Kaplan + Sadock's Synopsis of Psychiatry, 11e

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1.4 Neurophysiology and Neurochemistry

of activation of monoaminergic receptors. Reuptake is also a primary mechanism for replenishing terminal monoamine neu- rotransmitter stores. Moreover, transporters serve as molecular targets for a number of antidepressant drugs, psychostimulants, and monoaminergic neurotoxins. Whereas transporter mol- ecules for serotonin (SERT), dopamine (DAT), and norepineph- rine (NET) have been well characterized, transporters selective for histamine and epinephrine have not been demonstrated. Among drugs of abuse, cocaine binds with high affinity to all three known monoamine transporters, although the stimulant properties of the drug have been attributed primarily to its blockade of DAT. This view has been recently supported by the absence of cocaine-induced locomotor stimulation in a strain of mutant mice engineered to lack this molecule. In fact, psychostimulants produce a paradoxical locomotor suppression in these animals that has been attributed to their blockade of the serotonin transporter. The rewarding properties of cocaine have also been attributed primarily to dopamine transporter inhibition, although other targets mediate these effects as well, since cocaine still has reward- ing effects in mice lacking the dopamine transporter. It appears that serotonergic as well as dopaminergic mechanisms may be involved. Transporters may also provide routes that allow neurotoxins to enter and damage monoaminergic neurons; examples include the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the serotonergic neurotoxin MDMA. Vesicular Monoamine Transporter In addition to the reuptake of monoamines into the presynaptic nerve terminal, a second transport process serves to concentrate

and store monoamines within synaptic vesicles. The transport and storage of monoamines in vesicles may serve several pur- poses: (1) to enable the regulated release of transmitter under appropriate physiological stimulation, (2) to protect mono- amines from degradation by MAO, and (3) to protect neurons from the toxic effects of free radicals produced by the oxida- tion of cytoplasmic monoamines. In contrast with the plasma membrane transporters, a single type of vesicular monoamine transporter is believed to mediate the uptake of monoamines into synaptic vesicles within the brain. Consistent with this, blockade of this vesicular monoamine transporter by the antihy- pertensive drug reserpine (Serpasil) has been found to deplete brain levels of serotonin, norepinephrine, and dopamine and to increase the risk of suicide and affective dysfunction. Receptors Ultimately, the effects of monoamines on CNS function and behavior depend on their interactions with receptor molecules. The binding of monoamines to these plasma membrane proteins initiates a series of intracellular events that modulate neuronal excitability. Unlike the transporters, multiple receptor subtypes exist for each monoamine neurotransmitter (Table 1.4-1). Serotonin Receptors The 5-hydroxytryptophan type 1 (5-HT 1 ) receptors comprise the largest serotonin receptor subfamily, with human subtypes Antagonists used as antiallergenic and anti-inflammatory agents, also promote sedation, weight gain Antagonists used to treat peptic ulcers, GI reflux, and GI bleeding Antagonists proposed to treat sleep disorders, obesity, dementia Possible role for antagonists as anti-inflammatory agents Antagonists used in management of prostate disease Agonists sedative and hypertensive Regulation of cardiac function, antagonists may be anxiolytic Agonists used as bronchiodilators Possible role for agonists to treat obesity Partial agonists (buspirone) anxiolytic, role in hippocampal neurogenesis; 5-HT1B/D antagonists used as antimigraine agents (triptans) 2A antagonists → antipsychotic effects, 2A agonists → hallucinogens; 2B agonism → cardiac valvulopathy 2C agonists → under development as anorexigens, antiepileptics? Agonists (ondansetron) are antiemetics. Proposed Clinical Relevance

Table 1.4-1 Monoamine Receptors: Overview

Transmitter

Subtype

Primary Effector

↑ PI Turnover ↑ AC ↓ AC ↓ AC ↑ PI Turnover ↓ AC ↑ AC ↑ AC ↑ AC ↓ AC, ↑ GIRK currents ↑ PI Turnover

Histamine

H 1 H 2 H 3 H 4

a 1A,B,D a 2A,B,C

Epinephrine/ Norepi- nephrine

b 1 b 2 b 3

Serotonergic 5HT 1A,1B,1D,1E,1F 5-HT 2A , 5-HT 2B , 5-HT 2C

Na + channel, cell membrane depolarization

5-HT 3

↑ AC ↑ AC

5-HT 4 5-HT 5

Partial agonists used in IBS (tegaserod) Unclear Unclear Antagonists may have antidepressant potential

, 5-HT 6

, 5-HT 7

↑ AC ↓ AC

-like family (D 1 , D 5 ) -like family (D 2 , D 3 , D 4 )

D 1 agonists used in Parkinson’s disease D 2 antagonists are antipsychotics (e.g., haloperidol) D 3 agonists used in Parkinson’s disease, restless legs syndrome (e.g., pramipexole)

Dopaminergic D 1

D 2

From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:71.