Homer splice variants modulation within cortico-subcortical regions by dopamine D2 antagonists, a partial agonist, and an indirect agonist: implication for glutamatergic postsynaptic density in antipsychotics action

Abstract

Homer proteins are linked to both dopamine and glutamate neurotransmission and are putatively involved in the mechanisms of action of psychoactive drugs. In the present study, we evaluated the effects of compounds differently impacting dopaminergic neurotransmission on the transcripts of different Homer isoforms in rat forebrain by means of in situ hybridization histochemistry. Animals were treated with the typical antipsychotic haloperidol 0.8 mg/kg, the atypical antipsychotic clozapine 15 mg/kg, the dopamine partial agonist aripiprazole 12 mg/kg and 30 mg/kg and the dopamine transporter inhibitor GBR12909 30 mg/kg in acute and chronic paradigms. Homer 1a and ania-3 were induced in the caudate-putamen by acute administration of aripiprazole 12 mg/kg, while aripiprazole 30 mg/kg had no significant effects. Furthermore, acute haloperidol and GBR12909 induced both the splice variants of Homer 1 in the caudate-putamen. In the nucleus accumbens, aripiprazole 30 mg/kg and clozapine increased Homer 1a and ania-3 transcripts in the shell, whereas haloperidol induced expression of both isoforms in core and shell. Aripiprazole 30 mg/kg increased Homer 1a in the frontal cortex. Homer 1 splice variants were both up-regulated by GBR12909 in the frontal cortex, whereas GBR12909 induced only ania-3 in the parietal cortex. In the chronic paradigm, results showed a significant induction of Homer 1a and ania-3 in the striatum by haloperidol and aripiprazole. The constitutive Homer 2 isoform was overexpressed in the lateral septum by chronic administration of haloperidol and clozapine. In the cortex the expression of Homer 1a and ania-3 was down-regulated by chronic clozapine and aripiprazole. These results may indicate a differential modulation of Homer genes by compounds differently regulating dopaminergic neurotransmission in discrete regions of the rat forebrain and suggest that Homer could be a molecular marker of the involvement of the glutamatergic postsynaptic density in antipsychotic mechanisms of action.