The purpose of this research project is to assess the manner in which information processing in brain structures of nonhuman primates is re-organized by the introduction of and sustained exposure to cocaine as a reinforcer for complex cognitive tasks. It has long been implicitly assumed in analyses of human drug addiction that substances which are abused somehow take over normal reinforcement mechanisms in the brain, diverting such "reward pathways" to the control of drug seeking activities. Using a well-characterized short-term memory/executive function paradigm (multi-object delayed match to sample [DMS] task) studies will determine how cognitive processing is affected by acute and longterm exposure to cocaine as a reinforcer in this task. This primate model of cognitive function has been characterized in recent PET imaging and electrophysiological recording studies from this laboratory. On the basis of that work three important brain regions, medial temporal lobe (MTL), dorsal prefrontal cortex (DPFC) and the dorsal and ventral striatum (D/VStr), shown to be engaged during task performance, will be assessed for effects of cocaine on cognitive processing. Aim 1 will determine neuronal firing characteristics in these three brain regions associated with performance of the DMS task and will identify single neuron correlates of low vs. high cognitive load trials. Aim 2 will examine how these neural correlates change when the task is performed for cocaine injections delivered as the trial reinforcer in comparison to normal appetitive (juice) rewards. Aim 3 will extend the above analyses to animals that are repeatedly exposed to conditions in which cocaine and juice reinforcers are implemented in the same random manner during day-to-day testing for a period of six months in order to assess cumulative changes in DMS responding and associated neuronal correlates over a time period in which performance is sustained at criterion levels by both reinforcers. The final Aim 4 will assess the effects of stress on cocaine vs. juice reinforced DMS performance and associated neural correlates of cognitive load (Aim 1), induced by a method of sleep deprivation perfected for nonhuman primates in this laboratory.

Relevance: In a society that is evolving more and more toward increased stress and demand on its citizens the individual level of cocaine abuse is a major health care problem. Such behavior eventually results in inability of the addict to cope with the complex nuances of a complex technologically-based work place. Turning to drugs is a natural course of action for pressured, overworked and under employed personnel.How cocaine use advances to addiction in this context is directly related to effects on cognition, reasoning and decision making. Therefore understanding how cocaine modulates and gradually over time eliminates effective cognitive processing, as studied here, is of primary importance in the prevention of drug addiction.

R01DA023573

2007-09-01

2014-07-31