Serotonin Receptors

In 1957, the existence of two separate 5-HT receptors was first proposed primarily because of the opposing phenomenon this neurotransmitter produces in reference to cholinergic mediation of smooth muscle contraction (Gaddum and Picarelli 1957). Today, through the use of more precise molecular cloning and pharmacological and biochemical studies, seven distinct 5-HT receptor families have been identified (5-HT1-7), many of which contain several subtypes. With the exception of the 5-HT3 receptor, which is an excitatory ionotropic receptor, all the other 5-HT receptors are GPCRs. The 5-HT1A,B,D,E,F receptors are negatively coupled to adenylyl cyclase, the 5-HT2A,B,C subtypes are positively coupled to PLC, and the 5-HT4, 5-HT5, 5-HT6, and 5-HT7 subtypes are positively coupled to adenylyl cyclase (see Figure 1-3B) (Humphrey et al. 1993).

5-HT1 receptors

5-HT1A receptors are found in particularly high density in several limbic structures, including the hippocampus, septum, amygdala, and entorhinal cortex, as well as on serotonergic neuron cell bodies, where they serve as autoreceptors regulating 5-HT neuronal firing rates (Blier et al. 1998; Cooper et al. 2001; Pazos and Palacios 1985). The highest density of labeling is found in the DR, with lower densities observed in the remaining raphe nuclei (Pazos and Palacios 1985). The density and mRNA expression of 5-HT1A receptors appear insensitive to reductions in 5-HT transmission associated with lesioning the raphe or administering the serotonin-depleting agent p-chlorophenylalanine (PCPA). Similarly, elevation of 5-HT transmission resulting from chronic administration of an SSRI or monoamine oxidase inhibitor (MAOI) does not consistently alter 5-HT1A receptor density or mRNA in the cortex, hippocampus, amygdala, or hypothalamus. In contrast to the insensitivity to 5-HT, 5-HTj.a receptor density is downregulated by adrenal steroids. Postsynaptic 5-HTj.a receptor gene expression is under tonic inhibition by adrenal steroids in the hippocampus and some other regions. Thus, in rodents, hippocampal 5-HT1A receptor mRNA expression is increased by adrenalectomy and decreased by corticosterone administration or chronic stress. The stress-induced downregulation of 5-HT1A receptor expression is prevented by adrenalectomy. Mineralocorticoid receptor stimulation has the most potent effect on downregulating 5-HTj.a receptors, although glucocorticoid receptor stimulation also contributes to this effect.

In addition to being expressed on neurons, postsynaptic 5-HTj.a receptors are also abundantly expressed by astrocytes and some other glia (Whitaker-Azmitia et al. 1990) (see Figure 1-7 later in this chapter). Stimulation of astrocyte-based 5-HTj.a sites causes astrocytes to acquire a more mature morphology and to release the trophic factor S-10013, which promotes growth and arborization of serotonergic axons. Administration of 5~HTia receptor antagonists, antibodies to S-100&, or agents that deplete 5-HT produces similar losses of dendrites, spines, and/or synapses in adult and developing animals—effects that are blocked by administration of 5-HTj.a receptor agonists or SSRIs. These observations have led to the hypothesis that a reduction of 5-HT1A receptor function may play an important role in mood disorders that are known to be associated with glial reductions (Manji et al. 2001). The use of conditional knockouts of the 5-HTj.a receptor, in which gene expression is altered only in particular anatomical regions and/or during particular times, has illustrated the caution necessary in attributing complex behaviors to simple "too much" or "too little" neurotransmitter/receptor hypotheses. Using a knockout/rescue approach with regional and temporal specificity, Gross et al. (2002) demonstrated that the anxiety-related effect of the 5-HT1A receptor knockout was actually developmental. Specifically, expression limited to the hippocampus and cortex during early postnatal development was sufficient to counteract the anxious phenotype of the mutant, even though the receptor was still absent in adulthood (Gross et al. 2002). As is discussed in the chapters on antidepressants and axiolytics (see Chapters 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26), there is growing interest in the observation that antidepressants enhance hippocampal neurogenesis (Duman 2002; Malberg et al. 2000). It is noteworthy that preliminary data suggest that 5-HT1A receptor activation is required for SSRI-induced hippocampal neurogenesis in mice (Jacobs et al. 2000). Altering 5-HT levels with the SSRI fluoxetine does not affect division of stem cells in the dentate gyrus, but rather increases symmetric divisions of an early progenitor cell class that exists after stem cell division (Encinas et al. 2006).

5-HT1A receptors are now known to utilize a variety of signaling mechanisms to bring about their effects in distinct brain areas. Thus, somatodendritic 5-HT1A receptors appear to inhibit the firing of serotonergic neurons by opening a K+ channel through a pertussis toxin-sensitive G protein (likely Go, discussed later in the section on G proteins) (Andrade et al. 1986), as well as by reducing cAMP levels. Postsynaptic 5-HT1A receptors appear to exert many of their effects by inhibiting adenylyl cyclase via Gi (De Vivo and Maayani 1990) but have also been demonstrated to potentiate the activity of certain adenylyl cyclases (Bourne and Nicoll 1993) and to stimulate inositol-1,4,5-triphosphate (IP3) production and activate PKC (Y. F. Liu and Albert 1991).

5-HTid receptors are virtually absent in the rodent but have been detected in guinea pig and man (Bruinvels et al. 1993). On the basis of an approximately 74% sequence homology, it has been proposed that 5-HTxb receptors are the rodent homolog of 5-HTj.d receptors (see Saxena et al. 1998). Furthermore, the distribution of the 5-HTj.d receptors in guinea pig and man is roughly equivalent to that of the 5-HTj.b receptors in the rat (Bruinvels et al. 1993). Both 5-HT1B and 5-HT1D receptors have been proposed to represent the major nerve terminal autoreceptors regulating the amount of 5-HT released per nerve impulse (Pineyro and Blier 1999) (see Figure 1-3B). Like 5-HTj.a receptors, 5-HTj.b and 5-HTj.d receptors inhibit cAMP formation and stimulate IP3 production and activate PKC (Schoeffter and Bobirnac 1995). As we discuss later, this appears to be the case for many receptors coupled to Gi and Go (see Table 1-1). The a subunits of the G protein (ctj and K©) inhibit adenylyl cyclase and regulate ion channels, respectively, whereas the 13? subunits activate PLC isozymes to stimulate IP3 production and activate PKC.

Finally, it should be noted that the 5-HT1C receptor classification has been revoked, as these receptors have structural and transductional similarities to the 5-HT2 receptor class (Hoyer et al. 1986; Saxena et al. 1998).

5-HT2 receptors

There are three subtypes of 5-HT2 receptors: 5-HT2A, 5-HT2B, and 5-HT2C. The highest level of 5-HT2A binding sites and mRNA for these receptors exists in the cortex, and these receptors have been implicated in the psychotomimetic effects of agents like lysergic acid diethylamide (LSD) (for a review, see Aghajanian and Marek 1999). In addition, lesioning of 5-HT neurons with 5,7-DHT does not reduce the 5-HT2 receptor density reported in brain regions (Hoyer et al. 1986), indicating that these receptors are primarily (if not exclusively) postsynaptic. Autoradiography performed with the potent and selective radioligand [3H]MDL 100,907 has localized 5-HT2A receptors to many similar brain regions in the rat and primate brain (Lopez-Gimenez et al. 1997). Recent experiments show that mice expressing 5-HT2A receptors only in the frontal cortex have conserved receptor signaling and behavioral responses to hallucinogenic drugs similar to those of wild-type littermates, suggestive of cortical importance (Gonzalez-Maeso et al. 2007). Competition studies with other radioligands (Westphal and Sanders-Bush 1994) and their mRNA distribution indicate that 5-HT2C receptors are considerably widespread throughout the CNS, with the highest density in the choroid plexus (Hoffman and Mezey 1989). 5-HT2B receptors are detected sparingly in the brain and are more prominently located in the fundus, gut, kidney, lungs, and heart (Hoyer et al. 1986).

Several antidepressants (e.g., mianserin, mirtazapine) and antipsychotics (e.g., clozapine) bind to 5-HT2 receptors, raising the possibility that blockade of 5-HT2 receptors may play an important role in the therapeutic efficacy of these agents. Indeed, a leading hypothesis concerning the mechanism of action of atypical antipsychotic agents suggests that the ratio of D2/5-HT2 blockade confers "atypicality" properties on many currently available antipsychotic agents (Meltzer 2002). Evidence from animal experiments in which cortical 5-HT2A receptors are disrupted indicates a specific role of these receptors in modulation of conflict anxiety without affecting fear conditioning and depression-like behaviors (Weisstaub et al. 2006). Furthermore, chronic administration of many antidepressants downregulates 5-HT2 receptors, suggesting that this effect may be important for their efficacy (J. A. Scott and Crews 1986); however, chronic electroconvulsive shock (ECS) appears to upregulate 5-HT2 expression, precluding a simple mechanism for antidepressant efficacy. The obesity seen in 5-HT2C knockout animals suggests that in addition to histamine receptor blockade, 5-HT2C blockade may play a role in the weight gain observed with certain psychotropic agents; this is an area of considerable current research. In keeping, recent evidence suggests that the weight gain "orexigenic" properties of atypical antipsychotics are likely due to potent activation of hypothalamic AMP-kinase through histamine! (H1) receptors (Kim et al. 2007). The regulation of 5-HT2 receptors is intriguing, as not only is it important in psychiatric disorders and therapeutic benefit, but both agonists and antagonists appear to cause an internalization of the receptor. Moreover, emerging data suggest that mRNA editing may play an important role in regulating the levels and activity of this receptor subtype (Niswender et al. 1998). All of the 5-HT2 receptor subtypes are linked to the phosphoinositide signaling system, and their activation produces IP3 and diacylglycerol (DAG), via PLC activation (Conn and Sanders-Bush 1987) (see Figure 1-3B).

An exciting recent pharmacogenetic investigation searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and prospectively assessed (McMahon et al. 2006). In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. A significant and reproducible association was detected between treatment outcome and a marker in HTR2A (P = 1 x 10-6 to 3.7 x 10-5 in the total sample). The "A" allele (associated with better outcome) was six times more frequent in white than in black participants, for whom treatment was also less effective in this sample (McMahon et al. 2006). The "A" allele may thus contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.

5-HT3-7 receptors

Unlike the other 5-HT receptors, 5-HT3 receptors are ligand-gated ion channels capable of mediating fast synaptic responses (see Figure 1-3B). The cis-trans isomerization and molecular rearrangement at proline 8 is the structural mechanism that opens the 5-HT3 receptor protein pore (Lummis et al. 2005). 5-HT3 receptors are present in multiple brain areas, including the hippocampus, dorsal motor nucleus of the solitary tract, and area postrema (Laporte et al. 1992). The 5-HT3 receptor is effectively modulated by a variety of compounds, such as alcohols and anesthetics, and antagonists against this receptor are used as effective antiemetics in patients who are undergoing chemotherapy (e.g., ondansetron). 5-HT4, 5-HT6, and 5-HT7 are GPCRs that are preferentially coupled to Gs and activate adenylyl cyclases (see Figure 1-3B). 5-HT4 receptors are able to modulate the release of monoamines and GABA in the brain. 5-HT5 receptors are located in the hypothalamus, hippocampus, corpus callosum, cerebral ventricles, and glia (Hoyer et al. 2002). The 5-HTsa receptor is negatively coupled to adenylyl cyclase, whereas the 5-HTsb receptor does not involve cAMP accumulation or phosphoinositide turnover. 5-HT6 receptors are located in the striatum, amygdala, nucleus accumbens, hippocampus, cortex, and olfactory tubercle (Hoyer et al. 2002). Of interest, many antipsychotic agents and antidepressants have high affinity for 5-HT6 receptors and act as antagonists at this receptor. 5-HT7 receptors have been localized to the cerebral cortex, medial thalamic nuclei, substantia nigra, central gray, and dorsal raphe nucleus (Hoyer et al. 2002). It appears that chronic treatment with antidepressants is able to downregulate this receptor, whereas acute stress has been reported to alter 5-HT7 expression (Sleight et al. 1995; Yau et al. 2001).

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