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Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats

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Abstract

Rationale

The development of addiction is accompanied by a shift in the mechanisms motivating cocaine use from nucleus accumbens (NAc) dopamine D1 receptor (D1R) signaling to glutamate AMPA-kainate receptor (AMPA-R) signaling.

Objective

Here, we determined whether similar shifts occur for NAc-D2R signaling and following systemic manipulation of D1R, D2R, and AMPA-R signaling.

Methods

Male rats were given short-access (20 infusions/day) or extended-access to cocaine (24 h/day, 96 infusions/day, 10 days). Motivation for cocaine was assessed following 14 days of abstinence using a progressive-ratio schedule. Once responding stabilized, the effects of NAc-D2R antagonism (eticlopride; 0–10.0 μg/side) and systemic D1R (SCH-23390; 0–1.0 mg/kg), D2R (eticlopride; 0–0.1 mg/kg), and AMPA-R (CNQX; 0–1.5 mg/kg) antagonism, and NAc-dopamine-R gene expression (Drd1/2/3) were examined.

Results

Motivation for cocaine was markedly higher in the extended- versus short-access group confirming the development of an addiction-like phenotype in the extended-access group. NAc-infused eticlopride decreased motivation for cocaine in both the short- and extended-access groups although low doses (0.1–0.3 μg) were more effective in the short-access group and high doses (3–10 μg/side) tended to be more effective in the extended-access group. Systemic administration of eticlopride (0.1 mg/kg) was more effective in the extended-access group, and systemic administration of CNQX was effective in the extended- but not short-access group. NAc-Drd2 expression was decreased in both the short- and extended-access groups.

Conclusion

These findings indicate that in contrast to NAc-D1R, D2R remain critical for motivating cocaine use with the development of an addiction-like phenotype. These findings also indicate that shifts in the mechanisms motivating cocaine use impact the response to both site-specific and systemic pharmacological treatment.

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Acknowledgments

We would like to acknowledge Lasya Pidaparthi for technical assistance.

Funding

This study was supported by the National Institute on Drug Abuse (2R01DA024716; WJL).

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  1. Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, PO Box 801402, Charlottesville, VA, 22904, USA

    Wendy J. Lynch, Anousheh Bakhti-Suroosh, Jean M. Abel & Camilla Davis

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  1. Wendy J. Lynch
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Correspondence to Wendy J. Lynch.

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Lynch, W.J., Bakhti-Suroosh, A., Abel, J.M. et al. Shifts in the neurobiological mechanisms motivating cocaine use with the development of an addiction-like phenotype in male rats. Psychopharmacology 238, 811–823 (2021). https://doi.org/10.1007/s00213-020-05732-4

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