We developed the in vivo microdialysis technique to monitor prefrontal cortical-striatal interaction and neurochemical dynamics associated with cognitive behavior in the non-human primate. We have previously demonstrated that pharmacological manipulation in the prefrontal cortex may result in significant changes in striatal dopamine (DA) levels. For example, augmentation of prefrontal DA levels by infusion of amphetamine or cocaine resulted in dramatic decreases in DA in the caudate nucleus. In contrast, reduction, of prefrontal cortical function by infusion of TTX, or of cortical dopamine function using flupentixol, a D1/D2 antagonist, resulted in significant increases in caudate DA levels. These data were the first to demonstrate, in both directions, the regulation of subcortical DA systems via cortical pharmacological manipulation in the primate. This cortical regulation of striatal dopamine is purported to play an important role in schizophrenia. One proposal of the underlying pathophysiology associated with schizophrenia suggests that DA function may be altered by limbic system maldevelopment. Thus we attempted to study how maldevelopment of temporal lobe limbic structures effects cortico-striatal dopamine function. Neonatal limbic lesions had little effect on basal dopamine levels in the caudate nucleus. However, dopamine overflow evoked with K+ challenge was significantly less (50%) as compared with normal monkeys. Thus we have evidence that neonatal limbic lesions result in abnormal dopamine function in the striatum in the primate. Acute administration of haloperidol and clozapine, two common neuroleptics, resulted in similar patterns of increased basal dopamine levels, with animals with neonatal limbic lesions showing significantly lower levels (50%) than controls. There was however, a differential response to clozapine and haloperidol to depolarization evoked dopamine. K+ challenge after haloperidol administration resulted in significant increases in dopamine with the normal monkeys having nearly double the response as those with the limbic lesions. In contrast, K+ challenge after clozapine administration showed no effect in any monkey. Thus depolarization evoked dopamine release had differential effects with haloperidol and the atypical neuroleptic clozapine. The effects of neonatal limbic lesions on prefrontal regulation of striatal dopamine release was also examined. In contrast to the results shown previously augmentation of prefrontal cortical DA resulted in significant increases in caudate DA levels. This startling result shows the dopamine response in the striatum to be the opposite (hyperdopaminergic) of that found in normal adult monkeys as a consequence of the maldevelopment of the temporal lobe limbic system. Recently, we have extended our studies to monitor some of the purported amino acid neurotransmitters, such as glutamate, and GABA. Extracellular GABA and glutamate overflow were measured in the caudate nucleus and the prefrontal cortex and were characterized for voltage sensitivity and calcium-dependency. The results suggest that GABA and glutamate levels recovered from the rhesus monkey brain derive in significant part from neuronal pools and are release dependent. We have applied the in vivo dialysis technique to the awake behaving monkey. We have demonstrated that ACh was detectable and stable for many hours, was from neuronally derived pools, and was responsive to pharmacological manipulation. In both the hippocampus and PFC performance on a simple operant conditioning task, the recognition memory task, delayed nonmatching to sample (DNMS), and the working memory task, delayed response (DR) with short delays, increased ACh levels (20 to 30%) significantly above baseline levels. In contrast, performance on a control motor task increased ACh only slightly (10%). The increased levels of ACh after task completion was abolished with infusion of the sodium channel blocker, TTX, suggesting that the elevation was associated with neuronal release. We now have preliminary data demonstrating a double dissociation related to performance on the cognitive tasks DNMS and DR. While performance on both tasks raised ACh levels significantly above basal levels in both the hippocampus and PFC the levels varied within an area by cognitive difficulty of one of the tasks. This is the first demonstration of dynamic neurochemical events within a limited neural region that can be associated with specific performance on a cognitive task.
