in the brain:

– Nigrostriatal: Dopamine-containing neurons in the substantia nigra project to the striatum (caudate and putamen). This tract is concerned with initiation and execution of movement. The loss of neurons in the substantia nigra leads to Parkinson disease.

– Mesolimbic-mesocortical: Dopamine-containing neurons in the ventral tegmental area project to the amygdala and cortex. These tracts are involved in emotions and the organization of thoughts; they are implicated in schizophrenia and addictive disorders.

– Tuberoinfundibular: Dopamine-containing neurons in the arcuate nucleus of the hypothalamus project to the portal vessels of the infundibulum, where dopamine inhibits prolactin secretion. Dopamine receptor antagonists can therefore cause mild hyperprolactinemia.

Parkinson disease

Parkinson disease is a chronic, progressive, age-related neurodegenerative disease resulting from the loss of dopamine-containing neurons in the substantia nigra. Symptoms usually start between 60 and 70 years of age and include a “pill-rolling” tremor, rigidity (limbs resist extension throughout movement), and bradykinesia (slow execution of movement and speech), resulting in a mask-like face and shuffling gait. There are many drug treatment options for Parkinson disease. Levodopa is a dopamine precursor that is converted to dopamine in the brain by dopa decarboxylase. Levodopa is often used in combination with carbidopa, a drug that prevents the peripheral conversion of levodopa to dopamine by inhibiting dopa decarboxylase. Dopamine agonists (e.g., bromocriptine) mimic the effects of dopamine in the brain. Catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone) are used to prevent the peripheral breakdown of levodopa. Monoamine oxidase B (MAO-B) inhibitors (e.g., selegiline) prevent the breakdown of dopamine in the brain. Anticholinergic drugs (e.g., benztropine) may be given as an adjunct for the tremor (see Chapter 14).



Norepinephrine is also discussed on pages 3839, and 54.


The largest norepinephrine-containing nucleus in the brain is the locus ceruleus of the caudal pons. Ascending and descending fibers from the locus ceruleus are part of the reticular activating system, which is responsible for behavioral arousal and levels of awareness.


Norepinephrine may be involved in depression, anxiety, and panic disorders.

Fig. 7.1 image Neurotransmitters in the central nervous system.

Most receptors for neurotransmitters in the CNS are metabotropic (G-protein mediated), and the effects seen are due to differences in ion conductance and signal transduction via second messengers. (ADH, antidiuretic hormone; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-triphosphate; mGlu, metabotropic glutamic acid; NMDA, N-methyl-D-aspartate; PIP, phosphatidylinositol 4-phosphate; GHIH, growth hormone inhibiting hormone; SRIF, somatotropin release-inhibiting factor.)


Fig. 7.2 image Dopamine release, inactivation, and pharmacological uses.

Dopamine is released from dopaminergic neurons following an action potential. It then binds to two major types of receptors: D1-like (subtypes D1 and D5), which increase cyclic adenosine monophosphate (cAMP), and D2-like (subtypes D2, D3, and D4), which decrease cAMP, so the differing effects of dopamine-binding depend on signal transduction. Dopamine's action is terminated by reuptake into neurons, where it is stored in vesicles for reuse, or it is degraded by catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO). D2 agonists are used to treat Parkinson disease and to inhibit prolactin release, whereas D2 antagonists are used as antiemetics and in the treatment of schizophrenia.



Serotonin (5-hydroxytryptamine [5-HT]) is also discussed on page 340.


Serotonin is synthesized from tryptophan by tryptophan hydroxylase and metabolized by oxidative deamination via monoamine oxidase.


Serotonin receptors are located both pre- and postsynaptically. Major groups, 5-HT1 to 5-HT7, have been identified, and there are further subtypes. They are all G-protein coupled receptors except 5-HT3, which is a ligand-gated ion channel.


Cell bodies are located in the raphe nuclei of the brainstem. Descending systems innervate all spinal cord levels. Ascending systems innervate the cerebellum, substantia nigra, limbic system, and cortex.


Ascending systems are involved in the promotion of sleep, in determining mood, and in mental illness (through interactions in limbic areas). Descending 5-HT systems may be involved in modulating pain perception. Figure 7.3 illustrates some of the actions of serotonin and how various pharmacological agents influence serotonin levels to produce their effects.

Fig. 7.3 image Serotonin actions as influenced by drugs.

The effects of serotonin are complex because of the number of receptor subtypes and the differing, and sometimes opposing, effects at each subtype. In blood vessels, for example, serotonin acts on 5-hydroxytryptamine type 2 (5-HT2) receptors to produce vasoconstriction, but it can also act via 5-HT2B receptors to cause the release of vasorelaxant mediators from vascular endothelium, resulting in vasodilation. In the bowel, serotonin acts on 5-HT4 receptors to increase gut motility. Serotonin is involved in many aspects of brain functioning, and as such, many of its central actions are affected by drugs. Serotonin agonists are used to treat migraine and are used recreationally as psychedelic drugs. Fluoxetine, which blocks serotonin reuptake, is used as an antidepressant. Ondansetron, which is an antagonist at the 5-HT3 receptor, is used to treat emesis induced by cytotoxic drugs.



This neurotransmitter was discussed in depth on pages 37 and 38 in relation to its action in the peripheral nervous system, but acetylcholine also has an important role as a neurotransmitter in the CNS.


Both nicotinic and muscarinic receptors are found in the brain, but 95% of acetylcholine receptors in the brain are muscarinic. Acetylcholine may have excitatory or inhibitory actions in the brain.


Acetylcholine neurons are mainly interneurons throughout the cortex.


The result of loss of cholinergic neurons depends on the site. A global loss throughout the cortex results in senile dementia of the Alzheimer type, degeneration of acetylcholine neurons in the lateral horn of the spinal cord results in amyotrophic lateral sclerosis (ALS), and degeneration of cholinergic and gamma-aminobutyric acid (GABA) neurons in the striatum results in Huntington disease.

Huntington disease

Huntington disease is an autosomal dominant neurodegenerative disorder that usually starts in middle age. Its onset is insidious, but the course of the disease progresses with chorea (involuntary, continuous jerky movements), personality change, dementia, and death. There is no cure or any treatment to prevent progression of this disease.


Glutamate and Aspartate

Amino acids are the major transmitters in the CNS in terms of percentage of synapses at which they are transmitters.


Glutamate and aspartate are synthesized from glucose and other precursors by several routes (Fig. 7.4).


Glutamate and aspartate both act on glutamate receptors in the brain. There are two types of glutamate receptors: ionotropic and metabotropic.

Ionotropic Glutamate Receptors. There are three types of inotropic glutamate receptors; they are classified according to the amino acid that is most potent at that receptor:

– N-methyl-d-aspartate (NMDA)

– α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)

– Kainate

These receptors are said to be excitotoxic, as their prolonged activation increases the entry of cations, including Ca2+, into the cell. High intracellular Ca2+ levels trigger a cascade of events leading to neurotoxicity.

Metabotropic Glutamate Receptors. These are G-protein coupled glutamate receptors.


Nearly all of the neuronal pathways delineated thus far for glutamate are corticofugal, that is, from the cortex and hippocampus to other parts of the brain. Antagonists of these receptors are potential antiepileptic agents.


Glutamate and aspartate are powerful excitatory amino acid transmitters that are eventually neurotoxic.

Fig. 7.4 image Glutamate, glutamine, and gamma-aminobutyric acid (GABA).

Glutamate and GABA are important neurotransmitters synthesized and metabolized in the brain. To regulate their quantity in the extracellular space, glial cells supply glutaminergic and GABAergic neurons with the precursor, glutamine. In glutamate neurons, glutamine is hydrolyzed to glutamate, which is stored in vesicles and released when the nerve is stimulated. In GABA neurons, glutamate is hydrolyzed to glutamate and then converted to GABA. Both types of neurons take up their respective transmitter for reuse. Both transmitters are also taken back up into glial cells, where they are ultimately converted back to glutamine.




Glucose is probably the principal in vivo source of GABA. There is a GABA “shunt” of the Krebs cycle whereby α-ketoglutarate is transaminated to glutamic acid by GABA aminotransferase (GABA-T). Glutamic acid is decarboxylated by glutamic acid decarboxylase (GAD) to GABA (Fig. 7.4). This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter, GABA. There is 200 to 1000 times more GABA in the brain than dopamine, norepinephrine, serotonin, or acetylcholine.


– GABAA receptors are postsynaptically located, multisubunit ligand-gated ion channels. Activation leads to opening of the Cl channel and synaptic inhibition.

– GABAB are G-protein coupled receptors located on presynaptic terminals. Activation results in decreased release of GABA and other neurotransmitters from the terminal on which these receptors are located.


– GABA is the neurotransmitter of inhibitory interneurons found throughout the cerebral and cerebellar cortices.

– It is also found in neurons projecting from the globus pallidus and substantia nigra to the thalamus and from the striatum to the globus pallidus and substantia nigra.


GABA accounts for most of the inhibitory action in the CNS. It is also involved in inhibitory motor control in the spinal cord and is thus directly responsible for the regulation of muscle tone. Drugs that enhance GABA-mediated neurotransmission (e.g., benzodiazepines and barbiturates) are used as anxiolytic, sedative, and anticonvulsant drugs.

Fate of GABA

Free GABA can be transaminated by GABA-T to form succinic semialdehyde (only if α-ketoglutarate is the acceptor of the amine group). Succinic semialdehyde is oxidized to succinic acid by succinic semialdehyde dehydrogenase (SSADH) to reenter the Krebs cycle. This transforms α-ketoglutarate into glutamate. GABA can be packaged into synaptic vesicles for release and is picked up by glial cells. GABA-T transaminates to glutamate. Glial cells lack GAD, so glutamate is transformed by glutamine synthetase to glutamine before being transported back to the nerve ending (Fig. 7.4). Glutaminase converts glutamine back to glutamate. GABA-T and SSADH are attached to mitochondria. Glutaminase, GAD, and glutamine synthetase are cytoplasmic. GAD occurs only in neurons, glutamine synthesis only in glia, and glutaminase in both.


Krebs cycle

The Krebs cycle (also known as the citric acid cycle/tricarboxylic acid cycle) is one of the metabolic pathways involved in the conversion of carbohydrates, fats, and proteins into carbon dioxide, water, and adenosine triphosphate (ATP) in aerobic organisms. Throughout the cycle, many compounds are produced that are the precursors for other substances needed in the body.




Glycine is formed from serine by the enzyme serine hydroxymethyltransferase.


Glycine is released by the inhibitory interneurons that are activated by Ia muscle afferents.


Glycine binds to glycine receptors. These receptors can be blocked by strychnine.


– Inhibitory motor control in the spinal cord

Table 7.1 provides a summary of the CNS neurotransmitters.



Neuropeptide neurotransmitters (comprising 3–100 amino acids) are found in much lower concentrations than amino acid and amine transmitters. They are formed by cleavage of larger molecules and are frequently colocalized with other peptides or with amino acid or amine transmitters. They have no reuptake mechanisms and are generally broken down by peptidases. Neuropeptides are frequently colocalized in, and coreleased from, neurons that also contain one of the smaller molecule neurotransmitters mentioned above.

Table 7.2 lists some common drug-sensitive sites in synaptic transmission. The drugs and the conditions for which they are given are discussed in more detail in the following chapters in this unit.

  Table 7.2 image Drug-sensitive Sites in Synaptic Transmission



Therapeutic Use

Electrically excitable ion channels (includes voltage-dependent Na+, K+, and Ca2+ channels)

Na+ channels blocked by local anesthetics

Pain reduction

Chemically regulated ion channels (includes ligand-gated channels that are nicotinic cholinergic, glutamate, and GABAA receptors)

Benzodiazepines increase Cl– conductance of the GABAA receptor

Treatment of anxiety

Presynaptic synthetic pathways

Levodopa to increase dopamine levels

Parkinson disease

Transmitter reuptake mechanisms in neurons and glia


Treatment of depression

Extracellular and glial degradative enzymes

Acetylcholinesterase inhibitors block acetylcholine hydrolysis

Alzheimer disease

G-protein coupled membrane receptors (include norepinephrine, dopamine, serotonin, muscarinic cholinergic, GABAB, and neuropeptide receptors)


Pain reduction

Abbreviations: GABA, gamma-aminobutyric acid; SSRI, selective serotonin reuptake inhibitor.