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Eur Neuropsychopharmacol. 2015 Dec;25(12):2381-93. doi: 10.1016/j.euroneuro.2015.10.002. Epub 2015 Oct 21.

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

Author information

1
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Canada.
2
Department of Neuroscience, Faculty of Medicine, Université de Montréal, Canada.
3
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Canada; CNS Research Group, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. Electronic address: Anna.samaha@umontreal.ca.

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-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 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-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025-0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/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-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.

KEYWORDS:

5-HT(2) receptors; Amphetamine; Antipsychotic medication; Dopamine supersensitivity; Locomotor activity; Schizophrenia

PMID:
26508706
DOI:
10.1016/j.euroneuro.2015.10.002
[Indexed for MEDLINE]

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