Expression of 5-HT receptors sensitive to antipsychotic drugs in prefrontal cortex pyramidal neurons innervating the nucleus accumbens

Abstract

Antipsychotic drugs used to treat schizophrenia belong to two different families and have different primary targets. Thus, classical antipsychotics modulate cortico-limbic circuits through D2 receptor blockade in ventral striatum (nucleus accumbens ¿Nac- and anatomaically-related structures), whereas atypical antipsychotics preferentially target cortical 5HT2 receptors. The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. It contains a high density of serotoninergic receptors like 5HT2A and 5HT1A for which atypical antipsychotic drugs exhibit high affinity. Recent data indicate that a substantial proportion of PFC pyramidal neurons projecting to the ventral tegmental area or the dorsal raphe nucleus express 5HT2A receptor mRNA, which suggests that atypical antipsychotic drugs affect serotonergic and dopaminergic function by targeting PFC 5HT2A receptors1. In a similar way, atypical antipsychotic drugs targeting 5HT2A or 5HT1A receptors in pyramidal neurons projecting to nucleus accumbens (NAc) may normalize the activity of cortico-limbic circuits. Here we examined whether PFC neurons projecting to NAc express these 5-HT receptors. Fluorogold or choleratoxin B application into NAc showed retrogradely labeled neurons in PFC layer V of both hemispheres and in layer II of the ipsilateral PFC. Using a combination of retrograde tracing and in situ hybridization histochemistry we report that a proportion of ca. 45% of PFC pyramidal neurons projecting to NAc express 5HT2A receptor mRNA while ca. 38% express 5HT1A receptor mRNA. The present and past1 data indicate that pyramidal neurons expressing 5-HT receptors sensitive to antipsychotic drugs can control the activity of the mesolimbic dopaminergic pathway at cell body and terminal levels.