title: Valproic acid potentiates both typical and atypical antipsychotic-induced prefrontal cortical dopamine release.
abstract: Antipsychotic drugs (APD)s and anticonvulsant mood-stabilizers are now frequently used in combination with one another in treating both schizophrenia and bipolar disorder. We have recently reported that the atypical APDs, e.g. clozapine and risperidone, as well as the anticonvulsant mood-stabilizers, valproic acid (VPA), zonisamide, and carbamazepine, but not the typical APD haloperidol, increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). The increased DA release was partially (atypical APDs) or completely (mood-stabilizers) blocked by the serotonin (5-HT)1A receptor antagonist WAY100635. Diminished prefrontal cortical DA activity may contribute to cognitive impairment in virtually all the patients with schizophrenia and, perhaps, bipolar disorder. Thus, the enhanced release of cortical DA by these agents may be beneficial in this regard. It is, therefore, of considerable interest to determine whether combined administration of these agents augments prefrontal cortical DA release, and if so, whether the increase is dependent upon 5-HT1A receptor activation. VPA (50 mg/kg), which was insufficient by itself to increase prefrontal cortical DA release, potentiated the ability of clozapine (20 mg/kg) and risperidone (1 mg/kg) to increase DA release in the mPFC, but not in the nucleus accumbens (NAC). VPA (50 mg/kg) also potentiated haloperidol (0.5 mg/kg)-induced DA release in the mPFC; this increase was completely abolished by WAY100635 (0.2 mg/kg). These results suggest that, in combination with VPA, both typical and atypical APDs produce greater increases in prefrontal cortical DA release than either type of drug alone via a mechanism dependent upon 5-HT(1A) receptor activation. Furthermore, they provide a strong rationale for testing for possible clinical synergism of an APD and anticonvulsant mood-stabilizer in improving the cognitive deficits present in patients with schizophrenia and bipolar disorder.
authors.affiliation: Division of Psychopharmacology, Department of Psychiatry, Vanderbilt University School of Medicine, 1601 23rd Avenue South, The First Floor Laboratory Rm-1117, The Psychiatric Hospital at Vanderbilt, Nashville, TN 37212, USA. junji.ichikawa@vanderbilt.edu
authors.forename: Junji
authors.initials: J
authors.lastname: Ichikawa
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Chung
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D003956:Dialysis / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D014635:Valproic Acid; D004298:Dopamine