Journal
JOURNAL OF NEUROSCIENCE
Volume 39, Issue 9, Pages 1744-1754Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2615-18.2018
Keywords
addiction; alcohol; compulsivity; dopamine; seeking; striatum
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Funding
- Medical Research Council Programme Grant [MR/N02530X/1]
- R24 Alcohol Research Resource Award Grant from the National Institute on Alcohol Abuse and Alcoholism [R24 AA015512]
- MRC [MR/N02530X/1] Funding Source: UKRI
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The acquisition of drug, including alcohol, use is associated with activation of the mesolimbic dopamine system. However, over the course of drug exposure the control over drug seeking progressively devolves to anterior dorsal striatum (aDLS) dopamine-dependent mechanisms. The causal importance of this functional recruitment of aD LS in the switch from controlled to compulsive drug use in vulnerable individuals remains to be established. Here we tested the hypothesis that individual differences in the susceptibility to aDLS dopamine dependent control over alcohol seeking predicts and underlies the development of compulsive alcohol seeking. Male alcohol-preferring rats, the alcohol-preferring phenotype of which was confirmed in an intermittent two-bottle choice procedure, were implanted bilaterally with cannulae above the aDLS and trained instrumentally on a seeking taking chained schedule of alcohol reinforcement until some individuals developed compulsive seeking behavior. The susceptibility to aDLS dopamine control over behavior was investigated before and after the development of compulsivity by measuring the extent to which bilateral aDLS infusions of the dopamine receptor antagonist alpha-flupenthixol (0, 5, 10, and 15 mu g/side) decreased alcohol seeking at different stages of training, as follows: (1) after acquisition of instrumental taking responses for alcohol; (2) after alcohol-seeking behavior was well established; and (3) after the development of punishment-resistant alcohol seeking. Only alcohol-seeking, not alcohol-taking, responses became dependent on aDLS dopamine. Further, marked individual differences in the susceptibility of alcohol seeking to aDLS dopamine receptor blockade actually predicted the vulnerability to develop compulsive alcohol seeking, but only in subjects dependent on aDLS dopamine-dependent control.
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