The acute and chronic effects of combined antipsychotic-mood stabilizing treatment on the expression of cortical and striatal postsynaptic density genes.
The detection of changes in postsynaptic gene expression after the administration of mood stabilizers, alone or in combination with antipsychotics, and antidepressants in animal models of drug treatment, may represent a valuable strategy to explore the molecular targets of the mainstay treatments for bipolar disorder. In this study we investigated, in both acute and chronic paradigms, the expression of specific postsynaptic density genes (Homer1a, Homer1b/c, and PSD95) and genes putatively implicated in mood stabilizers mechanism of action (GSK3b, ERK) after administration of first (haloperidol) or second generation antipsychotics (quetiapine 30 mg/kg), alone or in combination with valproate. Moreover, we compared the effects of an antidepressant agent widely used in bipolar depression (citalopram) with a low dose of quetiapine (15 mg/kg), which has been demonstrated to display antidepressant action in bipolar depression. In striatal regions, Homer1a expression was strongly induced by haloperidol compared to all the other treatments. Haloperidol plus valproate also markedly induced Homer1a, but to a significant lesser extent than haloperidol alone. Also in the chronic paradigm haloperidol, but not haloperidol plus valproate, induced Homer1a expression in all the subregions of the caudate-putamen and in the nucleus accumbens core. The high dose of quetiapine significantly induced Homer1a in anterior cingulated, premotor and motor subregions of the cortex, and the extent of induction was significantly higher as compared to the lower dose. Oppositely, Homer1a expression was decreased in the cortex by citalopram acute administration. ERK gene was upregulated in cortex and striatum by the acute treatment with valproate and with the combination of haloperidol or quetiapine plus valproate, whereas no significant differences were noticed in GSK3b expression among treatments. PSD95 showed a significant upregulation by acute citalopram and by haloperidol plus valproate in both cortical and subcortical regions. Haloperidol and quetiapine 30 mg/kg, oppositely, significantly reduced the expression of the gene in the cortex. In conclusion, these results suggest that the combined treatment with a typical or an atypical antipsychotic plus valproate may induce differential modulation of postsynaptic genes expression when compared to the effects of these drugs individually administered.
Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Department of Neuroscience, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy.
Carmine
C
Tomasetti
Carmela
C
Dell'Aversano
Felice
F
Iasevoli
Federica
F
Marmo
Andrea
A
de Bartolomeis
D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001345:Autoradiography; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D000076122:Disks Large Homolog 4 Protein; D004338:Drug Combinations; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D018692:Antimanic Agents; D014150:Antipsychotic Agents; D002352:Carrier Proteins; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004338:Drug Combinations; D000072233:Homer Scaffolding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C033652:postsynaptic density proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3