The psychopharmacology of 5-HT3 receptors.

The review presents evidence that 5-HT3 receptors within the brain may contribute to the control of behavior. 5-HT3 receptor antagonists GR38032F, zacopride, ICS 205-930 and other agents are very potent in reducing mesolimbic dopamine hyperactivity caused by the injection of amphetamine or infusion of dopamine into the rat nucleus accumbens and amygdala, and the ventral striatum of the marmoset. Such actions are distinguished from those of neuroleptic agents by a failure to reduce normal levels of activity or to induce a rebound hyperactivity after discontinuation of treatment. Indeed, the 5-HT3 receptor antagonists can prevent the neuroleptic-induced rebound hyperactivity. Further evidence that 5-HT3 receptors moderate limbic dopamine function is shown by their ability to reduce both the behavioral hyperactivity and changes in limbic dopamine metabolism caused by DiMe-C7 injection into the ventral tegmental area. The 5-HT3 receptor antagonists also have an anxiolytic profile in the social interaction test in the rat, the light/dark exploration test in the mouse, the marmoset human threat test and behavioral observations in the cynomolgus monkey. They differ from the benzodiazepines by an absence of effect in the rat water lick conflict test and a withdrawal syndrome. Importantly, the 5-HT3 receptor antagonists are highly effective to prevent the behavioral syndrome following withdrawal from treatment with diazepam, nicotine, cocaine and alcohol. Intracerebral injection techniques in the mouse indicate that the dorsal raphe nucleus and amygdala may be important sites of 5-HT3 receptor antagonist action to inhibit aversive behavior. Studies with GR38032F indicate an additional effect in reducing alcohol consumption in the marmoset. The identification and distribution of 5-HT3 receptors in the brain using a number of 5-HT3 receptor ligands, [3H]65630, [3H]zacopride and [3H]ICS 205-930 correlates between studies, and the 5-HT3 recognition sites in cortical, limbic and other areas meet the criteria for 5-HT3 receptors to mediate the above behavioral effects. Thus the use of 5-HT3 receptor antagonists reveals an important role for 5-hydroxytryptamine in the control of disturbed behavior in the absence of effect on normal behavior. The profile of action of the 5-HT3 receptor antagonists has generated a major clinical interest in their potential use for schizophrenia, anxiety and in the control of drug abuse.