Psychostimulant abuse in humans is known to produce states similar to both positive and negative symptoms of schizophrenia. Studies in rats have suggested that hyper-dopaminergic activity in subcortical structures such as nucleus accumbens leads to behavioral abnormality that may have relevance to positive symptoms. Emotional and cognitive deficits that characterize negative symptoms have been recently demonstrated in monkeys similarly treated with low doses of amphetamine and that in many ways resemble those identified in human amphetamine abusers. These cognitive deficits are believed to result from a dysfunction in the prefrontal cortex, thus linking to a clinical state of hypofrontality. A basic dysfunction of prefrontal-accumbens circuits is thought to be critical to the cognitive dysfunction, negative affect and abnormal reward-related behavior that is characteristic of schizophrenia and drug abuse. My working hypotheses is that in amphetamine treated rats there exists deficits in the excitatory drive from the limbic afferents from the entorhinal cortex and the mediodorsal thalamus to the prefrontal cortex and/or deficits in the dopamine modulation of these excitatory afferents. Thus the proposed experiments using in vivo intracellular recording and labeling techniques will compare and contrast information arising intracortically (eg entorhinal cortex;
aim 1) and subcortically (eg mediodorsal thalamus;
aim 2), the latter of which transmits basal ganglia outflow back to the prefrontal cortex. Lastly cortical processing in influencing basal ganglia outflow from the nucleus accumbens. I predict attenuated intracortical processing (aim 1) to occur in conjunction with an augmented basal ganglia feedback circuit, as marked by increases in both mediodorsal thalamus-evoked activity in prefrontal cortex neurons (aim 2) and prefrontal cortex-evoked activity in nucleus accumbens neurons (aim 3), in amphetamine treated rats. The proposed study is of particular interest with respect to the deficit syndrome in schizophrenia and possibly other mental disorders such as drug addiction associated with negative affect and depression.
