Brain imaging and cognitive effects of cocaine self-administration in monkeys

Czoty, Paul

Abstract

Although cocaine addiction persists as a major public health concern, effective medications are currently unavailable. Development of treatments for cocaine dependence will be aided by a more thorough understanding of the effects of long-term cocaine use on the brain and the impact of these changes on cognitive function. Studies using animal models with proven validity in drug abuse research will help achieve this goal. The primary aim of this 1-year grant proposal is to implement the brain imaging techniques diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) in monkeys to generate data to support more extensive future proposals. Additional aims are to document the effects of chronic cocaine self- administration on the brain and behavior in monkeys. To accomplish these aims, a DTI/MRS scan will be performed twice on eight female cynomolgus monkeys to establish appropriate test-retest validity (Specific Aim 1). Subsequently, monkeys will self-administer cocaine (6.0 mg/kg/day) for three months, at which time a follow-up DTI/MRS scan will be conducted. After this point, four monkeys will continue to self-administer cocaine while cocaine exposure is discontinued in the remaining four, and a final DTI/MRS scan will be conducted three months later (Specific Aim 2). In addition, cognitive function will be assessed every other week using a delayed match-to-sample task (Specific Aim 3). The overarching hypothesis is that progressive and parallel alterations will be observed in white matter integrity, neurometabolite concentrations and cognitive function during cocaine self-administration and abstinence that implicate specific brain regions and pathophysiological mechanisms in the cognitive decline observed after long-term cocaine use. Thus, in addition to providing data to support the establishment of the P.I.'s independent research career, results of the present studies will considerably enhance our understanding of the effects of chronic cocaine use, interpretation of imaging studies in human cocaine abusers, medications development, and, ultimately, treatment of cocaine dependence.

Public Health Relevance

These studies will establish cutting-edge brain imaging techniques, currently used in humans to examine the health of brain areas and the strength of the connections between them, for use in monkey models of cocaine abuse. In addition, monkeys'cognitive function will be tested throughout the time they are using cocaine. Taken together, the results of these studies will identify mechanisms by which prolonged cocaine use causes declines in cognitive function and, ultimately, will aid the development of more effective treatments for cocaine addiction.