Ketamine-related expression of glutamatergic postsynaptic density genes: possible implications in psychosis.
Systemic administration of ketamine, a non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDA-R), produces a condition of NMDA-R hypofunction, which is considered one of the putative molecular mechanisms involved in psychosis. In this study, we evaluated the effect of ketamine on glutamatergic markers of the postsynaptic density (PSD), a pivotal site for dopamine-glutamate interaction. We assessed gene expression of Homer1a, alpha and betaCaMKII, and dopamine transporter (DAT) by two different doses of ketamine. These genes were chosen because of their impact on signal transduction and dopamine-glutamate interplay in postsynaptic density. Moreover, Homer1a is modulated by antipsychotics and represents a candidate gene for schizophrenia. Male Sprague-Dawley rats were injected with saline, 12mg/kg ketamine or 50mg/kg ketamine, and sacrificed 90 minutes after injections. In situ hybridization histochemistry was used to quantitate the rate of gene expression in rat forebrain. Homer1a was induced by 50mg/kg ketamine in ventral striatum and by both 50 and 12mg/kg ketamine in nucleus accumbens, whereas gene expression was not affected in dorsal striatum. alphaCaMKII was increased by 12mg/kg ketamine against saline in almost all subregions assessed. betaCaMKII was not affected by ketamine. DAT was increased by both doses of ketamine in the ventro-tegmental area and substantia nigra pars compacta. We suggest that these changes may represent molecular adaptations to the perturbation in glutamatergic transmission induced by ketamine blockade of NMDA receptors and may be implicated in molecular alterations occurring in schizophrenia.
Iasevoli
Felice
F
Laboratory of Molecular Psychiatry and Psychopharmacotherapy, Section of Psychiatry, Department of Neuroscience, University School of Medicine Federico II, Via Pansini 5, Naples, Italy.
Polese
Daniela
D
Ambesi-Impiombato
Alberto
A
Muscettola
Giovanni
G
de Bartolomeis
Andrea
A
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D018698:Glutamic Acid / Q000502:physiology; D000072233:Homer Scaffolding Proteins; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000503:physiopathology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D000072233:Homer Scaffolding Proteins; D012333:RNA, Messenger; D018698:Glutamic Acid; D007649:Ketamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases