5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity

Abstract Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT 2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT 2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT 2 receptor antagonist (ritanserin; 0.01 and 0.1 mg/kg) and of a 5-HT 2A receptor antagonist (MDL100,907; 0.025–0.1 mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naive rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1 mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT 2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT 2A receptor density in the caudate-putamen. Thus, activation of either 5-HT 2 receptors or of 5-HT 2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT 2 /5-HT 2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT 2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT 2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.