Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II

chapter 13
5-Hydroxytryptamine (Serotonin) and Dopamine

5-Hydroxytryptamine (5HT, serotonin) and dopamine (DA) have prominent actions in the CNS and the periphery. Fourteen 5HT receptor subtypes and five DA receptor subtypes have been delineated by pharmacological analyses and cDNA cloning. The availability of cloned receptors has allowed the development of subtype-selective drugs and the elucidation of actions of these neurotransmitters at a molecular level.


5HT is found in high concentrations in enterochromaffin cells throughout the GI tract, in storage granules in platelets, and broadly throughout the CNS. 5HT regulates smooth muscle in the cardiovascular system and the GI tract and enhances platelet aggregation.

SYNTHESIS AND METABOLISM OF 5HT. 5HT is synthesized by a 2-step pathway from the tryptophan (Figure 13–1).


Figure 13–1 Synthesis and inactivation of serotonin. Enzymes are identified in red lettering, and cofactors are shown in blue.

Tryptophan is actively transported into the brain by a carrier protein. Levels of tryptophan in the brain reflect its plasma concentration and the plasma concentrations of amino acids that compete for the same transporter. Tryptophan hydroxylase, the rate-limiting enzyme in the synthetic pathway, converts tryptophan to L-5-hydroxytryptophan; the enzyme is not regulated by end-product inhibition. Brain tryptophan hydroxylase is not generally saturated with substrate; consequently, the concentration of tryptophan in the brain influences the synthesis of 5HT.

Aromatic l-amino acid decarboxylase (AADC) converts L-5-hydroxytryptophan to 5HT; it is widely distributed and has broad substrate specificity. The synthesized product, 5HT, is accumulated in secretory granules by a vesicular monoamine transporter (VMAT2); vesicular 5HT is released by exocytosis from serotonergic neurons. In the nervous system, the action of released 5HT is terminated via neuronal uptake by a specific 5HT transporter (SERT), localized in the membrane of serotonergic axon terminals and in the membrane of platelets. This uptake system is the means by which platelets acquire 5HT, since they lack the enzymes required for 5HT synthesis. The amine transporters are distinct from VMAT2, which concentrates amines in intracellular storage vesicles and is a nonspecific amine carrier, whereas the 5HT transporter is specific.

The principal route of metabolism of 5HT involves oxidative deamination by monoamine oxidase (MAO); the aldehyde intermediate thus formed is converted to 5-hydroxyindole acetic acid (5-HIAA) byaldehyde dehydrogenase (see Figure 13–1). 5-HIAA is actively transported out of the brain by a process that is sensitive to the nonspecific transport inhibitor, probenecid. 5-HIAA from brain and peripheral sites of 5HT storage and metabolism is excreted in the urine along with small amounts of 5-hydroxytryptophol sulfate or glucuronide conjugates. The usual range of urinary excretion of 5-HIAA by a normal adult is 2-10 mg daily. Ingestion of ethanol results in elevated amounts of NADH2 (see Chapter 23), which diverts 5-hydroxyindole acetaldehyde from the oxidative route to the reductive pathway and tends to increase the excretion of 5-hydroxytryptophol and correspondingly reduce the excretion of 5-HIAA.

Of the 2 isoforms of monoamine oxidase (MAO; see Chapter 8), MAO-A preferentially metabolizes 5HT and NE. Dopamine and tryptamine are metabolized equally well by both isoforms. Neurons contain both isoforms of MAO, localized primarily in the outer membrane of mitochondria. MAO-B is the principal isoform in platelets, which contain large amounts of 5HT.



The multiple 5HT receptor subtypes cloned comprise the largest known neurotransmitter-receptor family. The 5HT receptor subtypes are expressed in distinct but often overlapping patterns and are coupled to different transmembrane-signaling mechanisms (Table 13–1).

Table 13–1

Serotonin Receptor Subtypes


Four of seven 5HT receptor families have defined functions. The 5HT1, 5HT2, and 5HT4–7 receptor families are members of the superfamily of GPCRs.

• The 5HT1-receptor subfamily consists of 5 members, all of which preferentially couple to Gi/o and inhibit adenylyl cyclase.

• The 3 subtypes of 5HT2 receptors couple to Gq/G11 proteins and activate the PLC-DAG/IP3-Ca2+-PKC pathway. 5HT2A and 5HT2C receptors also activate phospholipase A2, promoting the release of arachidonic acid.

• The 5HT3 receptor is the only monoamine neurotransmitter receptor that functions as a ligand-operated ion channel. Activation of 5HT3 receptors elicits a rapidly desensitizing depolarization, mediated by the gating of cations.

• 5HT4 receptors couple to Gs to activate adenylyl cyclase and increase intracellular cyclic AMP.

The 5HT1A, 5HT1B, and 5HT1D receptor subtypes also activate a receptor-operated K+ channel and inhibit a voltage-gated Ca2+ channel. The 5HT1A receptor is found in the raphe nuclei of the brainstem, where it functions as an inhibitory somatodendritic autoreceptor on cell bodies of serotonergic neurons (Figure 13–2). The 5HT1D/1B receptor functions as an autoreceptor on axon terminals, inhibiting 5HT release. 5HT1D receptors, abundantly expressed in the substantia nigra and basal ganglia, regulate the firing rate of DA-containing cells and the release of DA at axonal terminals.


Figure 13–2 Two classes of 5HT autoreceptors with differential localizations. Somatodendritic 5HT1A autoreceptors decrease raphe cell firing when activated by 5HT released from axon collaterals of the same or adjacent neurons. The receptor subtype of the presynaptic autoreceptor on axon terminals in the forebrain has different pharmacological properties and has been classified as 5HT1D (in humans) or 5HT1B (in rodents). This receptor modulates the release of 5HT. Postsynaptic 5HT1 receptors are also indicated.

5HT2A receptors are broadly distributed in the CNS (primarily in serotonergic terminal areas, with high densities in prefrontal and parietal areas, and somatosensory cortex), as well as in blood platelets (Figure 13–3) and smooth muscle cells. The 5HT2C receptor has been implicated in the control of cerebrospinal fluid production and in feeding behavior and mood.


Figure 13–3 The local influences of platelet 5HT. The release of 5HT stored in platelets is triggered by aggregation. The local actions of 5HT include feedback actions on platelets (shape change and accelerated aggregation) mediated by interaction with platelet 5HT2A receptors, stimulation of NO production mediated by 5HT1-like receptors on vascular endothelium, and contraction of vascular smooth muscle mediated by 5HT2A receptors. These influences act in concert with many other mediators that are not shown to promote thrombus formation and hemostasis. See Chapter 30 for details of adhesion and aggregation of platelets and factors contributing to thrombus formation and blood clotting.

5HT3 receptors are located on parasympathetic terminals in the GI tract, including vagal and splanchnic afferents. In the CNS, a high density of 5HT3 receptors occurs in the solitary tract nucleus and the area postrema. 5HT3 receptors in both the GI tract and the CNS participate in the emetic response, providing a basis for the antiemetic property of 5HT3 receptor antagonists.

In the CNS, 5HT4 receptors are found on neurons of the superior and inferior colliculi and in the hippocampus. In the GI tract, 5HT4 receptors are located on neurons of the myenteric plexus and on smooth muscle and secretory cells. In the GI tract, stimulation of the 5HT4 receptor is thought to evoke secretion and to facilitate the peristaltic reflex. The latter effect may explain the utility of prokinetic benzamides in GI disorders (see Chapter 46).

Two subtypes of the 5HT5 receptor have been cloned; although the 5HT5A receptor has been shown to inhibit adenylyl cyclase, functional coupling of the cloned 5HT5B receptor has not yet been described. Two other cloned receptors, 5HT6 and 5HT7, are linked to activation of adenylyl cyclase. 5HT7 receptors may play a role in the relaxation of smooth muscle in the GI tract and the vasculature. The atypical antipsychotic drug clozapine has a high affinity for 5HT6 and 5HT7 receptors; whether this property is related to the broader effectiveness of clozapine compared to conventional antipsychotic drugs is not known (see Chapter 16).


PLATELETS. Platelets differ from other formed elements of blood in expressing mechanisms for uptake, storage, and endocytotic release of 5HT. 5HT is not synthesized in platelets, but is taken up from the circulation and stored in secretory granules by active transport, similar to the uptake and storage of serotonin by serotonergic nerve terminals.

Thus, Na+-dependent transport across the platelet plasma membrane via the 5HT transporter is followed by VMAT2-mediated uptake into storage granules creating a gradient of 5HT as high as 1000:1 with an internal concentration of 0.6 M in the storage vesicles.

When platelets make contact with injured endothelium (see Chapter 30), they release substances that promote platelet aggregation, and secondarily, they release 5HT (see Figure 13–3). 5HT binds to platelet 5HT2A receptors and elicits a weak aggregation response that is markedly augmented by the presence of collagen. If the damaged blood vessel is injured to a depth where vascular smooth muscle is exposed, 5HT exerts a direct vasoconstrictor effect, thereby contributing to hemostasis, which is enhanced by locally released autocoids (thromboxane A2, kinins, and vasoactive peptides). Conversely, 5HT may interact with endothelial cells to stimulate production of NO and antagonize its own vasoconstrictor action, as well as the vasoconstriction produced by other locally released agents.

CARDIOVASCULAR SYSTEM. The classical response of blood vessels to 5HT is contraction, particularly in the splanchnic, renal, pulmonary, and cerebral vasculatures. 5HT also induces a variety of responses by the heart that are the result of activation of multiple 5HT receptor subtypes, stimulation or inhibition of autonomic nerve activity, or dominance of reflex responses to 5HT.

Thus, 5HT has positive inotropic and chronotropic actions on the heart that may be blunted by simultaneous stimulation of afferent nerves from baroreceptors and chemoreceptors. Activation of 5HT3receptors on vagus nerve endings elicits the Bezold-Jarisch reflex, causing extreme bradycardia and hypotension. The local response of arterial blood vessels to 5HT also may be inhibitory, the result of the stimulation of endothelial NO production and prostaglandin synthesis and blockade of NE release from sympathetic nerves. Conversely, 5HT amplifies the local constrictor actions of NE, ANGII, and histamine, which reinforce the hemostatic response to 5HT.

GI TRACT. Enterochromaffin cells in the gastric mucosa are the site of the synthesis and most of the storage of 5HT in the body and are the source of circulating 5HT. Motility of gastric and intestinal smooth muscle may be either enhanced or inhibited by at least 6 subtypes of 5HT receptors (Table 13–2).

Table 13–2

Some Actions of 5HT in the Gastrointestinal Tract


Basal release of enteric 5HT is augmented by mechanical stretching, such as that caused by food, and by efferent vagal stimulation. Released 5HT enters the portal vein and is subsequently metabolized by MAO-A in the liver. 5HT that survives hepatic oxidation may be captured by platelets or rapidly removed by the endothelium of lung capillaries and inactivated. 5HT released from enterochromaffin cells also acts locally to regulate GI function. Abundant 5HT3 receptors on vagal and other afferent neurons and on enterochromaffin cells play a pivotal role in emesis (see Chapter 46). Enteric 5HT triggers peristaltic contraction when released in response to acetylcholine, sympathetic nerve stimulation, increases in intraluminal pressure, and lowered pH.

CNS. All of the cloned 5HT receptors are expressed in the brain; 5HT influences a multitude of brain functions, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion. The roles of specific 5HT receptors in these functions have been defined in receptor knockout mice (Table 13–3).

Table 13–3

Physiological Roles of 5HT Receptors Defined by Phenotypes in Knockout Mice


The principal cell bodies of 5HT neurons are located in raphe nuclei of the brainstem and project throughout the brain and spinal cord (see Chapter 14). In addition to being released at discrete synapses, release of serotonin also seems to occur at sites of axonal varicosities that do not form distinct synaptic contacts. 5HT released at nonsynaptic varicosities is thought to diffuse to outlying targets, rather than acting on discrete synaptic targets, perhaps acting as a neuromodulator as well as a neurotransmitter (see Chapter 14). Serotonergic nerve terminals contain the proteins needed to synthesize 5HT from L-tryptophan. Newly formed 5HT is rapidly accumulated in synaptic vesicles (through VMAT2), where it is protected from MAO. 5HT released by nerve-impulse flow is reaccumulated into the presynaptic terminal by the 5HT transporter, SERT (SLC6A4; see Chapter 5). Presynaptic reuptake is a highly efficient mechanism for terminating the action of 5HT released by nerve-impulse flow. MAO localized in postsynaptic elements and surrounding cells rapidly inactivates 5HT that escapes neuronal reuptake and storage.

ELECTROPHYSIOLOGY. The physiological consequences of 5HT release vary with the brain area and the neuronal element involved, as well as with the 5HT receptor subtype(s) expressed (Table 13–4).

Table 13–4

Electrophysiological Effects of 5HT Receptors



SLEEP-WAKE CYCLE. 5HT plays a role in sleep-wake cycle.

Depletion of 5HT with p-Chlorophenylalanine, a tryptophan hydroxylase inhibitor, elicits insomnia that is reversed by the 5HT precursor, 5-hydroxytryptophan. Conversely, treatment with L-tryptophan or with nonselective 5HT agonists accelerates sleep onset and prolongs total sleep time. 5HT antagonists reportedly can increase and decrease slow-wave sleep, probably reflecting interacting or opposing roles for subtypes of 5HT receptors. One relatively consistent finding in humans and in laboratory animals is an increase in slow-wave sleep following administration of a selective 5HT2A/2C-receptor antagonist such as ritanserin.

AGGRESSION AND IMPULSIVITY. 5HT serves a critical role in aggression and impulsivity.

Human studies reveal a correlation between low cerebrospinal fluid 5-HIAA and violent impulsivity and aggression. Knockout mice lacking the 5HT1B receptor exhibit extreme aggression, suggesting either a role for 5HT1B receptors in the development of neuronal pathways important in aggression or a direct role in the mediation of aggressive behavior. A human genetic study identified a point mutation in the gene encoding MAO-A, which was associated with extreme aggressiveness and mental retardation; this has been confirmed in knockout mice lacking MAO-A.

ANXIETY AND DEPRESSION. The effects of 5HT–active drugs in anxiety and depressive disorders, like the effects of selective serotonin reuptake inhibitors (SSRIs), strongly suggest a role for 5HT in the neurochemical mediation of these disorders.

Inhibition of neuronal reuptake of 5HT via the transporter SERT (SLC6A4) prolongs the dwell-time of 5HT in the synapse. SSRIs, such as fluoxetine (PROZAC, others), potentiate and prolong the action of 5HT released by neuronal activity. When coadministered with L-5-hydroxytryptophan, SSRIs elicit a profound activation of serotonergic responses. SSRIs (citalopram [CELEXA], escitalopram [LEXAPRO], fluoxetine, fluvoxamine, paroxetine [PAXIL], and sertraline [ZOLOFT]) are the most widely used treatment for endogenous depression (see Chapter 15).

APPETITESibutramine (MERIDIA), an inhibitor of the reuptake of 5HT, NE, and DA, is used as an appetite suppressant in the management of obesity.

Sibutramine is classified as a selective serotonin-norepinephrine reuptake inhibitor (SNRI). Other SNRIs include duloxetine (CYMBALTA; approved for depression, anxiety, peripheral neuropathy, and fibromyalgia), venlafaxine (EFFEXOR; approved for the treatment of depression, anxiety, and panic disorders), desvenlafaxine (PRISTIQ; approved for depression), and milnacipran (SAVELLA; approved for fibromyalgia).



Direct-acting 5HT receptor agonists have widely different chemical structures, as well as diverse pharmacological properties and are used in the pharmacotherapy of migraine, anxiety, depression, chemotherapy-induced emesis, and disorders of GI motility (Table 13–5).

Table 13–5

Serotonergic Drugs: Primary Actions and Clinical Indications


5HT RECEPTOR AGONISTS AND MIGRAINE. 5HT seems to be a key mediator in the pathogenesis of migraine. Consistent with the 5HT hypothesis of migraine, 5HT receptor agonists are a mainstay for acute treatment of migraine headaches. The efficacy of antimigraine drugs varies with the absence or presence of aura, duration of the headache, its severity and intensity, and as yet undefined environmental and genetic factors.

5HT1B/1D RECEPTOR AGONISTS: THE TRIPTANS. The triptans are indole derivatives that are effective, acute antimigraine agents. Their capacity to decrease the nausea and vomiting of migraine is an important advance in the treatment of the condition. Available compounds include almotriptan (AXERT), eletriptan (RELPAX), frovatriptan (FROVA), naratriptan (AMERGE), rizatriptan (MAXALT, others), sumatriptan (IMITREX, others), and zolmitriptan (ZOMIG). Sumatriptan for migraine headaches is also marketed in a fixed-dose combination with naproxen (TREXIMET).


Pharmacological Properties. The pharmacological effects of the triptans appear to be limited to the 5HT1 family of receptors, providing evidence that this receptor subclass plays an important role in the acute relief of a migraine attack. The triptans interact potently with 5HT1B and 5HT1D receptors and have a low or no affinity for other subtypes of 5HT receptors, as well as α1 and α2 adrenergic, β adrenergic, dopaminergic, muscarinic cholinergic, and benzodiazepine receptors. Clinically effective doses of the triptans correlate well with their affinities for both 5HT1B and 5HT1D receptors, supporting the hypothesis that 5HT1B and/or 5HT1D receptors are the most likely receptors involved in the mechanism of action of acute antimigraine drugs.

Mechanism of Action. The mechanism of the efficacy of 5HT1B/1D agonists in migraine is not resolved. One hypothesis of migraine suggests that unknown events lead to the abnormal dilation of carotid arteriovenous anastomoses in the head and shunting of carotid arterial blood flow, producing cerebral ischemia and hypoxia perceived as migraine pain; activation of 5HT1B/1D receptors may cause constriction of intracranial blood vessels including arteriovenous anastomoses, closing the shunts and restoring blood flow to the brain. An alternative hypothesis proposes that both 5HT1B and 5HT1Dreceptors serve as presynaptic autoreceptors that may block the release of pro-inflammatory neuropeptides from the nerve terminal in the perivascular space, which could account for their efficacy in the acute treatment of migraine.

Absorption, Fate, and Excretion. When given subcutaneously, sumatriptan reaches its peak plasma concentration in ~12 min. Following oral administration, peak plasma concentrations occur within 1-2 h. Bioavailability following the subcutaneous route of administration is ~97%; after oral administration or nasal spray, bioavailability is only 14-17%. The elimination t1/2 is ~1-2 h. Sumatriptan is metabolized predominantly by MAO-A, and its metabolites are excreted in the urine.

Zolmitriptan reaches its peak plasma concentration 1.5-2 h after oral administration. Zolmitriptan is converted to an active N-desmethyl metabolite, which has severalfold higher affinity for 5HT1B and 5HT1D receptors than does the parent drug. Both the metabolite and the parent drug have half-lives of 2-3 h.

Naratriptan, administered orally, reaches its peak plasma concentration in 2-3 h. It is the second longest acting of the triptans, with a t1/2 of ~6 h. Fifty percent of an administered dose of naratriptan is excreted unchanged in the urine, and ~30% is excreted as products of oxidation by CYPs.

Rizatriptan reaches peak plasma levels within 1-1.5 h after oral ingestion of the drug. An orally disintegrating dosage form has a somewhat slower rate of absorption. The principal route of metabolism of rizatriptan is by oxidative deamination by MAO-A.

ADVERSE EFFECTS AND CONTRAINDICATIONS. Rare but serious cardiac events have been associated with the administration of 5HT1 agonists, including coronary artery vasospasm, transient myocardial ischemia, atrial and ventricular arrhythmias, and myocardial infarction, predominantly in patients with risk factors for coronary artery disease. In general, however, only minor side effects are seen with the triptans in the acute treatment of migraine. After subcutaneous injection of sumatriptan, patients often experience irritation at the site of injection (transient mild pain, stinging, or burning sensations). The most common side effect of sumatriptan nasal spray is a bitter taste. Orally administered triptans can cause paresthesias; asthenia and fatigue; flushing; feelings of pressure, tightness, or pain in the chest, neck, and jaw; drowsiness; dizziness; nausea; and sweating.

Because triptans may cause an acute, usually small, increase in blood pressure, they also are contraindicated in patients with uncontrolled hypertension. Naratriptan is contraindicated in patients with severe renal or hepatic impairment. Rizatriptan should be used with caution in patients with renal or hepatic disease but is not contraindicated in such patients. Eletriptan is contraindicated in hepatic disease. Almotriptan, rizatriptan, sumatriptan, and zolmitriptan are contraindicated in patients who have taken an MAO inhibitor within the preceding 2 weeks, and all triptans are contraindicated in patients with near-term prior exposure to ergot alkaloids or other 5HT agonists.

TRIPTANS IN TREATMENT OF MIGRAINE. The triptans are effective in the acute treatment of migraine (with or without aura).

Approximately 70% of individuals report significant headache relief from a 6-mg subcutaneous dose of sumatriptan. This dose may be repeated once within a 24-h period. The oral dose of sumatriptan is 25-100 mg, which may be repeated after 2 h up to a total dose of 200 mg over a 24-h period. When administered by nasal spray, from 5-20 mg of sumatriptan is recommended, repeatable after 2 h up to a maximum dose of 40 mg over a 24-h period. The onset of action with nasal spray is as early as 15 min. Zolmitriptan is given orally in a dose of 1.25-2.5 mg, which can be repeated after 2 h, up to a maximum dose of 10 mg over 24 h. Naratriptan is given orally in a dose of 1-2.5 mg, repeated after 4 h (maximum dose 5 mg/24-h period). The oral dose of rizatriptan is 5-10 mg. The dose can be repeated after 2 h up to a maximum dose of 30 mg over a 24-h period.

ERGOT ALKALOIDS. Ergot is the product of a fungus (Claviceps purpurea) that grows on rye and other grains. The pharmacological effects of the ergot alkaloids are varied and complex; in general, the effects result from their actions as partial agonists or antagonists at serotonergic, dopaminergic, and adrenergic receptors. The history, chemistry, and pharmacological properties of the ergot alkaloids are covered in detail in Chapter 13 of the 12th edition of the parent text. The main uses of the ergot alkaloids are:

• In treatment of migraine (ergotamine tartrate and dihydroergotamine mesylate, in many dosage formulations; methysergide for prophylaxis)

• To control the secretion of prolactin (bromocriptine, taking advantage of its DA agonist effect)

• To increase uterine tone (all natural ergot alkaloids have this effect but ergonovine and its semisynthetic derivative methylergonovine have replaced other ergot preparations as uterine-stimulating agents in obstetrics)

ERGOT IN THE TREATMENT OF MIGRAINE. The multiple pharmacological effects of ergot alkaloids have complicated the determination of their precise mechanism of action in the acute treatment of migraine. The actions of ergot alkaloids at 5HT1B/1D receptors likely mediate their acute antimigraine effects. The use of ergot alkaloids for migraine should be restricted to patients having frequent, moderate migraine or infrequent, severe migraine attacks. Ergot preparations should be administered as soon as possible after the onset of a headache. GI absorption of ergot alkaloids is erratic, perhaps contributing to the large variation in patient response to these drugs.

USE OF ERGOT ALKALOIDS IN POSTPARTUM HEMORRHAGE. All of the natural ergot alkaloids markedly increase the motor activity of the uterus. As the dose is increased, contractions become more forceful and prolonged, resting tone is dramatically increased, and sustained contracture can result. This characteristic is quite compatible with their use postpartum or after abortion to control bleeding and maintain uterine contraction. In current obstetric practice, ergot alkaloids are used primarily to prevent postpartum hemorrhage.

ADVERSE EFFECTS AND CONTRAINDICATIONS OF ERGOT ALKALOIDS. Ergot alkaloids are contraindicated in women who are, or may become, pregnant because the drugs may cause fetal distress and miscarriage. Ergot alkaloids also are contraindicated in patients with peripheral vascular disease, coronary artery disease, hypertension, impaired hepatic or renal function, and sepsis. Ergot alkaloids should not be taken within 24 h of the use of the triptans or used with other drugs that can cause vasoconstriction.

METHYSERGIDE. Methysergide (SANSERT; 1-methyl-d-lysergic acid butanolamide) interacts with 5HT1 receptors, but its therapeutic effects appear primarily to reflect blockade of 5HT2A and 5HT2C receptors.

Although methysergide is an ergot derivative, it has only weak vasoconstrictor and oxytocic activity. Methysergide is used for the prophylactic treatment of migraine and other vascular headaches. A potentially serious complication of prolonged treatment is inflammatory fibrosis, giving rise to various syndromes that include pleuropulmonary fibrosis, and coronary and endocardial fibrosis. Usually the fibrosis regresses after drug withdrawal, although persistent cardiac valvular damage has been reported. If methysergide is used chronically, treatment should be interrupted for 3 weeks or more every 6 months. Methysergide is not available in the U.S.

D-LYSERGIC ACID DIETHYLAMIDE (LSD). LSD is a nonselective 5HT agonist. This ergot derivative profoundly alters human behavior, eliciting sensory distortion (especially visual) and hallucinations at doses as low as 1 μg/kg. The potent, mind-altering effects of LSD explain its abuse by humans.

LSD interacts with brain 5HT receptors as an agonist/partial agonist. LSD mimics 5HT at 5HT1A autoreceptors on raphe cell bodies, producing a marked slowing of the firing rate of serotonergic neurons. In the raphe, LSD and 5HT are equi-effective; however, in areas of serotonergic axonal projections (such as visual relay centers), LSD is far less effective than is 5HT. In an animal behavioral model, the discriminative stimulus effects of LSD and other hallucinogenic drugs appear to be mediated by activation of 5HT2A receptors. LSD also interacts potently with many other 5HT receptors, including cloned receptors whose functions have not yet been determined. The hallucinogenic phenethylamine derivatives are selective 5HT2A/2C receptor agonists. Current theories of the mechanism of action of LSD and other hallucinogens focus on 5HT2A receptor-mediated disruption of thalamic gating with sensory overload of the cortex. Positron emission tomography imaging studies revealed that administration of the hallucinogen psilocybin (the active component of “shrooms”) mimics the pattern of brain activation found in schizophrenic patients experiencing hallucinations. This action of psilocybin is blocked by pretreatment with a 5HT2A/2C antagonist.

BUSPIRONE (BUSPAR, OTHERS). Buspirone, gepirone, and ipsapirone are selective partial agonists at 5HT1A receptors. Buspirone has been effective in the treatment of anxiety (seeChapter 15). Buspirone mimics the antianxiety properties of benzodiazepines but does not interact with GABAA receptors and or display the sedative and anticonvulsant properties of benzodiazepines.

VILAZODONE (VIIBRYD). Vilazadone is an SSRI and a partial agonist at the 5HT1A receptor. It is FDA-approved in adults for treatment of major depressive disorder.

m-CHLOROPHENYLPIPERAZINE (MCPP). The actions of mCPP in vivo primarily reflect activation of 5HT1B and/or 5HT2A/2C receptors; mCPP is an active metabolite of the antidepressant drug trazodone.

Animal studies suggest a greater involvement of the 5HT2C receptor in the anxiogenic actions of mCPP. mCPP elevates cortisol and prolactin secretion, probably through a combination of 5HT1 and 5HT2A/2C receptor activation. It also increases growth hormone secretion, apparently by a 5HT independent mechanism.

LORCASERIN (BELVIQ). Lorcaserin is a 5HT2C receptor agonist approved for weight loss.

The drug is thought to decrease food consumption and promote satiety by selectively activating 5HT2C receptors on anorexigenic proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus.


The properties of 5HT receptor antagonists vary widely. Ergot alkaloids and related compounds tend to be nonspecific 5HT receptor antagonists; however, a few ergot derivatives, such as metergoline, bind preferentially to members of the 5HT2 receptor family. A number of selective antagonists for 5HT2A/2C and 5HT3 receptors are currently available. Ketanserin is the prototypic 5HT2A receptor antagonist. A large series of 5HT3 receptor antagonists are being explored for treatment of various GI disturbances (e.g., ondansetron [ZOFRAN, others], dolasetron [ANZEMET], granisetron [KYTRIL, others], and palonosetron [ALOXI]). All 5HT3 receptor antagonists have proven to be highly efficacious in the treatment of chemotherapy-induced nausea, and alosetron (LOTRONEX) is licensed for irritable bowel syndrome (see Chapter 46).

KETANSERIN. Ketanserin (SUFREXAL, others) potently blocks 5HT2A receptors, less potently blocks 5HT2C receptors, and has no significant effect on 5HT3 or 5HT4 receptors or any members of the 5HT1-receptor family. Ketanserin also blocks α adrenergic receptors and histamine H1 receptors.


Ketanserin lowers blood pressure in patients with hypertension, causing a reduction comparable to that seen with α adrenergic receptor antagonists or diuretics. This effect likely relates to its blockade of α1adrenergic receptors. Ketanserin inhibits 5HT-induced platelet aggregation. Its oral bioavailability is ~50%, and its plasma t1/2 is 12-25 h. The primary mechanism of inactivation is hepatic metabolism. Ketanserin is not marketed in the U.S. Chemical relatives of ketanserin such as ritanserin are more selective 5HT2A receptor antagonists with low affinity for α1 adrenergic receptors. Ritanserin, as well as most other 5HT2A receptor antagonists, also potently antagonize 5HT2C receptors.

ATYPICAL ANTIPSYCHOTIC DRUGS. Clozapine (CLOZARIL, others), a 5HT2A/2C receptor antagonist, represents a class of atypical antipsychotic drugs with reduced incidence of extrapyramidal side effects compared to the classical neuroleptics (see Chapter 16). Clozapine also has a high affinity for subtypes of DA receptors.

A common strategy for the design of atypical antipsychotic drugs is to combine 5HT2A/2C and dopamine D2 receptor–blocking actions in the same molecule. Risperidone (RISPERDAL, others) is a potent 5HT2A and D2 receptor antagonist. Low doses of risperidone have been reported to attenuate negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.

CYPROHEPTADINE. Cyproheptadine is an effective H1-receptor antagonist. Cyproheptadine blocks 5HT activity on smooth muscle by binding to 5HT2A receptors. In addition, it has weak anticholinergic activity and possesses mild CNS depressant properties.

Cyproheptadine shares the properties and uses of other H1-receptor antagonists (see Chapter 32). The 5HT blocking actions of cyproheptadine explain its value in the off-label uses for postgastrectomy dumping syndrome, intestinal hypermotility of carcinoid, and migraine prophylaxis. Cyproheptadine is not a preferred treatment for these conditions.

METHYSERGIDE. Methysergide has both agonist and antagonist activities at multiple 5HT receptors. See its section, above.


Excessive elevation of 5HT levels in the body can cause serotonin syndrome, a constellation of symptoms sometimes observed in patients starting new or increased antidepressant therapy or combining an SSRI with an NE reuptake inhibitor or a triptan (for migraine). Symptoms may include restlessness, confusion, shivering, tachycardia, diarrhea, muscle twitches/rigidity, fever, seizures, loss of consciousness, and death.


The highest concentrations of DA are found in the brain; DA stores are also present peripherally in the adrenal medulla and the transmitter is detectable in the plexuses of the GI tract and in enteric nervous system. DA modulates peripheral vascular tone, renal perfusion, and heart rate.

DA consists of a catechol moiety linked to an ethyl amine, leading to its classification as a catecholamine. DA is closely related to melanin, a pigment that is formed by oxidation of DA, tyrosine, or L-dopa. Melanin exists in the skin and cuticle and gives the substantia nigra its namesake dark color. Both DA and L-dopa are readily oxidized by nonenzymatic pathways to form cytotoxic reactive oxygen species (ROS) and quinones. DA- and DOPA-quinones form adducts with α-synuclein, a major constituent of Lewy bodies in Parkinson disease (see Chapter 22). DA is a polar molecule that does not readily cross the blood-brain barrier.

SYNTHESIS AND METABOLISM OF DA. The biosynthesis and metabolism of DA are summarized by Figure 13–4.


Figure 13–4 Synthesis and inactivation of dopamine. Enzymes are identified in blue lettering, and cofactors are shown in black letters. See legend to Figure 13–5 for key to abbreviations.

Phenylalanine and tyrosine are the precursors of DA. For the most part, mammals convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Tyrosine crosses readily into the brain through uptake; normal brain levels of tyrosine are typically saturating. Conversion of tyrosine to L-dopa (3,4-dihydroxyphenylalanine) by the enzyme tyrosine hydroxylase is the rate-limiting step in the synthesis of DA (as in NE synthesis; see Chapter 8). Once generated, L-dopa is rapidly converted to DA by AADC, the same enzyme that generates 5HT from L-5-hydroxytryptophan. Unlike DA, L-dopa readily crosses the blood-brain barrier and is converted to DA in the brain, which explains its utility in therapy for Parkinson disease (see Chapter 22). Diminished levels of phenylalanine hydroxylase lead to high levels of phenylalanine, producing a condition known as phenylketonuria, which must be controlled by dietary restrictions in order to avoid intellectual impairment.

THE DOPAMINERGIC SYNAPSE. The neurochemical events that underlie DA neurotransmission are summarized in Figure 13–5.


Figure 13–5 Dopaminergic nerve terminal. Dopamine (DA) is synthesized from tyrosine in the nerve terminal by the sequential actions of tyrosine hydrolase (TH) and aromatic amino acid decarboxylase (AADC). DA is sequestered by vesicular monoamine transporter (VMAT2) in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 transporters. Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyltransferase (COMT) and MAO/ALDH in nonneuronal cells; the final metabolic product is homovanillic acid (HVA). PH, phenylalanine hydroxylase. See structures in Figure 13–4.

In dopaminergic neurons, synthesized DA is packaged into secretory vesicles (or into granules within adrenal chromaffin cells) by the vesicular monoamine transporter, VMAT2. By contrast, in adrenergic or noradrenergic cells, the DA is not packaged; instead, it is converted to NE by DA β-hydroxylase and, in adrenergic cells, further altered to epinephrine in cells expressing phenylethanolamine N-methyltransferase (see Chapter 8). Synaptically released DA is subject to transporter clearance and metabolism. The DA transporter (DAT) is not selective for DA; moreover, DA can also be cleared from the synapse by the NE transporter, NET. Reuptake of DA by DAT is the primary mechanism for termination of DA action, and allows for either vesicular repackaging of transmitter or metabolism. The DA transporter is regulated by phosphorylation, offering the potential for DA to regulate its own uptake.

The DA transporter is predominantly localized perisynaptically so that DA is cleared at a distance from its release site. The DA transporter is a site of action for cocaine and methamphetamine. The DA transporter is also the molecular target for some neurotoxins, including 6-hydroxydopamine and 1-methyl-4-phenylpyridinium (MPPm), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following uptake into dopaminergic neurons, MPP and 6-hydroxydopamine elicit intra- and extracellular DA release, ultimately resulting in neuronal death. This selective dopaminergic degeneration mimics Parkinson disease, and serves as an animal model for this disorder.

Metabolism of DA occurs primarily by MAO localized in both pre- and postsynaptic elements. MAO acts on DA to generate an inactive aldehyde derivative by oxidative deamination (see Figures 13–4 and13–5), which is subsequently metabolized by aldehyde dehydrogenase to form 3,4-dihydroxyphenylacetic acid (DOPAC). DOPAC can be further metabolized by COMT to form homovanillic acid (HVA). COMT can convert DA to 3-methoxytyramine, which is subsequently converted to HVA by MAO. DOPAC, and HVA, as well as DA, are excreted in the urine.

COMT in the periphery also metabolizes L-dopa to 3-O-methyldopa, which then competes with L-dopa for uptake into the CNS. Consequently, L-dopa given in the treatment of Parkinson disease must be coadministered with peripheral COMT inhibitors to preserve L-dopa and allow sufficient entry into the CNS (see Chapter 22).



Five distinct GPCRs have been cloned and determined to mediate the actions of DA. The family of DA receptors is divided into the D1 and D2 subfamilies based on their effector-coupling profiles (Figure 13–6).


Figure 13–6 Distribution and characterization of DA receptors in the CNS.

The D1 subfamily consists of the D1 and D5 receptor subtypes; both are GPCRs that couple to Gs to stimulate cellular cyclic AMP production couple, but they differ in their pharmacological profiles.

The D1 receptor is the most highly conserved and the most highly expressed of the DA receptors. The highest levels of D1 receptor protein are found within the CNS. The neostriatum expresses the highest levels of D1 receptor but does not express any detectable Gas. In this region, the D1 receptor appears to couple to Golf to increase levels of cAMP and its downstream effectors. The D1 receptor is also located in the kidney, retina, and cardiovascular system. The D5 gene is polymorphic; several functional single nucleotide polymorphisms (SNPs) within the transmembrane domains alter binding properties of numerous ligands, including DA. The D5 receptor is most highly expressed in the substantia nigra, hypothalamus, striatum, cerebral cortex, nucleus accumbens, and olfactory tubercle.

The D2 subfamily contains the D2, D3, and D4 receptors. All reduce intracellular cyclic AMP production by coupling to Gi/o proteins, but they diverge in amino acid sequence and pharmacology.

The D2 receptor is expressed throughout the brain. D2S and D2L receptors have similar pharmacological properties and both function as autoreceptors, inhibiting cAMP formation. D2 receptor signaling through ββγ also regulates a variety of cellular functions, including inwardly rectifying K+ channels, N-type Ca2+ channels, PLA2, ERK, and L-type Ca2+ channels. The D2 receptor can activate Gi/o proteins independent of agonist (constitutive activity). The D3 receptor is less abundant than the D2 receptor, and is only expressed in the limbic regions of the brain. The D4 receptor is abundantly expressed in the retina, and is also found in the hypothalamus, prefrontal cortex, amygdala, hippocampus, and pituitary. D4 is the most polymorphic of the DA receptors, containing a variable number of tandem repeats (VNTR) within the third intracellular loop. There are several SNPs in the D4 receptor, 1 of which results in dramatic alterations in ligand binding. There are associations between a 7-repeat D4 VNTR variant and attention deficit hyperactivity disorder (ADHD).


Heart and Vasculature. At low concentrations, circulating DA primarily stimulates vascular D1 receptors, causing vasodilation and reducing cardiac afterload. The net result is a decrease in blood pressure and an increase in cardiac contractility. As circulating DA concentrations rise, DA is able to activate β adrenergic receptors to further increase cardiac contractility.

At very high concentrations, circulating DA activates A adrenergic receptors in the vasculature, thereby causing vasoconstriction; thus, high concentrations of DA increase blood pressure. Clinically, DA administration is used to treat severe congestive heart failure, sepsis, or cardiogenic shock. It is only administered intravenously and is not considered a long-term treatment.

KIDNEY. DA is a paracrine/autocrine transmitter in the kidney and binds to both receptors of both the D1 and D2 subfamily. Renal DA primarily serves to increase natriuresis, though it can also increase renal blood flow and glomerular filtration. Under basal sodium conditions, DA regulates Na+ excretion by inhibiting the activity of various Na+ transporters, including the apical Na+-H+ exchanger and the basolateral Na+, K+-ATPase. Activation of D1 receptors increases renin secretion, whereas DA, acting on D3 receptors, reduces renin secretion. Abnormalities in the DA system and its receptors have been implicated in human hypertension.

PITUITARY GLAND. DA is the primary regulator of prolactin secretion from the pituitary gland. DA released from the hypothalamus into the hypophyseal portal blood supply acts on lactotroph D2S and D2L receptors to decrease prolactin secretion (see Chapter 38).

CATECHOLAMINE RELEASE. Both D1 and D2 receptors modulate the release of NE and EPI. The D2 receptor provides tonic inhibition of EPI release from chromaffin cells of the adrenal medulla, and of NE release from sympathetic nerve terminals. In contrast, the D1 receptor promotes the release of catecholamines from the adrenal medulla.

CNS. There are 3 major groups of DA projections in the brain (Figure 13–7): mesocortico/-mesolimbic (originating in the ventral tegmental area), nigrostriatal (originating in the substantia nigra pars compacta) and tuberoinfundibular (originating in the hypothalamus). The physiological processes under dopaminergic control include reward, emotion, cognition, memory, and motor activity. Dysregulation of the dopaminergic system is critical in a number of disease states, including Parkinson disease, Tourette syndrome, bipolar depression, schizophrenia, ADHD, and addiction/substance abuse.


Figure 13–7 Major dopaminergic projections in the CNS.

• The nigrostriatal (or mesostriatal) pathway. Neurons in the substantia nigra pars compacta (SNc) project to the dorsal striatum (upward dashed blue arrows); this is the pathway that degenerates in Parkinson disease.

• The mesocortico/mesolimbic pathway. Neurons in the ventral tegmental area project to the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate gyrus (solid blue arrows).

• The tuberoinfundibular pathway. Neurons in the arcuate nucleus of the hypothalamus project by the tuberoinfundibular pathway in the hypothalamus, from which DA is delivered to the anterior pituitary (red arrows).

The mesolimbic pathway is associated with reward and, less so, with learned behaviors. Dysfunction in this pathway is associated with addiction, schizophrenia, and psychoses (including bipolar depression), and learning deficits. The mesocortical projections are important for “higher-order” cognitive functions including motivation, reward, emotion, and impulse control; they are also implicated in psychoses, including schizophrenia, and in ADHD. The nigrostriatal pathway is a key regulator of movement (see Chapter 22). Impairments in this pathway are evident in Parkinson disease and underlie detrimental movement side effects associated with dopaminergic therapy, including tardive dyskinesia. DA released in the tuberoinfundibular pathway is carried by the hypophyseal blood supply to the pituitary, where it regulates prolactin secretion.

ELECTROPHYSIOLOGY. DA is not a classical excitatory or inhibitory neurotransmitter; rather, DA acts as a modulator of neurotransmission. D1-like receptor activation modulates Na+, as well as N-, P- and L-type Ca2+ currents, via a PKA-dependent pathway. D2 receptors regulate K+ currents. DA also modulates the activity of ligand-gated ion channels, including NMDA and AMPA receptors.

Dopaminergic neurons are strongly influenced by excitatory glutamate and inhibitory GABA input. In general, glutamate inputs enable burstlike firing of dopaminergic neurons, resulting in high concentrations of synaptic DA. GABA inhibition of DA neurons causes a tonic, basal level of DA release into the synapse. DA release also modulates GABA and glutamate neurons, thus providing an additional level of interaction between DA and other neurotransmitters. Strong phasic or slow tonic release of DA, and the subsequent activation of DA receptors, has differential effects on the induction of long-term potentiation (LTP) and long-term depression (LTD). In the striatum, phasic activation of DA neurons and stimulation of D1 receptors favors LTP induction, while tonic DA release with concomitant activation of both D1- and D2-like receptors favors LTD.


LOCOMOTION: MODELS OF PARKINSON DISEASE (PD). In the early 1980s, several young people in California developed rapid-onset parkinsonism. All of the affected individuals had injected a synthetic analog of meperidine that was contaminated with MPTP. MPTP is metabolized by MAO-B to the neurotoxic MPP+. Because of the high specificity of MPP+ for the DA transporter, neuronal death is largely restricted to the substantia nigra and ventral tegmental area, resulting in a phenotype remarkably similar to Parkinson disease.

6-Hydroxydopamine (6-OHDA) is similar to MPTP in both mechanism of action and utility in animal models. Lesioning animals with MPTP or 6-OHDA results in tremor, grossly diminished locomotor activity, and rigidity. As with Parkinson disease, these motor deficits are alleviated with L-dopa therapy or dopaminergic agonists.

Other pharmacological agents are also known to alter locomotor activity via dopaminergic actions, including cocaine and amphetamine. These drugs bind to DAT and inhibit reuptake of synaptic DA.

Studies with D1 receptor knockout mice indicate that the D1 receptor, but not the D5 receptor, is primarily responsible for the increase in locomotor activity that occurs following administration of D1-family agonists. D2 receptor knockout mice display marked reductions in locomotor activity, initiation of movement, and rearing behaviors. This reduction in motor activity is also present in mice that are specifically lacking only the D2L receptor. The D3 and D4 receptor knockout animals display unique locomotor alterations in response to novel environments.

REWARD: IMPLICATIONS IN ADDICTION. In general, drugs of abuse cause increased DA levels in the nucleus accumbens, an area critical for rewarded behaviors. This role for mesolimbic DA in addiction has led to numerous studies on abused drugs in DA receptor knockout mice that suggest complex roles of D1, D2, and D3 receptors in addiction that are reviewed in the parent text.

COGNITION, LEARNING, AND MEMORY. Mice lacking the D1 receptor display deficits in multiple forms of memory. Other findings in animal models imply an important role for the D2 receptor in disorders with defects in sensorimotor gating, most notably schizophrenia. Indeed, many of the antipsychotic drugs used in the treatment of schizophrenia are high affinity antagonists for the D2 receptor.


DA RECEPTOR AGONISTS. DA receptor agonists are currently used in the treatment of Parkinson disease (PD), restless leg syndrome, and hyperprolactinemia.

One of the primary limitations to the therapeutic use of dopaminergic agonists is the lack of receptor subtype selectivity. Recent advances in receptor-ligand structure-function relationships have enabled the development of subtype-specific drugs, many of which have already proven to be useful experimental tools (Table 13–6). DA receptor activity can be modulated by drugs that bind to allosteric sites on the receptor, thereby enhancing or decreasing endogenous DA signaling in a receptor-specific manner.

Table 13–6

Experimental Tools at DA Receptors


DA RECEPTOR AGONISTS AND PARKINSON DISEASE. PD is characterized by extensive degeneration of dopaminergic neurons within the substantia nigra, resulting in tremor, rigidity, and bradykinesia. The principal pharmacotherapy for PD is L-dopa, but limitations to its therapeutic effects (see Chapter 22) have generated intense interest in developing alternative therapies for PD, with the intent of either delaying the usage of L-dopa or alleviating its side effects. DA agonists can be used in conjunction with lower doses of L-dopa in a combined therapy approach. Two general classes of dopaminergic agonists are used in the treatment of PD: ergots and non-ergots. The use of these drugs in the management of PD is described in Chapter 22.

D1/D2 RECEPTOR AGONISTS: ERGOT ALKALOIDS. Ergot derivatives act on several different neurotransmitter systems, including DA, 5HT, and adrenergic receptors.Bromocriptine (PARLODEL) and pergolide (PERMAX) have been used for the treatment of PD; however, their use is associated with risk for serious cardiac complications.

Bromocriptine is a potent D2 receptor agonist and a weak D1 antagonist. Pergolide is a partial agonist of D1 receptors and a strong D2-family agonist with high affinity for both D2 and D3 receptor subtypes. Ergot derivatives are commonly reported to cause unpleasant side effects, including nausea, dizziness, and hallucinations. Pergolide was removed from the U.S. market as therapy for PD after as it was associated with an increased risk for valvular heart disease.

ERGOT ALKALOIDS IN THE TREATMENT OF HYPERPROLACTINEMIA. The ergot-based DA agonists bromocriptine and cabergoline (DOSTINEX) are used in the treatment of hyperprolactinemia. Both are strong agonists at D2 receptors, with lower affinity for D1, 5HT, and α adrenergic receptors; both activate D2 receptors in the pituitary to reduce prolactin secretion. The risk of valvular heart disease in ergot therapy is not associated with the lower doses used in treating hyperprolactinemia. The use of bromocriptine and cabergoline in the management of hyperprolactinemia is described in Chapter 38.

D1/D2 RECEPTOR AGONISTS (NON-ERGOT ALKALOIDS). Apomorphine (APOKYN) is approved for the treatment of PD. Apomorphine binds with the order of potency D4 > D2 > D3 > D5, and with lower affinity to D1, α adrenergic, 5HT1A, and 5HT2 receptors. Apomorphine is most commonly used in combination with L-dopa to surmount the sudden “off” periods that can occur after long-term L-dopa treatment.

Rotigotine is offered in a transdermal patch (NEUPRO) that is approved for the treatment of PD and restless leg syndrome (RLS). Rotigotine preferentially binds to D2 and D3 receptors and has much lower affinity for D1 receptors. In addition, rotigotine is an agonist at 5HT1A and 5HT2 receptors, and an antagonist at α2 adrenergic receptors.

D2 FAMILY RECEPTOR AGONISTS (NON-ERGOT ALKALOIDS). Pramipexole (MIRAPEX) and ropinirole (REQUIP) are agonists at all D2 family receptors and also bind with highest affinity to the D3 receptor subtype. In addition to its utility in the treatment of PD, ropinirole has also been FDA-approved as pharmacotherapy for RLS. Mild dopaminergic hypofunction has been noted in patients with RLS.

D4 RECEPTOR AGONISTS AND ADHD. The D4 receptor is significant in ADHD; there is an association between the 7-repeat D4 VNTR variant and patients with ADHD. D4-selective agonists show significant promise for the next generation of ADHD therapy.


As with the DA receptor agonists, a lack of subtype-specific antagonists has limited the therapeutic utility of this group of ligands. Selective antagonists are now available as experimental tools (see Table 13–6). Many subtype-selective antagonists are in early stages of preclinical testing for therapeutic utility.

DA RECEPTOR ANTAGONISTS AND SCHIZOPHRENIA. DA receptor antagonists are a mainstay in the pharmacotherapy of schizophrenia. While many neurotransmitter systems likely contribute to the complex pathology of schizophrenia (see Chapter 16), DA dysfunction is considered the basis of this disorder. The DA hypothesis of schizophrenia has its origins in the characteristics of the drugs used to treat this disorder: All antipsychotic compounds used clinically have high affinity for DA receptors. The drugs used to treat schizophrenia are classified as either typical (first generation) antipsychotics or atypical antipsychotics (characterized by lack of extrapyramidal side effects). Most atypical antipsychotics are low affinity antagonists at the D2 receptor and high affinity antagonists or inverse agonists at the 5HT2A receptor. Some of the newer drugs in development do not fit into this classification scheme, including the D1-selective agonist, dihydrexidine.


Typical Antipsychotics. The first antipsychotic drug used to treat schizophrenia was chlorpromazine (THORAZINE). Its antipsychotic properties were attributed to its antagonism of DA receptors, especially the D2 receptor. More D2-selective ligands were developed to improve the antipsychotic properties, including haloperidol (HALDOL) and similar D2-selective drugs (see Chapter 16).

Atypical Antipsychotics. This class of antipsychotic drugs originated with clozapine (FAZACLO). The lack of extrapyramidal side effects has been attributed to a much lower affinity for the D2 receptor compared to the typical antipsychotics. Atypical agents are also less likely to stimulate prolactin production. Clozapine has higher affinity for the D4 receptor. Most atypical antipsychotics are low affinity antagonists at the D2 receptor and high affinity antagonists or inverse agonists at the 5HT2A receptor.

Aripiprazole (ABILIFY) has fewer side effects than earlier atypical antipsychotics. Aripiprazole diverges from the traditional atypical profile in 2 ways: first, it has higher affinity for D2 receptors than for 5HT2A receptors; second, it is a partial agonist at D2 receptors. As a partial agonist, aripiprazole may diminish the subcortical DA hyperfunction by competing with DA for receptor binding, while simultaneously enhancing dopaminergic neurotransmission in the prefrontal cortex by acting as an agonist. The dual mechanism afforded by a partial agonist may thus treat both the positive and negative symptoms associated with schizophrenia.

D3 RECEPTOR ANTAGONISTS AND DRUG ADDICTION. D3-selective antagonists show promise in the treatment of addiction.