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Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving

Neuropsychopharmacology (2024)Cite this article

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Abstract

Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or “incubates” during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

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Fig. 1: Behavior and virus expression in rats destined for fiber photometry.
Fig. 2: Fiber photometry recordings during cue-induced seeking tests.
Fig. 3: Analysis of behavior and DA responses during specific periods of cue-induced seeking tests.
Fig. 4: Intra-NAcc infusion of the D1R antagonist SCH39166 reduces cue-induced seeking on FAD40-50 but not FAD1.
Fig. 5: Intra-NAcc infusion of the D2R antagonist L-741,626 reduces cue-induced seeking on FAD40-50 but not FAD1.

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Acknowledgements

We thank Dr. John Williams for providing the GRAB_DA2m virus, Dr. Rajtarun Madangopal for assistance with MedPC code and python code, Dr. Venus Sherathiya for assistance with GuPPy, and Randall Olson for assistance with MATLAB code.

Funding

F31 DA057063 to SJW (as well as support from T32 DA007262); K99-R00 DA057360 to ABK; DA049930 and OHSU startup funds to MEW.

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  1. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA

    Sophia J. Weber, Alex B. Kawa, Madelyn M. Beutler, Hayley M. Kuhn, Alana L. Moutier, Jonathan G. Westlake, Lara M. Koyshman, Cloe D. Moreno, Amanda M. Wunsch & Marina E. Wolf

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  1. Sophia J. Weber
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Contributions

SJW and MEW developed the experiments and wrote the manuscript. SJW, ABK, MMB, HMK, ALM, JGW, LMK, and CDM conducted the experiments. AMW provided input on fiber photometry.

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Correspondence to Marina E. Wolf.

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MEW and OHSU have a financial interest in Eleutheria Pharmaceuticals LLC, a company that may have a commercial interest in results related to the research described herein. This potential conflict of interest has been reviewed and managed by OHSU. Wolf also serves as a Consultant for the University of Texas-Austin and has received compensation. The other authors declare no competing interests.

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Weber, S.J., Kawa, A.B., Beutler, M.M. et al. Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01992-2

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