Mood stabilizers (e.g.,
valproic acid) and
antipsychotic drugs (APDs) are commonly co-administered in the treatment of
bipolar disorder and
schizophrenia. The basis for any synergism between these classes of drugs in either group of disorders has been little studied. Previous studies have shown that atypical APDs (e.g.,
clozapine) preferentially increases
dopamine (DA) and
acetylcholine (ACh) efflux in rat medial prefrontal cortex (mPFC) and hippocampus (HIP), both of which have been suggested to contribute to their ability to improve cognition in patients with
schizophrenia. We have recently reported that the
anticonvulsant mood stabilizers (AMS),
valproic acid,
carbamazepine, and
zonisamide, but not
lithium, also preferentially increase DA efflux in the rat mPFC, and that, at subthreshold doses, the AMS also augment the ability of the atypical APDs
clozapine and
risperidone to increase DA but not ACh efflux in the mPFC. The present study examined the ability of
divalproex (DVX), which is chemically related to
valproic acid, to enhance DA and ACh efflux in the HIP and to augment the effect of atypical APDs on ACh efflux in the HIP and mPFC. DVX, 500 mg/kg, significantly increased DA and ACh efflux in the HIP, and DA, but not ACh, efflux in the mPFC, whereas a lower dose of DVX, 50 mg/kg, had no effect on DA or ACh in either region. However, DVX, 50 mg/kg, combined with the atypical APDs
olanzapine (1.0 mg/kg) or
aripiprazole (0.3 mg/kg) significantly potentiated the effect of both APDs on DA, but not ACh efflux in the HIP and mPFC. Pretreatment of
olanzapine or
aripiprazole with the selective
serotonin 5-HT(1A) antagonist, WAY100635 (1.0 mg/kg) partially but significantly blocked the effect of the combination of DVX, 50 mg/kg, and
olanzapine or
aripiprazole, on DA efflux in both the HIP and mPFC. WAY100635 did not affect the ability of the combination of
olanzapine or
aripiprazole and DVX to enhance ACh efflux in the HIP or mPFC. Subchronic administration of the combination of DVX, 50 mg/kg, and
risperidone, produced significantly greater increases in DA and ACh efflux in the mPFC, but these increases were not significantly different from those following the acute administration of the combination of
risperidone and DVX. These results provide further evidence that the AMS, DVX, augments the ability of atypical APDs to increase DA or ACh efflux in either the HIP or mPFC or both. The clinical significance of this potentiation for the beneficial clinical effects of this combination of agents and the differences between AMS in this regard warrants further study.