Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Nature Publishing Group
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Zhukovsky, P., Puaud, M., Jupp, B., Sala-Bayo, J., Alsiö, J., Xia, J., Searle, L., et al. (2019). Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44 (13), 2163-2173. https://doi.org/10.1038/s41386-019-0381-0
Addiction is regarded as a disorder of inflexible choice with behavior dominated by immediate positive rewards over longer-term negative outcomes. However, the psychological mechanisms underlying the effects of self-administered drugs on behavioral flexibility are not well understood. To investigate whether drug exposure causes asymmetric effects on positive and negative outcomes we used a reversal learning procedure to assess how reward contingencies are utilized to guide behavior in rats previously exposed to intravenous cocaine self-administration (SA). Twenty-four rats were screened for anxiety in an open-field prior to acquisition of cocaine SA over six daily sessions with subsequent long-access cocaine SA for seven days. Control rats (n=24) were trained to lever-press for food under a yoked schedule of reinforcement. Higher rates of cocaine SA were predicted by increased anxiety and preceded impaired reversal learning, expressed by a decrease in lose-shift as opposed to win-stay probability. A model-free reinforcement learning algorithm revealed that rats with high, but not low cocaine escalation failed to exploit previous reward learning and were more likely to repeat the same response as the previous trial. Eight-day withdrawal from high cocaine escalation was associated, respectively, with increased and decreased dopamine receptor D2 (DRD2) and serotonin receptor 2C (HTR2C) expression in the ventral striatum compared with controls. Dopamine receptor D1 (DRD1) expression was also significantly reduced in the orbitofrontal cortex of high cocaine-escalating rats. These findings indicate that withdrawal from escalated cocaine SA disrupts how negative feedback is used to guide goal-directed behavior for natural reinforcers and that trait anxiety may be a latent variable underlying this interaction.
Prefrontal Cortex, Animals, Rats, Cocaine, Receptors, Dopamine D1, Receptors, Dopamine D2, Receptors, Serotonin, 5-HT2, Conditioning, Operant, Reward, Reversal Learning, Models, Neurological, Male, Drug-Seeking Behavior, Ventral Striatum
Pinsent Darwin Studentship, Cambridge University Swedish Research Council AXA Research Fund National Health and MRC of Australia Cambridge Isaac Newton Trust Boehringer Ingelheim Pharma GmbH, Germany
Wellcome Trust (093875/Z/10/Z)
MEDICAL RESEARCH COUNCIL (G0001354)
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External DOI: https://doi.org/10.1038/s41386-019-0381-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/291186
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