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Cognitive Consequences of Alterations in Functional Circuitry Induced by Chronic Cocaine Use and the Potential Impact for Treatment

  • Stacy A. Castner
    Correspondence
    Address correspondence to: Stacy A. Castner, Ph.D., Department of Psychiatry, Yale School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511
    Affiliations
    Department of Psychiatry, Yale University School of Medicine, New Haven, and VA Connecticut Healthcare System, West Haven, Connecticut
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  • Graham V. Williams
    Affiliations
    Department of Psychiatry, Yale University School of Medicine, New Haven, and VA Connecticut Healthcare System, West Haven, Connecticut
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      Chronic cocaine exposure induces changes in brain function that persist into abstinence. Although direct mechanisms of action on glutamatergic and dopaminergic transmission have been identified, there are long-term consequences for corticostriatal function and cognition. The extent to which perturbations in functional circuitry persist during abstinence may predict the efficacy of different treatments depending on distinct cognitive processes. In Gould et al. (
      • Gould R.W.
      • Gage H.D.
      • Nader M.A.
      Effects of chronic cocaine self-administration on cognition and cerebral glucose utilization in rhesus monkeys.
      ), the effects of chronic cocaine were examined on cognitive flexibility—the ability to switch responses away from one stimulus to another, based on learning from outcome and selective attention. In reversal learning, the response to a particular stimulus must be inhibited once it is no longer rewarded, and both attention and response must then be directed to an alternative stimulus. Monkeys with a prolonged history of cocaine self-administration performed significantly worse than naive animals, suggesting that they had a reduced ability to inhibit a previously goal-directed response. The capacity for response inhibition has been strongly linked to regions of prefrontal cortex (PFC), particularly orbitofrontal cortex (OFC), when primary reinforcers are used as reward. OFC plays a major role in incentive motivation, linking the perceived reward value of a stimulus to the propensity to respond to it rather than other stimuli of lesser value. The finding that chronic cocaine impaired reversal learning strongly pinpoints a potential deficit in OFC function. In a previous study (
      • Liu S
      • Heitz RP
      • Sampson AR
      • Zhang W
      • Bradberry CW
      Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration.
      ), cocaine-experienced monkeys seldom reached criterion for acquisition of a visual discrimination task required for testing on stimulus reversal. This result was interpreted as indicating a possible impairment of medial temporal lobe (MTL) function in the perceptual discrimination of the visual stimuli. However, findings from the Gould et al. study (
      • Gould R.W.
      • Gage H.D.
      • Nader M.A.
      Effects of chronic cocaine self-administration on cognition and cerebral glucose utilization in rhesus monkeys.
      ) suggest that such impairment may depend on the task parameters used: criterion for discrimination was set by six correct trials in a row, whereas in the earlier study, 18 of 20 correct trials were required. Thus, it may not have been visual discrimination that was impaired per se in the previous study but rather the ability to maintain a particular stimulus–response relationship over more than a few trials. Performance in the current study (
      • Gould R.W.
      • Gage H.D.
      • Nader M.A.
      Effects of chronic cocaine self-administration on cognition and cerebral glucose utilization in rhesus monkeys.
      ) may have been primarily guided by habit and prepotent responding dependent on striatal function, whereas that in the previous study (
      • Liu S
      • Heitz RP
      • Sampson AR
      • Zhang W
      • Bradberry CW
      Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration.
      ) may have relied more on working memory for reward valency, in which OFC plays a pivotal role. Interpreted this way, the results are consistent, especially considering that the current study used a complete distinction between reward (food pellet) or no reward, whereas that of Liu et al. (
      • Liu S
      • Heitz RP
      • Sampson AR
      • Zhang W
      • Bradberry CW
      Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration.
      ) used a subtle difference in reward magnitude between responses to the S+ and S– stimuli, a distinction normally conveyed by OFC. Porter et al. (
      • Porter JN
      • Olsen AS
      • Gurnsey K
      • Dugan BP
      • Jedema HP
      • Bradberry CW
      Chronic cocaine self-administration in rhesus monkeys: Impact on associative learning, cognitive control and working memory.
      ) later demonstrated that cocaine-experienced animals were able to reach criterion on the task when a much higher contrast in reward contingency was used, further implicating a potential paucity of OFC function for the impaired performance in the earlier study (
      • Liu S
      • Heitz RP
      • Sampson AR
      • Zhang W
      • Bradberry CW
      Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration.
      ). This reasoning extends to findings from studies of other stimulants; amphetamine sensitization in monkeys profoundly impairs acquisition of working memory tasks but not visual discrimination (
      • Castner SA
      • Vosler PS
      • Goldman-Rakic PS
      Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex.
      ). Taken together, this suggests that when explicit reward is present, visual discrimination can still be acquired after prolonged stimulant exposure and that OFC rather than MTL disruption is involved.
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