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 confe 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.
Alcoholics are plagued by cognitive impairments that include deficits in inhibitory control (impulsive action), poor evaluation of consequence (impulsive choice) and ineffective reversal of compulsive or habitual behavior (cognitive flexibility). However, it is not known whether these cognitive impairments pre-date and contribute to abusive alcohol use or result from long-term alcohol consumption. This project will characterize a rodent model of alcohol-induced cognitive disruption and will use this to study investigate the aberrant neurochemistry underlying alcohol-related cognitive disruption and to screen potential therapeutic drugs.
|Matzeu, Alessandra; Terenius, Lars; Martin-Fardon, Remi (2018) Exploring Sex Differences in the Attenuation of Ethanol Drinking by Naltrexone in Dependent Rats During Early and Protracted Abstinence. Alcohol Clin Exp Res 42:2466-2478|
|Schmeichel, Brooke E; Matzeu, Alessandra; Koebel, Pascale et al. (2018) Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. Neuropsychopharmacology 43:2373-2382|
|Berger, Anthony L; Henricks, Angela M; Lugo, Janelle M et al. (2018) The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 84:611-623|
|Pavon, Francisco J; Serrano, Antonia; Sidhpura, Nimish et al. (2018) Fatty acid amide hydrolase (FAAH) inactivation confers enhanced sensitivity to nicotine-induced dopamine release in the mouse nucleus accumbens. Addict Biol 23:723-734|
|Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850|
|Natividad, Luis A; Steinman, Michael Q; Laredo, Sarah A et al. (2017) Phosphorylation of calcium/calmodulin-dependent protein kinase II in the rat dorsal medial prefrontal cortex is associated with alcohol-induced cognitive inflexibility. Addict Biol :|
|Irimia, Cristina; Buczynski, Matthew W; Natividad, Luis A et al. (2017) Dysregulated Glycine Signaling Contributes to Increased Impulsivity during Protracted Alcohol Abstinence. J Neurosci 37:1853-1861|
|Curran, H Valerie; Freeman, Tom P; Mokrysz, Claire et al. (2016) Keep off the grass? Cannabis, cognition and addiction. Nat Rev Neurosci 17:293-306|
|Bilbao, Ainhoa; Serrano, Antonia; Cippitelli, Andrea et al. (2016) Role of the satiety factor oleoylethanolamide in alcoholism. Addict Biol 21:859-72|
|Parsons, Loren H; Hurd, Yasmin L (2015) Endocannabinoid signalling in reward and addiction. Nat Rev Neurosci 16:579-94|
Showing the most recent 10 out of 13 publications