CONTRASTING EFFECTS OF EXCITOTOXIC LESIONS OF THE PREFRONTAL CORTEX ON THE BEHAVIORAL-RESPONSE TO D-AMPHETAMINE AND PRESYNAPTIC AND POSTSYNAPTIC MEASURES OF STRIATAL DOPAMINE FUNCTION IN MONKEYS

The effects of excitotoxic lesions of the prefrontal cortex on behavio ural, neurochemical and molecular indices of dopamine function in the caudate nucleus were studied in the marmoset. The lesion, which encomp assed both the lateral and orbital regions of prefrontal cortex, made the animals more sensitive to the performance disrupting effects of th e dopamine releasing drug, D-amphetamine, in a variation of the object retrieval task. Specifically, following drug administration, the lesi oned marmosets were less able to gain access to food reward in the min imum number of responses. Analysis of the nature of the errors suggest ed that the deficit was not due to inhibition of a prepotent response as the lesioned monkeys were just as likely to make a detour reach to the unopened side of the box as a direct ''line-of-sight'' reach into the unopened front of the box. Rather, the data indicated a general di sorganization of behaviour. The enhanced behavioural responsiveness to manipulations increasing presynaptic dopamine function was accompanie d by neurochemical changes indicating a reduced responsiveness, as rev ealed by in vivo microdialysis. Thus, in lesioned animals, whilst ther e were no effects on baseline levels of extracellular dopamine in dors olateral caudate, evoked release, both to systemic D-amphetamine and t o a local depolarizing pulse of potassium ions, was attenuated. These opposite effects of the prefrontal cortex lesion on behavioural and ne urochemical indices of striatal dopamine function occurred in the abse nce of any changes in striatal dopamine receptors of the D-1 and D-2 s ubtype, as determined both by radioligand binding assays and measureme nts of messenger RNA using in situ hydridization techniques. These dat a provide further insight into the interactions between prefrontal cor tex and striatal dopamine function in the non-human primate. In partic ular, when taken in the light of our previous studies they indicate th at following prefrontal manipulations, concurrence between behavioural and neurochemical indices of striatal dopamine function depends, crit ically, on the behavioural task. These findings are discussed with res pect to the growing body of evidence implicating abnormalities in fron tostriatal neurotransmission in complex disorders such as schizophreni a. (C) 1997 IBRO. Published by Elsevier Science Ltd.