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Inactivation of the infralimbic cortex decreases discriminative stimulus-controlled relapse to cocaine seeking in rats

Abstract

Persistent susceptibility to cue-induced relapse is a cardinal feature of addiction. Discriminative stimuli (DSs) are one type of drug-associated cue that signal drug availability (DS+) or unavailability (DS−) and control drug seeking prior to relapse. We previously established a trial-based procedure in rats to isolate DSs from context, conditioned stimuli, and other drug-associated cues during cocaine self-administration and demonstrated DS-controlled cocaine seeking up to 300 abstinence days. The behavioral and neural mechanisms underlying trial-based DS-control of drug seeking have rarely been investigated. Here we show that following discrimination training in our trial-based procedure, the DS+ and DS− independently control the expression and suppression of cocaine seeking during abstinence. Using microinjections of GABAA + GABAB receptor agonists (muscimol + baclofen) in medial prefrontal cortex, we report that infralimbic, but not prelimbic, subregion of medial prefrontal cortex is critical to persistent DS-controlled relapse to cocaine seeking after prolonged abstinence, but not DS-guided discriminated cocaine seeking or DS-controlled cocaine self-admininstration. Finally, using ex vivo whole-cell recordings from pyramidal neurons in the medial prefrontal cortex, we demonstrate that the disruption of DS-controlled cocaine seeking following infralimbic cortex microinjections of muscimol+baclofen is likely a result of suppression of synaptic transmission in the region via a presynaptic mechanism of action.

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Fig. 1: Individual contributions of DS+ and DS− to persistent DS-controlled cocaine seeking during abstinence.
Fig. 2: Microinjections of muscimol + baclofen into infralimbic cortex prior to DS-controlled cocaine relapse following abstinence.
Fig. 3: Microinjections of muscimol + baclofen into prelimbic cortex prior to DS-controlled cocaine relapse following abstinence.
Fig. 4: Microinjections into IL or PL prior to DS-controlled cocaine self-administration.
Fig. 5: Pharmacological manipulation of GABA receptors in infralimbic neurons using ex vivo brain slice electrophysiology.

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Acknowledgements

The authors thank Dr. David H. Epstein for statistical input and for thoughtful comments during the writing of this manuscript.

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R.M., L.A.R., B.J.T., J.M.B., Y.S., and B.T.H. designed the experiments; R.M., L.A.R., B.J.T., J.M.B., S.J.W., M.B.B., V.A.L., O.R.D., and L.E.K. ran the experiments and collected the data; R.M., L.A.R., B.J.T., S.J.W., M.B.B., V.A.L., O.R.D., and L.E.K. analyzed the data; R.M., L.A.R., B.J.T., Y.S., and B.T.H. wrote the paper. All authors reviewed and approved the final version prior to submission.

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Correspondence to Bruce T. Hope.

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Madangopal, R., Ramsey, L.A., Weber, S.J. et al. Inactivation of the infralimbic cortex decreases discriminative stimulus-controlled relapse to cocaine seeking in rats. Neuropsychopharmacol. 46, 1969–1980 (2021). https://doi.org/10.1038/s41386-021-01067-6

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