A review of central 5-HT receptors and their function

It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).

Structure and function of the brain serotonin system.

Part two of this three-part series commences with anomalous dominance and special talents. Part one appears in a previous issue of theArchives. 1 ANOMALOUS DOMINANCE AND SPECIAL TALENTS According to our hypothesis, slowed growth within certain zones of the left hemisphere is likely to result in enlargement of other cortical regions, in particular, the homologous contralateral area, but also adjacent unfaffected regions. The influences that favor anomalous dominance may thus favor talents associated with superior development of certain regions either in the right hemisphere or in adjacent parts of the left hemisphere. Even with excessive retardation of growth and the resultant migration abnormalities and learning disorders (LD), high talents may exist as a result of compensatory enlargement of other cortical regions. Several types of data are in concordance with these conclusions. Several studies have claimed that the average level of spatial talents is higher in male subiects. 2 Hier

https://jamanetwork.com/journals/jamaneurology/articlepdf/584161/archneur_42_5_008.pdf

Cerebral lateralization. Biological mechanisms, associations, and pathology: II. A hypothesis and a program for research.

Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors.

There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effectors by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin2A (5-HT2A) and 5-HT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.

Effector pathway-dependent relative efficacy at serotonin type 2a and 2c receptors : evidence for agonist-directed trafficking of receptor stimulus

The inhibition of forskolin-stimulated adenylate cyclase activity by 5-hydroxytryptamine (5-HT) receptor agonists was measured in guinea pig and rat hippocampal membranes. The results were consistent with the inhibition being mediated by a single, homogeneous population of receptors. In guinea pig hippocampal membranes 8-hydroxy-2-(di-n-propylamino)tetralin, d-lysergic acid diethylamide, 5-HT and buspirone were potent in inhibiting forskolin-stimulated adenylate cyclase activity, with EC50 values of 18, 24, 53 and 146 nM, respectively. Spiperone (Kb = 26 nM) and methiothepin (Kb = 13 nM) were potent competitive antagonists at this receptor whereas ketanserin, a high affinity 5-HT2 receptor ligand, and ICS 205-930, a high affinity peripheral neuronal (M) receptor ligand, were not. In rat hippocampal membranes, 8-hydroxy-2-(di-n-propylamino)tetralin, d-lysergic acid diethylamide, 5-HT and buspirone were potent agonists and exhibited the same rank order of potency as in guinea pig hippocampal membranes. The maximal percentage of inhibition by buspirone was significantly less than the maximal percentage of inhibition by 5-HT in rat membranes, suggesting that it is a partial agonist at this receptor, with an intrinsic activity relative to 5-HT of 0.5. The concentration-response data show that the inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes is mediated by a receptor with the characteristics of the 5-HT1A binding site. We propose that the inhibition of adenylate cyclase activity is a functional correlate of this binding site. This response is suitable for measuring activities and affinities of drugs acting at 5-HT1A receptors.

Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes.

THE observation that cyproheptadine is a competitive antagonist of the histamine H2 receptor linked to adenylate cyclase in brain1 suggested that the chemically similar tricyclic antidepressant drugs may also have this activity. To test this hypothesis, four tricyclic antidepressants—representing four different structural types—were tested on the H2 receptor linked to adenylate cyclase in homogenates of the guinea pig hippocampus and cortex. Both dimaprit and histamine were used as agonists. Dimaprit has potent activity at the H2 receptor with negligible activity at the H1 receptor, that is, less than 0.0001% of that of histamine2.

Tricyclic antidepressant drugs block histamine H2 receptor in brain.

Interest in the physiological functions of 5-hydroxytryptamine (5-HT; seroto­ nin) has increased steadily since its discovery in the intestine (1) and in serum (2). Its identification in brain in the early 1950s (3), followed a decade later by the initial studies of its distribution in brain by histofluorescence (4), stimulated investigations of the possible behavioral functions of this in­ dolealkylamine. In addition to studies of its function in brain, a steady stream of investigations have described its possible functions in the periphery, particularly in the gastrointestinal tract (see 5) and, more recently, in the cardiovascular system (see 6). Indeed, the initial suggestion that there might be more than one type of receptor for 5-HT came from experiments on the isolated guinea pig ileum. Gaddum & Picarelli (7) demonstrated that only a portion of its contractile response to 5-HT could be blocked by high con­ centrations of morphine but that the remainder of the response could be

Saul Maayani

Papers

Effector pathway-dependent relative efficacy at serotonin type 2a and 2c receptors : evidence for agonist-directed trafficking of receptor stimulus

Characterization of the 5-hydroxytryptamine1a receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes.

Tricyclic antidepressant drugs block histamine H2 receptor in brain.

Subtypes of receptors for serotonin.

Multiple and interrelated functional asymmetries in rat brain