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The 5-HT and 5-HT receptors are major determinants of the activity of serotonergic cells and of serotonin, 5-hydroxytrytamine (5-HT), release because of their role as somatodendritic and terminal autoreceptors, respectively. As such, their physiological role is to limit unwanted increases in serotonergic activity and 5-HT release and play an important role in the action of drugs used to treat psychiatric diseases, like anxiety or depression. Additionally, those receptors are located postsynaptically to serotonergic axons, in cortical, limbic, and hypothalamic areas (5-HT receptors), and in the basal ganglia (5-HT receptors). 5-HT, acting on those postsynaptic receptors, is involved in cognition, mood, impulse control, and motor functions by modulating the activity of different neuronal types and inhibiting the release of various neurotransmitters, such as glutamate, GABA, acetylcholine, and dopamine.

The feature that distinguishes psychedelic agents from some other classes of psychotomimetic drug is their capacity reliably to induce states of altered perception, thought, and feeling without producing marked disorientation or delirium. There is an accumulation of evidence that the 5-hydroxytryptamine (5-HT) subtype of serotonin (5-HT) receptor mediates the actions of psychedelic hallucinogens. The majority of 5-HT receptors are found in the cerebral cortex. Here, we explore the electrophysiology of 5-HT receptors in the prefrontal cortex and their relevance for normal brain function and for hallucinogen and atypical antipsychotic drug actions.

The long-term use of certain drugs, such as fenfluramine, dihydroergotamine, and pergolide, has been associated with an increased risk for valvular heart disease (VHD) and pulmonary hypertension (PH). Recent investigations have implicated the 5-hydroxytryptamine (5-HT) receptor in the pathogenesis of VHD and PH. Specifically, the activation of 5-HT receptors by VHD- and PH-associated drugs leads to proliferative lesions in the valves of the heart and the pulmonary arterial wall, respectively. For heart valve interstitial cells in vitro, mitotic responses to fenfluramine and its metabolite norfenfluramine have been demonstrated and shown to be mediated almost exclusively by 5-HT receptor activation. Furthermore, the activity at recombinant 5-HT receptors appears sufficient to predict the ability of a drug to induce mitosis in heart valve interstitial cells in vitro and, likely, VHD-inducing potential in humans.

In mice, hypoxia-induced smooth muscle cell proliferation that gives rise to pulmonary hypertension has been shown genetically and pharmacologically to require 5-HT receptors. Additionally, hypoxia-induced pulmonary artery remodeling in mice is significantly exacerbated by prolonged treatment with the PH-associated drug fenfluramine, likely the result of high plasma levels of the metabolite norfenfluramine, a more potent and efficacious 5-HT receptor agonist than the parent compound. Thus, drug-induced PH and VHD both seem to result from activation ofmitogenic 5-HT receptors by the parent compound and/or an active metabolite. As such, current and novel pharmaceuticals and their metabolites that are 5-HT receptor agonists should not be used in humans because of their likelihood to induce fenfluraminelike VHD and PH.

The 5-HT receptor is a member of the Cys-loop neurotransmitter-gated ion channel family. It has five symmetrically placed subunits surrounding a central ion-conducting pore. Each subunit consists of an extracellular N-terminal ligand-binding domain, and C-terminal domain containing four transmembrane α helices (M1–M4); M2 lines the channel and controls ion selectivity and gating. A long intracellular loop between M3 and M4 is responsible for channel conductance and intracellular modulation. In this chapter we look at each of these regions, exploring the structure of the ligand binding site and its pharmacophore model, the importance of M2 and the complex modulatory mechanisms within the intracellular region that underlie the regulation, assembly, targeting, and trafficking of the 5-HT receptor.

Serotonin (5-hydroxytryptamine) 5-HT and 5-HT receptors are widely distributed in central and peripheral nervous systems, where they participate in many physiological functions. With the availability of selective 5-HT and 5-HT receptor ligands and the molecular identification of 5-HT and 5-HT receptors, the involvement of these receptors in cognitive processes has been largely suggested. This chapter reviews recent data on the brain distribution and pharmacological properties of 5-HT receptor subunits and 5-HT receptor C-terminal splice variants. The potential use of 5-HT and 5-HT receptor ligands as therapeutical agents influencing the cholinergic system and the amyloid precursor protein processing for the treatment of Alzheimer’s disease and other dementia are discussed.

Serotonin receptors of the 5-HT and 5-HT subtypes couple to heterotrimeric G proteins of the Gα type and signal their electrophysiological effects by stimulating adenylate cyclase, increasing intracellular cAMP, and activating protein kinase A (PKA). These receptors, like many other receptors coupling to Gα, modulate three classic currents in excitable tissues: the hyperpolarization-activated cation current , a calcium-activated potassium current generally known as , and the L-type calcium current. 5-HT and 5-HT receptors inhibit and facilitate L-type calcium currents by increasing cAMP and activating PKA. However, these receptors facilitate by a direct effect of cAMP that is independent of PKA. Other currents might also contribute to the postsynaptic effects signaled by these receptors in specific neuronal cell types. Little is known at the present time regarding the electrophysiological responses signaled by the activation of 5-HT receptors. A key remaining question is how these receptors and currents are regulated by synaptically released serotonin in a physiological context.

Cloned in the human in 1996 and localized to human chromosome 1p35–p36 (), the 5-hydroxytryptamine 5-ht receptor was initially discovered in the rat central nervous system (CNS) using methods from molecular biology (,). A 440-amino-acid polypeptide, the human receptor exhibits 89% homology to that of the resequenced rat receptor (). The almost exclusive distribution of the receptor in the rat CNS (but refs. and ), the high abundance of receptor expression in limbic, cortical, and striatal brain regions (–), as well as the high affinity of tricyclic antidepressants and atypical antipsychotic drugs for this receptor () have prompted extensive investigation into the role of this receptor in psychiatric disorders. To date, the receptor has been implicated in affective disorder (–), anxiety (,), epilepsy (), and regulation of food consumption (,), with the most compelling evidence suggesting a role in cognitive function. Since the role in cognitive function with respect to Alzheimer’s disease has received the most attention (reviewed in ref. ), herein we have chosen to focus more specifically on the biological rationale for the treatment of cognitive deficits in schizophrenia and we provide recommendations for the evaluation of the potential of 5-ht receptor antagonists in this indication.

The 5-hydroxytryptamine (5-HT) receptor was among a group of 5-HT receptors discovered through targeted cloning strategies 13 yr ago. It is a seven-transmembrane-domain G protein-coupled receptor positively linked to adenylyl cyclase. The distributions of 5-HT receptor mRNA, immunolabeling, and radioligand binding show strong similarities, with the highest densities found in the thalamus and hypothalamus, but with significant presence also in the hippocampus and cortex. The recent availability of selective antagonists and knockout mice strains has dramatically increased our knowledge about this receptor. Together with unselective agonists, these new tools have revealed the 5-HT receptor distribution and function in more detail. Important functional roles have been established for the 5-HT receptor in thermoregulation, circadian rhythm, learning and memory, hippocampal signaling, and sleep. The 5-HT receptor is possibly also involved in other psychiatric and neurological disorders, such as schizophrenia, epilepsy, and migraine. Hypotheses driving current research strongly indicate an involvement in mood regulation, suggesting the 5-HT receptor as a putative target in the treatment of depression.

To better understand the roles of individual serotonin receptor subtypes in modulating the neural circuitry of complex behavior, a number of groups have generated “knockout” mice lacking individual serotonin receptor subtypes over the last decade. Overall, 10 (at least 14) serotonin receptor subtypes have been knocked out in mice, as well as several genes that regulate the development and activity of serotonin neurons (e.g., Pet-1, the serotonin transporter, and tryptophan hydroxylase). We review these studies, discuss their relevance to the pathophysiology of neuropsychiatric disorders, and close with a perspective on where the field may head in the future.

Recent advances in molecular technology have made possible the generation of mice lacking specific serotonin (5-hydroxytryptamine [5-HT]) receptors or regulatory targets governing 5-HT neurotransmission. The goal of this review is to summarize the effects of deleting serotonin-related genes on certain behavioral and neurochemical outcomes in mice. The influence of various mutations of 5-HT receptors and the 5-HT transporter on behaviors related to anxiety and depression is reviewed. In addition, changes in transmission of 5-HT and other neuro-transmitters, measured principally by in vivo microdialysis, produced by genetic mutations of 5-HT targets is summarized. Most of the literature refers to mutations of genes for the 5-HT receptor, 5-HT receptor, and the 5-HT transporter (5-HTT) and comprise the largest part of this review. However, data regarding other murine knockouts were included where available. Although some phenotypes might be expressed as a result of developmental compensation, comparison with pharmacological antagonists has been helpful in distinguishing a functional role for the absence of the targeted receptor. Advanced techniques, involving evaluation of the effects of inducible gene deletion, gene rescue, or selective topographical expression of receptors in the contribution of 5-HT receptors to mood disorders, are discussed.