Central Nervous System

A multitude of brain functions are influenced by 5-HT, including sleep, cognition, sensory perception, motor activity, temperature regulation, nociception, mood, appetite, sexual behavior, and hormone secretion. All of the cloned 5-HT receptors are expressed in the brain, often in overlapping domains. The principal cell bodies of 5-HT neurons are located in raphe nuclei of the brain-stem and project throughout the brain and spinal cord. In addition to being released at discrete synapses, release of serotonin also seems to occur at sites of axonal swelling, termed varicosities, which do not form distinct synaptic contacts. 5-HT 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 12). Serotonergic nerve terminals contain all of the proteins needed to synthesize 5-HT from l-tryptophan (Figure 11—1). Newly formed 5-HT is rapidly accumulated in synaptic vesicles, where it is protected from MAO. 5-HT released by nerve-impulse flow is reaccumulated into the presynaptic terminal by the 5-HT transporter, SERT (see Chapter 2); thus, reuptake terminates the neurotransmitter action of 5-HT. 5-HT taken up by nonneuronal cells is destroyed by MAO. 5-HT has direct excitatory and inhibitory actions (Table 11-3), which may occur in the same preparation, but with distinct temporal patterns.

Behavior Sleep-Wake Cycle

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

194 SECTION II Drugs Acting at Synaptic and Neuroeffector Junctional Sites Table 11-3

Electrophysiological Effects of 5-HT Receptors

Subtype Response

Increase K+ conductance; hyperpolarization Decrease K+ conductance; slow depolarization Gating of Na+, K+; fast depolarization Decrease K+ conductance; slow depolarization

Aggression and Impulsivity

Studies in laboratory animals and in human beings suggest that 5-HT serves a critical role in aggression and impulsivity. Low 5-HIAA is associated with violent suicidal acts, but not with suicidal ideation per se. Knockout mice lacking the 5-HT1B receptor exhibit extreme aggression, suggesting either a role for 5-HT1B 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. Laboratory genetic studies add credence to the proposition that abnormalities in 5-HT are related to aggressive behaviors.

Anxiety and Depression

A mechanism for altering synaptic availability of 5-HT is inhibition of presynaptic reaccumulation of neuronally released 5-HT. Selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine [prozac]) potentiate and prolong the action of 5-HT released by neuronal activity. Effects of 5-HT-active drugs, like the SSRIs, in anxiety and depressive disorders strongly suggest an effect of 5-HT in the neurochemical mediation of these disorders. SSRIs are the most widely used treatment for endogenous depression (see Chapter 17).


Two halogenated amphetamines, fenfluramine and dexfenfluramine, have been used to reduce appetite; these drugs were withdrawn from the U.S. market after reports of cardiac toxicity associated with their use. The mechanism of action of this class of drugs is controversial. A profound reduction in levels of 5-HT in the brain lasts for weeks and is accompanied by a loss of proteins (5-HT transporter and tryptophan hydroxylase) selectively localized in 5-HT neurons, suggesting that the halogenated amphetamines have a neurotoxic action, although neuroanatomical signs of neuronal death are not readily apparent.

Sibutramine (meridia), an inhibitor of the reuptake of 5-HT, NE, and DA, is used as an appetite suppressant in the management of obesity; two active metabolites probably account for sibu-tramine's therapeutic effects. Whether effects on a single neurotransmitter system are primarily responsible for sibutramine's effects in obese patients is unclear.


Direct-acting 5-HT receptor agonists have diverse chemical structures and diverse pharmacological properties (Table 11-4), not surprising considering the plethora of 5-HT receptor subtypes. 5-HT1A receptor-selective agonists have helped elucidate the functions of this receptor in the brain and have resulted in a new class of antianxiety drugs including buspirone, gepirone, and ipsapirone (see Chapter 17). 5-HT1D receptor-selective agonists (e.g., sumatriptan) cause constriction of intracranial blood vessels and are used for treatment of acute migraine attacks (see below). A number of 5-HT4 receptor-selective agonists have been developed or are being developed for the treatment of disorders of the GI tract (see Chapter 37).

5-HT RECEPTOR AGONISTS AND MIGRAINE Migraine headaches afflict 10-20% of the population in the U.S., producing a morbidity estimated at 64 million missed workdays/year. Although migraine is a specific neurological syndrome, manifestations vary widely: migraine without aura (common migraine); migraine with aura (classic migraine), which includes subclasses of migraine with typical aura, migraine with prolonged aura, migraine without headache, and migraine

5-HT1 5-HT12 5-HT3


Serotonergic Drugs: Primary Actions and Clinical Uses



Drug Examples

Clinical Disorder


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