Mediating Vulnerability to Stress-Induced Cocaine Relapse by Blocking the PACAP Cascade in the BNST

Amy Maldonado

 Introduction Cocaine is a Schedule II psychostimulant that causes dopaminergic overstimulation of the mesolimbic reward pathway. Monthly prevalence of cocaine use in United States is estimated at 1.9% of those age 12 years and older1. Although several aspects of the biological mechanisms underlying cocaine use are known, knowledge about pathways that distinguish relapse-vulnerable users from their more resilient counterparts is a considerable mystery with obvious therapeutic value2,3. Currently, behavioral interventions are the only FDA approved treatment for cocaine relapse prevention. Identification of key molecular and cellular components unique to cocaine stress-induced relapse may prove essential in increasing efficiency and efficacy of prevention, diagnostic, and treatment options. The bed nucleus of the striatum terminalis (BNST) is a well-connected structure that may mediate stress-induced relapse4,5. Pituitary Adenylate Cyclase Activating Peptide (PACAP) has been demonstrated to induce neuronal survival and synapse strengthening and is present within the BNST5,6,7. Methods Rats were trained to self-administer cocaine using light cue and lever presses for ten days followed by 20 days of extinction. The animals were subsequently tested for reinstatement of use given a footshock stressor. Further, intra-BNST PACAP agonist (PACAP38), antagonist (PACAP6-38), and vehicle were infused prior to reinstatement tests. Active lever presses were observed and interpreted as cocaine-seeking behavior. PACAP transcripts were measured via qPCR of micropunched BNST at varying timepoints8,9. Results Response to cocaine self-administration training corresponded with increase in intra-BNST PACAP transcript levels. Further, stress-induced cocaine reinstatement was eliminated by intraBNST infusion of PACAP6-38. It was exaggerated by intraBNST infusion of PACAP388,9. Conclusions Stress-induced cocaine reinstatement is controlled both subconsciously and consciously. However, the pathways controlling this are regulated by PACAP within the BNST. Furthermore, recent studies demonstrate the use of antibody therapy to block the PACAP38/PAC1 receptor interaction for therapeutic use in humans to treat headaches10. By directly targeting PACAP within the BNST, much therapeutic potential exists for preventing stress-induced cocaine relapse.

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