Emily Haque

Introduction. Cocaine addiction or substance use disorder is a chronic disease of dysfunction in the brain’s reward pathways resulting in persistent cocaine-seeking behaviors despite adverse consequences¹. There are currently no FDA-approved medications for the prevention or treatment of cocaine addiction. Cocaine exposure leads to altered BDNF expression in the ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)². BDNF signaling through TrkB receptors has a well-established role in cocaine reinforcement². However, the effects of BDNF vary based on brain-region, cell-type and phase of addiction making it a complex therapeutic target. Albeit, three recent studies have identified systemic BDNF-signaling antagonists, endocannabinoid-1 (eCB₁) antagonists, and epigenetic modification as promising therapeutic interventions for cocaine addiction^3-5. Methods. Utilizing a cocaine self-administration (SA) rat model, the effect of a systemic TrkB antagonist was examined in subjects after cocaine intake escalation stabilized³. This was achieved by using immunofluorescence to quantify the abundance of BDNF in the NAc and PFC brain slices³. To better understand the eCB-BDNF interaction involved in cocaine addiction, electrophysiological changes (long-term potentiation (LTP)) in VTA neurons were recorded in BNDF conditional knock-out mice (cKO) that were subjected to conditioned place preference (CPP) training and cocaine exposure⁴. CPP was compared before and after treatment with a TrkB agonist and/or CB₁ antagonist⁴. In order to examine the epigenetic contribution to cocaine addiction, mutant mice lacking a nucleosome remodeling protein, BAF53b, underwent CPP training and cocaine-induced LTP in NAc neurons was recorded⁵. CPP and LTP of mutants were compared before and after BDNF treatment⁵. Results. The systemic TrkB antagonist decreased cocaine SA and restored levels of BDNF to normal in the NAc and PFC³. BDNF cKO mice showed diminished LTP in VTA neurons and decreased CPP that was restored by a TrkB agonist⁴. However, this restoration of LTP and CPP was blocked when treated with a CB₁ antagonist⁴. Mutant mice lacking BAF53b showed diminished LTP in NAc neurons and decreased CPP that was restored to normal with BDNF treatment⁵. Conclusion. Despite the complexity of BDNF signaling in cocaine addiction, this pathway can be manipulated at a molecular level to induce cocaine-associated behavioral changes. Potential drug targets that impair BDNF signaling include TrkB antagonists and CB₁ antagonists which could prevent relapse of cocaine addiction. Additionally, impairment of BAF53b epigenetic modification could decrease cocaine-associated memory formation. These results indicate the need for further investigation of BDNF signaling targets in human models of cocaine addiction.

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3. Verheij MM, Vendruscolo LF, Caffino L, Giannotti G, Cazorla M, Fumagalli F, Riva MA, Homberg JR, Koob GF, Contet C. Systemic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self-Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex. J Neurosci. 2016 Aug 3;36(31):8149-59. doi: 10.1523/JNEUROSCI.2711-14.2016.
4. Zhong P, Liu Y, Hu Y, Wang T, Zhao Y, Liu Q. BDNF Interacts with Endocannabinoids to Regulate Cocaine-Induced Synaptic Plasticity in Mouse Midbrain Dopamine Neurons. The Journal of Neuroscience. 2015;35(10):4469-4481. doi:10.1523/JNEUROSCI.2924-14.2015.
5. White AO, Kramár EA, López AJ, et al. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens. Nature Communications. 2016;7:11725. doi:10.1038/ncomms11725.