Brain 5-hydroxytryptamine (5HT) system has been implicated in the processes associated with the response to punishment and the suppression of behavior, as in conflict situations (29). The selective neurotoxin lesions of the 5HT forebrain pathways reverse the suppressive effects of punishment, as do anxiolytic drugs, supporting the view that 5HT may play a role in conflict behavior and in the biology of anxiety disorders. It has been reported that release of behavioral suppression following intraraphe chlordiazepoxide was abolished by prior 5,7-dihydroxytryptamine infusion in this nucleus (27). On the other hand, evidence against the involvement of se­rotonergic neurons in the antipunishment activity of diazepam in the rat has been also demonstrated (28). However, it is known that different classes of anxiolytics, including benzodi­azepines, cause marked inhibition of dorsal raphe neuronal firing (7). Consistent with this finding is the fact that benzodiazepines significantly reduce 5HT turn­over in the central neurons system (32). The role of 5HT neurons in the effects of anxiolytic drugs has recently become of interest in studying a novel nonben-zodiazepine agent, buspirone (8) (Table 1). Unlike diazepam, buspirone has no effect on the benzodiazepine-GABA receptor complex. It is inactive at benzo


diazepine binding sites, does not antagonize induced seizures, and does not cause motor incoordination and sedation; moreover, it is equipotent with benzodi­azepines in animal models of anxiety and aggression (19). Biochemical and physiological data underline a potent and selective effect of buspirone on central 5HT neurons. The drug caused a significant decrease in 5-hydroxytryptophan formation and elicited a behavioral syndrome consistent with 5HT receptor activation (10). Both iontophoretic and systemic adminis­tration of buspirone cause marked inhibition of dorsal raphe neuronal firing (30). Unlike benzodiazepines, buspirone did not potentiate the effects of ion-tophoretically applied GABA on these cells. The availability of recent selective radioligands has made it possible to dem­onstrate that buspirone binds to 5HT iA subtype sites (16). Conversely, benzo­diazepines do not interact with these binding sites. From the comparison of the biochemical and pharmacological properties of benzodiazepines and buspirone, it emerges that, even if they utilize different sites of action, both classes of drugs have the same net effect in experimental and clinical studies as regards the anxiolytic action. Therefore, it could be hy­pothesized that the serotonergic neurotransmission might be the common effector system. Compounds like benzodiazepines interacting on the GABA receptor complex and buspirone acting on 5HT 1A autoreceptors both located on dorsal raphe neurons reduce serotonergic transmission. This mechanism can explain the anticonflict activity of both classes of anxiolytic agents. Since the benzodi-azepine-GABA receptor complex is evenly distributed in the brain, the interaction with different neuronal systems may account for the other pharmacological effects induced by benzodiazepines. In conclusion, the concept that only one neurotransmitter mediates anxiety and its relief is under revision; an alternative, that multiple neurotransmitters at multiple brain sites regulate anxiety, and that modification of activity within a neuronal matrix of anxiety mediates anxiolysis, is currently suggested by the studies performed with atypical benzodiazepines and nonbenzodiazepine-anxiolytics.









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Anxious Depression: Assessment and Treatment. edited by G. Racagni and E. Smeraldi. Raven Press, New York &cop
y; 1987.

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