Clozapine, but Not Haloperidol , Increases Hippocampal Dopamine and Acetylcholine Release

Atypical antipsychotics (APDs) such as clozapine, but not the typical APD haloperidol, produce greater increases in dopamine and acetylcholine release in rat medial prefrontal cortex (mPFC), compared to the nucleus accumbens (NAC) or striatum (STR), a mechanism postulated to lead to improvements of negative symptoms and neurocognitive deficits in patients with schizophrenia. The present study determined whether typical and atypical APDs modulate dopamine and acetylcholine release in the ventral hippocampus (vHIP) as well as mPFC, both of which are important to neurocognitive functions in schizophrenia. Clozapine (3and 10 mg/kg) produced comparable increases in dopamine release in the mPFC and vHIP. Clozapine (3 and 10 mg/kg) also increased acetylcholine release in both regions, without significant effect at 3 mg/kg in the mPFC. The perfusion of tetrodotoxin (1 μM) into the vHIP eliminated clozapine-induced dopamine and acetylcholine release in that region. Haloperidol (0.1, but not1 mg/kg) only increased dopamine release in the mPFC, without an effect of all the doses on either release in either region. These results suggest that clozapine, but not haloperidol, increases dopamine and acetylcholine release in the vHIP as well as in the mPFC. This may further indicate that clozapine and perhaps related atypical APDs may differ from the typical APDs such as haloperidol in enhancing dopamine and acetylcholine transmission in the hippocampal-PFC pathway that may be responsible for neurocognitive deficits in schizophrenia.