GRANT NUMBER:  R01 AA022249-02S1

ABSTRACT:  This application for an Administrative Supplement to Promote Collaborative Research on Addiction at NIH (CRAN) is tied to our research project entitled “Cognitive Function in Alcohol Dependence and Protracted Withdrawal” (1R01 AA022249-01A1). The parent RO1 application received a 1st percentile ranking based on the review by the NIH-CSR Neurotoxicology and Alcohol study section, and the project was funded earlier this year (project period 07/15/013 – 06/30/18). The abstract of the parent RO1 project is as follows: Impaired cognitive processing is a hallmark of addiction. Deficits in inhibitory control (impulsive action), poor evaluation of consequences (impulsive choice) and ineffective reversal of compulsive or habitual behaviors (cognitive flexibility) can propel continued drug use despite adverse consequences. A persistent question in alcohol research regards the relative influence of pre-existing cognitive disruptions that confer susceptibility to problem drinking versus the induction of cognitive impairment related to cortical damage induced by repeated alcohol intoxication and withdrawal. In this regard animal models can provide important insight into the etiology of alcohol-induced cognitive impairment and can provide a platform for mechanistic studies and rapid pharmacotherapy screening. Using behavioral paradigms analogous to clinically employed tasks we have gathered preliminary evidence of significant increases in impulsive action and impulsive choice behaviors that emerge in rats during protracted withdrawal from long-term intermittent alcohol consumption. These cognitive impairments persist for several weeks, and can be ameliorated by a pharmacological manipulation known to improve cognitive function in human alcoholics. Based on these findings and knowledge of the neural mechanisms governing these behaviors in rats we hypothesize that withdrawal-associated dysregulation of monoamine and amino acid signaling in frontal cortical regions contributes to increased impulsivity and deficient cognitive flexibility during protracted alcohol withdrawal. This hypothesis will be tested through three Specific Aims. Aim 1 will characterize the emergence, nature and persistence of cognitive disruption during protracted alcohol withdrawal. Different facets of impulsive action will be explored using a novel 5-Choice Continuous Performance Task (5C-CPT) and the Stop Signal Reaction Time task (SSRT). Impulsive choice behavior will be indexed using the Delay Discount Test, and cognitive flexibility will be assessed using an operant spatial reversal learning task. The experiments in Aim 2 will employ in vivo microdialysis and biochemical approaches to characterize monoamine, and amino acid function in the orbitofrontal and medial prefrontal cortices during protracted alcohol withdrawal. Aim 3 will evaluate the efficacy of pharmacologic agents for ameliorating withdrawal associated increases in impulsive action and impulsive choice. The experiments in this administrative supplement request are directly related to this parent grant, and substantially increase the scope of this project in two major ways: 1) Extending the focus on chronic alcohol-induced impairments in impulse control to include comparative evaluations of the effects produced by combined alcohol and Δ 9-THC exposure. As described in the sections that follow, marijuana is the most commonly used illicit drug by alcohol dependent individuals, and the prevalence of this drug combination is more than 2-fold higher than the concurrent use of alcohol with opioids, cocaine or other illicit substances. Clinical evidence demonstrates that combined alcohol and marijuana use is associated with more severe psychological and social dysfunctions (including impulsivity and risky behaviors) and greater difficulties in the treatment of Alcohol Use Disorders as compared with alcohol use alone. However, the nature and magnitude of potential additive effects of chronic alcohol and Δ9-THC exposure on impulse control have not been characterized. 2) Comparing the effects of chronic drug exposure during adolescence and adulthood on impulse control and related cognitive functions. Alcohol and marijuana abuse are particularly prevalent in adolescents and young adults and this is associated with greater levels of impulsivity and risky behavior as compared with adolescents who use either drug exclusively. Adolescent rats are known to be particularly susceptible to the neurotoxic and behavioral effects of EtOH and Δ9-THC. However, the cognitive consequences of adolescent exposure to these drugs, individually or in combination, are relatively unexplored. Two Specific Aims are proposed in this administrative supplement: (1) To compare the effects of repeated intermittent EtOH, Δ9-THC and combined EtOH/Δ9-THC exposure during adolescence versus adulthood on impulsive action and attentional capacity in the 5-CSRTT, and (2) To characterize the nature of dysregulated cortical neurotransmitter signaling induced by chronic exposure to EtOH, Δ9-THC and their combination during adolescence and adulthood. These Aims directly correlate with Specific Aims 1 & 2 of the parent RO1 project.


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