Dynamic CRMP2 regulation of CaV2.2 in the prefrontal cortex contributes to the reinstatement of cocaine seeking

Abstract

227/250 words) Cocaine addiction is 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.Keywords (6 max): CaV2.2, cocaine reinstatement, collapsin response mediator protein 2 (CRMP2), myr-TAT-CBD3, prefrontal cortex (PFC)

Genetic diversity fuels gene discovery for tobacco and alcohol use

“…By contrast, this locus was fine-mapped to two variants in high LD with rs16969968 for CigDay (r 2 = 0.84 and 0.86), suggesting that the variants underlying this signal for smoking initiation may be distinct from those for cigarettes per day. We also found a novel association between SmkInit and CACNA1B, which encodes a voltage-gated calcium channel (Ca v 2.2) that controls neuronal neurotransmitter release and has been associated with cocaine reinstatement 13 , increased aggression and vigilance, and reduced startle and exploration 14 . CACNA1B is linked to multiple psychiatric disorders, including schizophrenia, bipolar disorder and autism spectrum disorders [15][16][17] .…”

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

“…The receptor might also be part of a group of modulators that localize Ca V 2.2 to postsynaptic sites, particularly in layer V/VI pyramidal neurons of the mPFC. It was recently shown that the collapsing response mediator protein 2 (CRMP2) augments Ca V 2.2 protein in PFC neurons, an effect tied to cue reinstatement after cocaine self-administration extinction ( Buchta et al, 2020 ). Thus, it is possible that Ca V 2.2, a typically presynaptic calcium channel, is playing a noncanonical role at postsynaptic sites in PFC neurons, and that D1R, among other modulators, stabilizes Ca V 2.2 protein at these sites.…”

Reduced cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice

“…Nowadays, there are few effective pharmacological treatments available for cocaine use disorders, and frequently, psychosocial interventions in combination with pharmacotherapy are needed (Kampman, 2019). Studies performed in mice have pinpointed multiple potential therapeutic approaches for the reinstatement of cocaine-seeking behavior, targeting the reward circuit (Buchta et al, 2020). In humans, treatment with bupropion, topiramate, or disulfiram has been widely used.…”