Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking

William C. Buchta, Aubin Moutal, Bethany Hines, Constanza Garcia-Keller, Alexander C.W. Smith, Peter Kalivas, Rajesh Khanna, Arthur C. Riegel

Research output: Contribution to journalArticle

Abstract

Cocaine addiction remains a major health concern with limited effective treatment options. A better understanding of mechanisms underlying relapse may help inform the development of new pharmacotherapies. Emerging evidence suggests that collapsin response mediator protein 2 (CRMP2) regulates presynaptic excitatory neurotransmission and contributes to pathological changes during diseases, such as neuropathic pain and substance use disorders. We examined the role of CRMP2 and its interactions with a known binding partner, CaV2.2, in cocaine-seeking behavior. We employed the rodent self-administration model of relapse to drug seeking and focused on the prefrontal cortex (PFC) for its well-established role in reinstatement behaviors. Our results indicated that repeated cocaine self-administration resulted in a dynamic and persistent alteration in the PFC expression of CRMP2 and its binding partner, the CaV2.2 (N-type) voltage-gated calcium channel. Following cocaine self-administration and extinction training, the expression of both CRMP2 and CaV2.2 was reduced relative to yoked saline controls. By contrast, cued reinstatement potentiated CRMP2 expression and increased CaV2.2 expression above extinction levels. Lastly, we utilized the recently developed peptide myr-TAT-CBD3 to disrupt the interaction between CRMP2 and CaV2.2 in vivo. We assessed the reinstatement behavior after infusing this peptide directly into the medial PFC and found that it decreased cue-induced reinstatement of cocaine seeking. Taken together, these data suggest that neuroadaptations in the CRMP2/CaV2.2 signaling cascade in the PFC can facilitate drug-seeking behavior. Targeting such interactions has implications for the treatment of cocaine relapse behavior.

Original languageEnglish (US)
JournalMolecular Neurobiology
DOIs
StatePublished - Jan 1 2019

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Prefrontal Cortex
Cocaine
Self Administration
Recurrence
Drug-Seeking Behavior
Cocaine-Related Disorders
Peptides
Neuralgia
Calcium Channels
collapsin response mediator protein-2
Synaptic Transmission
Substance-Related Disorders
Cues
Rodentia
Drug Therapy
Health
Therapeutics
Pharmaceutical Preparations

Keywords

  • CaV2.2
  • Cocaine reinstatement
  • Collapsin response mediator protein 2 (CRMP2)
  • myr-TAT-CBD3
  • Prefrontal cortex (PFC)

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Buchta, W. C., Moutal, A., Hines, B., Garcia-Keller, C., Smith, A. C. W., Kalivas, P., ... Riegel, A. C. (2019). Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking. Molecular Neurobiology. https://doi.org/10.1007/s12035-019-01711-9

Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking. / Buchta, William C.; Moutal, Aubin; Hines, Bethany; Garcia-Keller, Constanza; Smith, Alexander C.W.; Kalivas, Peter; Khanna, Rajesh; Riegel, Arthur C.

In: Molecular Neurobiology, 01.01.2019.

Research output: Contribution to journalArticle

Buchta, William C. ; Moutal, Aubin ; Hines, Bethany ; Garcia-Keller, Constanza ; Smith, Alexander C.W. ; Kalivas, Peter ; Khanna, Rajesh ; Riegel, Arthur C. / Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking. In: Molecular Neurobiology. 2019.
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