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.
- Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: Results from the 2016 National Survey on Drug Use and Health. HHS Publication No. SMA 17-5044. 2016; NSDUH Series H-52.
- Korpi ER, den Hollander B, Farooq U, Vashchinkina E, Rajkumar R, Nutt DJ, et al. Mechanisms of action and persistent neuroplasticity by drugs of abuse. Pharmacological Reviews. 2015; 67(4), 872-1004.
- Bough KJ, Amur S, Lao G, Hemby SE, Tannu NS, Kampman KM, et al. Biomarkers for the development of new medications for cocaine dependence. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 2014; 39(1), 202-219.
- Bobadilla AC, Heinsbroek JA, Gipson CD, Griffin WC, Fowler CD, Kenny PJ, Kalivas PW. Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res. 2017;235:93-112.
- Ch’ng S, Fu J, Brown RM, McDougall SJ, Lawrence AJ. The intersection of stress and reward: BNST modulation of aversive and appetitive states. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Dec 20;87(Pt A):108-125.
- Castren E, Antila H. Neuronal plasticity and neurotrophic factors in drug responses. Molecular Psychiatry. 2017; 22(8), 1085-1095.
- May V, Lutz E, MacKenzie C, Schutz KC, Dozark K, Braas KM. Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J Biol Chem. 2010 Mar 26;285(13):9749-61.
- Miles OW, May V, Hammack SE. Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Signaling and the Dark Side of Addiction. J Mol Neurosci. 2018 Aug 3.
- Miles OW, Thrailkill EA, Linden AK, May V, Bouton ME, Hammack SE. Pituitary Adenylate Cyclase-Activating Peptide in the Bed Nucleus of the Stria Terminalis Mediates Stress-Induced Reinstatement of Cocaine Seeking in Rats. Neuropsychopharmacology. 2018 Apr;43(5):978-986.
- Rubio-Beltrán E, Correnti E, Deen M, Kamm K, Kelderman T, Papetti L, Vigneri S, MaassenVanDenBrink A, Edvinsson L; European Headache Federation School of Advanced Studies (EHF-SAS). PACAP38 and PAC(1) receptor blockade: a new target for headache? J Headache Pain. 2018 Aug 7;19(1):64.