5-Hydroxytryptamine receptors
Gaddum and Picarelli, in 1957, were the first investigators to provide evidence for the existence of two different types of 5-HT receptor in peripheral smooth muscle. These receptors were termed D (for dibenzyline, an a1 adrenoceptor antagonist which also blocked 5-HT receptors) and M (for morphine, which blocked the contractile response mediated through the myenteric plexus in the intestinal wall). Studies undertaken in the 1980s revealed the existence of multiple binding sites for 5-HT receptors. The 5- HTD receptor was shown to have the characteristics of the 5-HT2 receptor, while the M receptor has been shown to be identical to the 5-HT3 receptor in the brain and gastrointestinal tract. This biogenic amine transmitter contributes to the regulation of a variety of psychological functions which include mood, arousal, attention, impulsivity,ag gression, appetite, pain perception and cognition. In addition, serotonin plays a crucial role in regulating the sleep–wake cycle and in the control of brain maturation. It is therefore understandable that a dysfunction of the serotonergic system has been implicated in a variety of psychiatric disorders such as schizophrenia, depression, alcoholism and in phobic states. Undoubtedly interest in the role of the serotonergic system in psychiatry has been stimulated by the therapeutic success of the selective serotonin reuptake inhibitors (SSRIs) which have proven to be effective in alleviating the
symptoms of many of these disorders. The complexity of the serotonergic system lies in the number of different serotonin receptors within the brain. These are classified into seven distinct types that are heterogeneously distributed in the brain, each with its specific physiological function. The function of the serotonin receptors is a reflection of their structure. Thus the 5-HT3 receptors are ionotropic in nature whereas the remainder are metabotropic, coupled to specific G-proteins and share a common sevenmembrane domain structure. These receptors have been cloned and their physiological activity shown to be associated with the activation of either phospholipase C (5-HT2 receptors) or adenylate cyclase (5-HT4–5-HT7). The 5- HT1A, 1B and 1D receptors are also coupled to adenylate cyclase but they inhibit the function of this second messenger system. Although the precise physiological activity of the different serotonin receptors is still the subject of ongoing studies, links between specific receptor subtypes and their possible involvement in specific neurological and psychiatric disorders have been identified. For example, the antimigraine drug sumatriptan decreases headache by activating the inhibitory 5-HT1B receptors located presynaptically on perivascular nerve fibres. This blocks the release of pain-causing neuropeptides and the conduction in the trigeminal vascular neurons. With regard to the 5-HT1A receptors, agonists such as buspirone and ipsapirone act as anxiolytics while the antidepressant effects of the SSRIs have been associated with an indirect reduction in the activity of the 5-HT1A receptors. Conversely the sexual side effects of the SSRIs are attributed to their indirect action on 5-HT2C receptors which follows the enhanced serotonergic function; these receptors may also be involved in the regulation of food intake which could help to explain the antibulimic action of the SSRIs. Several different types of serotonin receptor (for example, 5-HT1A, 5- HT2A, 5-HT2C, 5-HT1B/1D) have been associated with the motor side effects of the SSRIs which may arise should these drugs be administered in conjunction with a monoamine oxidase inhibitor. The 5-HT3 receptor is an example of a non-selective cation channel receptor which is permeable to both sodium and potassium ions and, because both calcium and magnesium ions can modulate its activity, the 5-H T3 receptor resembles the glutamate–NMDA receptor. Antagonists of the 5-HT3 receptor, such as ondansetron, are effective antiemetics and are particularly useful whennausea is associated with the administration of cytotoxic drugs or some anaesthetic agents. However, they are ineffective against the nausea of motion sickness or that induced by apomorphine, suggesting that the 5-HT3 receptors function at the level of the vomiting centre in the brain. In addition, there is evidence from experimental studies that these receptors are involved in anxiety and in cognition. 5-HT3 antagonists have both anxiolytic and cognitive enhancing properties but it still remains to be proven that such properties are therapeutically relevant. The precise function of the 5-HT4,5,6 and 7 receptors is less certain. All these receptors have been cloned and their distribution in the brain determined. There is some evidence that 5-HT4 receptors act as heteroceptors on cholinergic terminals and thereby modulate the release of acetylcholine. While the physiological role of the 5-HT5,6 and 7 receptors is unclear, it is of interest to note that several atypical neuroleptics, such as clozapine, and several antidepressants have a good affinity for these receptors. There is also evidence that selective agonists and antagonists, such as zacopride, ergotamine,methysergide and LSD, have a high affinity for the 5-HT4 and 5-HT5 receptors but how these effects relate to their pharmacological actions is presently unknown. Clearly, much remains to be learned about the distribution and functional activity of these receptor subtypes before their possible roles in mental illness can be elucidated.
Gaddum and Picarelli, in 1957, were the first investigators to provide evidence for the existence of two different types of 5-HT receptor in peripheral smooth muscle. These receptors were termed D (for dibenzyline, an a1 adrenoceptor antagonist which also blocked 5-HT receptors) and M (for morphine, which blocked the contractile response mediated through the myenteric plexus in the intestinal wall). Studies undertaken in the 1980s revealed the existence of multiple binding sites for 5-HT receptors. The 5- HTD receptor was shown to have the characteristics of the 5-HT2 receptor, while the M receptor has been shown to be identical to the 5-HT3 receptor in the brain and gastrointestinal tract. This biogenic amine transmitter contributes to the regulation of a variety of psychological functions which include mood, arousal, attention, impulsivity,ag gression, appetite, pain perception and cognition. In addition, serotonin plays a crucial role in regulating the sleep–wake cycle and in the control of brain maturation. It is therefore understandable that a dysfunction of the serotonergic system has been implicated in a variety of psychiatric disorders such as schizophrenia, depression, alcoholism and in phobic states. Undoubtedly interest in the role of the serotonergic system in psychiatry has been stimulated by the therapeutic success of the selective serotonin reuptake inhibitors (SSRIs) which have proven to be effective in alleviating the
symptoms of many of these disorders. The complexity of the serotonergic system lies in the number of different serotonin receptors within the brain. These are classified into seven distinct types that are heterogeneously distributed in the brain, each with its specific physiological function. The function of the serotonin receptors is a reflection of their structure. Thus the 5-HT3 receptors are ionotropic in nature whereas the remainder are metabotropic, coupled to specific G-proteins and share a common sevenmembrane domain structure. These receptors have been cloned and their physiological activity shown to be associated with the activation of either phospholipase C (5-HT2 receptors) or adenylate cyclase (5-HT4–5-HT7). The 5- HT1A, 1B and 1D receptors are also coupled to adenylate cyclase but they inhibit the function of this second messenger system. Although the precise physiological activity of the different serotonin receptors is still the subject of ongoing studies, links between specific receptor subtypes and their possible involvement in specific neurological and psychiatric disorders have been identified. For example, the antimigraine drug sumatriptan decreases headache by activating the inhibitory 5-HT1B receptors located presynaptically on perivascular nerve fibres. This blocks the release of pain-causing neuropeptides and the conduction in the trigeminal vascular neurons. With regard to the 5-HT1A receptors, agonists such as buspirone and ipsapirone act as anxiolytics while the antidepressant effects of the SSRIs have been associated with an indirect reduction in the activity of the 5-HT1A receptors. Conversely the sexual side effects of the SSRIs are attributed to their indirect action on 5-HT2C receptors which follows the enhanced serotonergic function; these receptors may also be involved in the regulation of food intake which could help to explain the antibulimic action of the SSRIs. Several different types of serotonin receptor (for example, 5-HT1A, 5- HT2A, 5-HT2C, 5-HT1B/1D) have been associated with the motor side effects of the SSRIs which may arise should these drugs be administered in conjunction with a monoamine oxidase inhibitor. The 5-HT3 receptor is an example of a non-selective cation channel receptor which is permeable to both sodium and potassium ions and, because both calcium and magnesium ions can modulate its activity, the 5-H T3 receptor resembles the glutamate–NMDA receptor. Antagonists of the 5-HT3 receptor, such as ondansetron, are effective antiemetics and are particularly useful whennausea is associated with the administration of cytotoxic drugs or some anaesthetic agents. However, they are ineffective against the nausea of motion sickness or that induced by apomorphine, suggesting that the 5-HT3 receptors function at the level of the vomiting centre in the brain. In addition, there is evidence from experimental studies that these receptors are involved in anxiety and in cognition. 5-HT3 antagonists have both anxiolytic and cognitive enhancing properties but it still remains to be proven that such properties are therapeutically relevant. The precise function of the 5-HT4,5,6 and 7 receptors is less certain. All these receptors have been cloned and their distribution in the brain determined. There is some evidence that 5-HT4 receptors act as heteroceptors on cholinergic terminals and thereby modulate the release of acetylcholine. While the physiological role of the 5-HT5,6 and 7 receptors is unclear, it is of interest to note that several atypical neuroleptics, such as clozapine, and several antidepressants have a good affinity for these receptors. There is also evidence that selective agonists and antagonists, such as zacopride, ergotamine,methysergide and LSD, have a high affinity for the 5-HT4 and 5-HT5 receptors but how these effects relate to their pharmacological actions is presently unknown. Clearly, much remains to be learned about the distribution and functional activity of these receptor subtypes before their possible roles in mental illness can be elucidated.
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