Increased responsiveness of dopamine to atypical, but not typical antipsychotics in the medial prefrontal cortex of rats reared in isolation

Dopaminergic hypofunction in the medial prefrontal cortex (mPFC) has teen a ssociated with the aetiology of negative symptoms and cognitive dysfunction of schizophrenia, which are both alleviated by clozapine and other atypica l antipsychotics such as olanzapine. In rodents, early life exposure to str essful experiences such as social isolation produces a spectrum of symptoms emerging in adult life, which can be restored by antipsychotic drugs. The present series of experiments sought to investigate the effect of clozapine (5-10 mg/kg SC), olanzapine (5 mg/kg SC), and haloperidol (0.5 mg/kg SC) o n dopamine (DA) and amino acids in the prelimbic/infralimbic subregion of t he mPFC in group- and isolation-reared rats. Rats reared in isolation showe d significant and robust deficits in prepulse inhibition of the acoustic st artle. In group-reared animals, both clozapine and olanzapine produced a si gnificant increase in DA outflow in the mPFC. Isolation-reared rats showed a significant increase in responsiveness to both atypical antipsychotics co mpared with group-reared animals. In contrast, the administration of halope ridol failed to modify dialysate DA levels in mPFC in either group- or isol ation-reared animals. The results also show a positive relationship between the potency of the tested antipsychotics to increase the release of DA in the mPFC and their respective affinities for 5-HT1A relative to DA D-2 or D -3 receptors. Finally, isolation-reared rats showed enhanced neurochemical responses to the highest dose of clozapine as indexed by alanine, aspartate , GABA, glutamine, glutamate, histidine, and tyrosine. The increased DA res ponsiveness to the atypical antipsychotic drugs clozapine and olanzapine ma y explain, at least in part, clozapine- and olanzapine-induced reversal of some of the major behavioral components of the social isolation syndrome, n amely hyperactivity and attention deficit.