Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole.
BACKGROUND
A pivotal role for glutamate in the pathophysiology and treatment of schizophrenia has been suggested. Few reports have investigated the impact of antipsychotics on postsynaptic density (PSD) molecules involved in glutamatergic transmission and synaptic remodeling. Homer is a key PSD molecule putatively implicated in schizophrenia.


OBJECTIVE
We studied the effect, in acute and chronic paradigms, of a first and a second generation antipsychotic (haloperidol and sertindole, respectively) on the expression of Homer1a and Homer-interacting PSD molecules.


RESULTS
In the acute paradigm, Homer1a expression was induced by haloperidol but not sertindole in the striatum, consistent with the less propensity of sertindole to affect nigrostriatal neurotransmission. The profile of expression of two other inducible genes, Ania3 and Arc, was highly similar to Homer1a. In the cortex, haloperidol reduced Homer1a and induced Ania3. In the chronic paradigm, striatal expression of Homer1a and Ania3 resembled that observed in the acute paradigm. In the cortex, haloperidol induced Homer1a, while sertindole did not. Homer1b expression was increased by haloperidol in the striatum and cortex whereas sertindole selectively induced Homer1b in the cortex. The expression of mGluR5 was increased by both antipsychotics. A modulation by haloperidol was also seen for PSD-95 and αCaMKII.


CONCLUSIONS
These results suggest that haloperidol and sertindole may significantly modulate glutamatergic transcripts of the postsynaptic density. Sertindole induces constitutive genes in the cortex predominantly, which may correlate with its propensity to improve cognitive functions. Haloperidol preferentially modulates gene expression in the striatum, consistent with its action at nigrostriatal projections and its propensity to give motor side effects.
Iasevoli
Felice
F
Laboratory of Molecular Psychiatry and Psychopharmacotherapeutics, Section of Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Edificio 18, Via Pansini 5, 80131, Naples, Italy.
Tomasetti
Carmine
C
Marmo
Federica
F
Bravi
Daniele
D
Arnt
Jørn
J
de Bartolomeis
Andrea
A
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D000072233:Homer Scaffolding Proteins; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics; D057907:Post-Synaptic Density / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
D014150:Antipsychotic Agents; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C578937:Grm5 protein, rat; D000072233:Homer Scaffolding Proteins; D007093:Imidazoles; D007211:Indoles; D009419:Nerve Tissue Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C092069:activity regulated cytoskeletal-associated protein; C066304:sertindole; D006220:Haloperidol