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Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels

Molecular Psychiatry volume 25, pages 2373–2391 (2020)Cite this article

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Abstract

Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→ NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals.

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Acknowledgements

We would like to thank Nii Addy, Kristen Pleil, and Francis Lee for their input and edits on the paper. This work was supported by grants to AMR from the National Institute of Drug Abuse (5R01DA029122), The New York Weill Cornell Alumni Council Award, and the Paul Fund along with grants to CL from the National Institute of Mental Health, the One Mind Institute, The Hartwell Foundation, the Rita Allen foundation, the Klingenstein–Simons Foundation Fund, and the Brain and Behavior Research Foundation. Grants to NVD from Kellen Jr Faculty (Anna-Maria and Stephen Kellen Foundation) and Affinito-Stewart (President’s Council of Cornell Women), grants to TLK from NIAAA (U24AA025475 and U01AA020911), and grants to TAM from NIH (DA08259 and HL098351). CCB was supported by a T32 grant from NIDA (T32DA039080-01), a TL1 grant from the National Center for Advancing Translation Sciences (TL1TR002386), and the Frank & Blanche Mowrer Memorial Fellowship. RNF was supported by a T32 grant from NIGMS (T32GM007739) and an NRSA from NIMH (F30MH115622). CEB was supported by a T32 grant from NIDA (T32DA039080-01) and the Frank & Blanche Mowrer Memorial Fellowship. BSH was supported by an NSF GRFP fellowship (ID# 2015174265, Award# 1257284) and the Jacques Cohenca Predoctoral Fellowship. RB was supported by a T32 grant from NIGMS (T32GM007739) and an NRSA from NIMH (F30MH117939).

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Authors and Affiliations

  1. Department of Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, 10065, USA

    Charlotte C. Bavley, Caitlin E. Burgdorf, Alexander P. Walsh, Delaney K. Fischer, Jonathan E. Hackett, Susan A. Antigua & Anjali M. Rajadhyaksha

  2. Feil Family Brain and Mind and Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA

    Charlotte C. Bavley, Robert N. Fetcho, Caitlin E. Burgdorf, Delaney K. Fischer, Baila S. Hall, Nicole M. Sayles, Natalina H. Contoreggi, Rachel Babij, Teresa A. Milner, Conor Liston & Anjali M. Rajadhyaksha

  3. Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, Weill Cornell Medicine, New York, NY, 10065, USA

    Robert N. Fetcho & Rachel Babij

  4. Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10021, USA

    Natalia V. De Marco García

  5. Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Thomas L. Kash

  6. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, 10065, USA

    Teresa A. Milner

  7. Sackler Institute for Developmental Psychobiology, Weill Cornell Medicine, New York, NY, 10065, USA

    Conor Liston

  8. Department of Psychiatry, Weill Cornell Medicine, New York, NY, 10065, USA

    Conor Liston

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  1. Charlotte C. Bavley
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Contributions

CCB, AMR, and CL designed experiments and wrote the paper. CCB, CEB, and DKF ran behavioral experiments. CCB and BH ran fiber photometry experiments. CCB performed stereotaxic surgeries. CCB and NS analyzed data for behavioral experiments. RNF analyzed data for fiber photometry experiments. APW, JH, and SA ran immunohistological experiments. TLK provided reagents. APW, NHC, and TAM performed RNAscope experiments. RB and NVD took confocal images for RNAscope experiments. NVD provided guidance for viral experiments.

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Correspondence to Anjali M. Rajadhyaksha.

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Bavley, C.C., Fetcho, R.N., Burgdorf, C.E. et al. Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels. Mol Psychiatry 25, 2373–2391 (2020). https://doi.org/10.1038/s41380-019-0513-2

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