Dopamine receptor subtypes contribution to Homer1a induction: insights into antipsychotic molecular action.
The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce Homer1a expression, although the specific role of the different dopamine receptors in its induction is not completely known. In this study, we explored Homer1a expression induced by selective antagonists at dopamine receptors (SCH-23390, D(1) receptor selective antagonist, 0.5 mg/kg; L-741,626, D(2) receptor selective antagonist, 2 mg/kg; U-99194, D(3) receptor selective antagonist, 5 mg/kg; L-745,870, D(4) receptor selective antagonist, 3 mg/kg), haloperidol (0.8 mg/kg), and terguride (0.5 mg/kg), a partial agonist at D(2) receptors. Moreover, we evaluated the expression of two Homer1a-related genes which play essential roles in synaptic plasticity: mGluR5 and Homer1b. Gene expression was analyzed in brain regions relevant for schizophrenia pathophysiology and therapy, namely the striatum, the cortex, and the hippocampus. In striatum, Homer1a was induced by D(2) receptor antagonists and, with a different distribution, by SCH-23390. In the cortex, Homer1a was differentially induced by D(1), D(2), and D(3) receptors antagonists, while haloperidol and terguride did not affect or reduced its expression. Homer1b expression was reduced by L-741,626, L-745,870, terguride, and haloperidol in the ventral caudate-putamen, in the nucleus accumbens and in the cortex, while SCH-23390 increased the expression in the core of the accumbens. mGluR5 expression was increased by SCH-23390 in the dorsomedial putamen, the core of the accumbens, and in some hippocampal subregions. A reduction of gene expression by terguride and an increase by L-745,870 was observed in the dorsomedial putamen. The changes in expression suggest that these gene transcripts are differentially regulated by antagonism at different dopamine receptors.
Iasevoli
Felice
F
Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neurosciences, University School of Medicine Federico II, Via Pansini 5, 80131 Naples, Italy.
Tomasetti
Carmine
C
Ambesi-Impiombato
Alberto
A
Muscettola
Giovanni
G
de Bartolomeis
Andrea
A
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D000072233:Homer Scaffolding Proteins; D008297:Male; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000145:classification; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000096:biosynthesis* / Q000145:classification
D014150:Antipsychotic Agents; D002352:Carrier Proteins; D018492:Dopamine Antagonists; D000072233:Homer Scaffolding Proteins; D021122:Protein Subunits; D011954:Receptors, Dopamine