213 121 121 1 1 J. De Vry Troponwerke GmbH & Co. KG Institute for Neurobiology Berliner Strasse 156 D-51063 Cologne Germany Abstract During the last decade, serotonin (5-HT) 1A receptors have been a major target for neurobiological research and drug development. 5-HT 1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT 1A receptors, however, depend highly on the particular assay system. This may be due to the possible existence of receptor subtypes and to assay (or brain region)-dependent differences in receptor reserve and the nature of receptor-effector coupling. Nevertheless, the apparent intrinsic activity of 8-OH-DPAT seems to be higher (although possibly not yet maximal) than that of the pyrimidinylpiperazines. In the brain, 5-HT 1A receptors are located presynaptically as somatodendritic receptors on 5-HT neurons and postsynaptically in particular limbic and cortical regions. Although it is generally accepted that presynaptic 5-HT 1A receptors control 5-HT neuronal activity, recent evidence suggests an additional role of postsynaptic 5-HT 1A receptors in cortex as part of a negative feedback loop. Anxiolytic and antidepressive properties of selective 5-HT 1A receptor agonists have now been confirmed by clinical studies. Although it is well established that the latter properties depend on the agonistic activity of these compounds, the optimal level of intrinsic activity is still a matter of debate and may be dependent on the clinical indication. Such compounds may also have antiaggressive effects, and possibly anticraving effects (manifested by their alcohol intake-reducing effects in dependent animals), but the specificity of these so-called anti-impulsivity effects is still controversial and not yet tested clinically. Anticataleptic, antiemetic and neuroprotective properties have been demonstrated in different species. Behavioral studies on the mechanisms underlying the anxiolytic and antidepressive effects have examined the relative contribution of pre-and postsynaptic 5-HT 1A receptors by means of local cerebral application and lesion techniques. Most evidence points towards a critical involvement of presynaptic receptors in the anxiolytic effects of 5-HT 1A receptor agonists (although a possible contribution of postsynaptic receptors cannot be excluded). With regard to the antidepressive properties, a case can be made for the reverse; i.e., a strong involvement of postsynaptic receptors and a questionable contribution of presynaptic receptors. However, as the therapeutic effects of those 5-HT 1A receptor (partial) agonists which have been tested clinically require repeated administration, attention has been directed increasingly towards chronic studies. These studies have shown that a number of electrophysiological, biochemical, behavioral and endocrinological 5-HT 1A receptor-related events adapt differentially to repeated or sustained administration. Thus, several hypotheses accounting for the delayed onset of action have been advanced. Among these, time-dependent downregulation /desensitization of either pre - or post synaptic 5-HT 1A receptors, or cortical 5-HT 2 receptors have received much attention. However, these hypotheses have their weaknesses, and it is argued that functional sensitization of particular postsynaptic 5-HT 1A receptor-mediated events remains a valuable alternate hypothesis. Basic research on the role of 5-HT 1A receptors in psychopathology and in the therapeutic effects of clinically effective therapeutics, as well as on the mechanism of action of 5-HT 1A receptor ligands, will enable rational design of ligands with particular profiles of intrinsic activity at different 5-HT 1A receptor populations, and may contribute to a more efficient treatment of a multiplicity of brain disorders.
Psychopharmacology – Springer Journals
Published: Sep 1, 1995
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