The purpose of this research project is to assess changes in the brains of nonhuman primates (NHPs) during information processing in a cognitive task that involves exposure to cocaine as a reward for successful performance. Evidence is presented that structures in the brain of NHPs are affected by the introduction of cocaine as a reward on signaled trials within a session where appetitive (juice) rewards are also available. The Project will utilize a well-characterized short-term memory/executive function paradigm consisting of a multi- object delayed match to sample (DMS) task. The task provides for testing whether the "cognitive load" on any given trial is directly related to performance in association with the functional neuronal activity in prefrontal cortex (PFC), medial temporal lobe (MTL) and dorsal and ventral striatum (Str) that is imaged from the same behavioral sessions. The proposed studies will determine how cognitive processing is affected by acute and long-term exposure to cocaine in this paradigm and how agents currently utilized in human clinical studies alter the detrimental effects of cocaine on cognitive function.
Aims 1 and 2 will assess and characterize PET imaging of 18FDG brain metabolic activity in the above three brain regions and determine the effects of cocaine rewards on performance of the DMS task.
Aim 3 will examine the effects of cocaine rewarded cognitive performance as a function of the animal's preference for choosing cocaine vs. juice signaled trials. These analyses will partial out cocaine effects across individual animals in terms of their choice of cocaine vs. juice trials and examine difference in PET imaging of 18FDG brain metabolic activity in the above three brain regions to determine functional differences in animals that prefer cocaine vs. juice rewarded trials in the same DMS paradigm.
Aim 3 will also extend the above analyses to animals that are repeatedly exposed to conditions in which cocaine and appetitive rewards are implemented in the same random manner during day-to-day testing for a period of six months. Changes in DMS responding (performance) and preferences for cocaine vs. juice rewards and associated neuronal correlates over this time period will be determined as a baseline for in order to ascertaining the long-term effectiveness of agents administered as part of Aim 4.
Aim 4 will examine how the above behavioral and 18FDG imaging correlates of cognitive demand in the DMS task change as a function of prior treatment with two candidate treatment agents, Modafinil and the hypocretin-1 receptor antagonist SB334867, that can alter cocaine's reinforcing effects in self-administration paradigms and are currently considered as possible compounds to treat cocaine addiction in human clinical trials. These actions of these drugs in the early phase of testing will be compared with the effects following long-term exposure to the same paradigm using performance and preference measures as indicants of changes in cocaine's actions in association with altered 18FDG imaging correlates.
The relevance of this Project to public health is directly related to finding agents and drugs that will alleviate the dependence on substances that are abused in society. Primarily the Program will focus on the effects of cocaine on cognition in nonhuman primates which serves as the final testbed for candidate drugs that can lead to therapeutic treatment of cocaine abusers.
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