Effects of chronic cocaine on cognition and glutamate levels in nonhuman primates

Mclean Hospital, Belmont MA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Cocaine abuse and dependence are long-standing, significant public health issues. Yet, no drug treatments have been approved for these disorders. People with chronic cocaine use histories exhibit cognitive deficits including impulsivity and impaired executive function. Among those attempting to quit, cognitive deficits increase relapse vulnerability and reduce effectiveness of behavioral interventions. Accordingly, developing a better understanding of the cognitive sequelae of chronic cocaine exposure and their relationships to neurochemical abnormalities may lead to new treatments and new ways to optimize existing behavioral interventions. Controlled prospective studies in nonhuman primates will play a key role in this endeavor because they enable baseline (pre-cocaine) cognitive assessment and because amounts and durations of cocaine exposure are defined. Further, such studies are absent the many confounds present in human studies, including polydrug abuse and pre-/co-morbid psychiatric and medical disorders. With this R21 Exploratory/Developmental project, we aim to establish a translational platform to assess, within individual subjects, effects of chronic cocaine self-administration on cognition and on neurochemistry, using touch screen technology and ultra high magnetic field (9.4 Tesla) in vivo proton magnetic resonance spectroscopy (MRS), respectively. Both methodologies have been implemented in our laboratories and used separately to assess cognition or MRS effects of chronic cocaine in squirrel monkeys. Our prior MRS studies have revealed striatal intracellular glutamate increases after chronic cocaine administration to squirrel monkeys, which may be relevant as glutamate abnormalities contribute to behavioral inflexibility (e.g., impulsivity). We will prospectively assess effects of chronic cocaine self-administration on acquisition and reversal learning, on reinstatement as a measure of relapse vulnerability, and on brain glutamate levels. Then, we will examine effects of short-term treatment with N-acetylcysteine (NAC), which has shown promise in human cocaine users for reducing cocaine use and for correcting brain glutamate abnormalities. We will assess NAC effects on cognition, glutamate levels, reinstatement, and on relationships between these variables. We hypothesize that chronic cocaine will impair acquisition and reversal learning, will enhance reinstatement, and will increase intracellular glutamate levels, and that NAC treatment will normalize cognition, reduce reinstatement, and reduce glutamate levels. These experiments will establish a platform for future studies evaluating effects of chronic cocaine or other chronic drug exposures on cognitive function across a number of cognitive domains, on neurochemistry, and for evaluating novel interventions designed to improve cognition, neurochemistry, and cocaine/other drug treatment outcomes.