Authors: Richiez-Mateo Wilma V. ¹, Torres-Rodríguez Cristal M.³, Lloret-Torres Mario², Bonilla-Rullan Pedro³, Pagán-Ayala Roxsana², Hernández-Román Leslievette³, Barreto-Estrada Jennifer².

Affiliations: ¹Department of Biology, University of Puerto Rico-Bayamón Campus 00959-1919; ²Department of Anatomy and Neurobiology, University of Puerto Rico-Medical Sciences Campus 00936 and ³Department of Biology, University of Puerto Rico, Rio Piedras Campus 00925-253.

Introduction: Drug-related overdoses in the United States have steadily increased over the past decades; however, opioids account for 74.8% of these deaths (CDC, 2022). Addiction is recognized as a cognitive disorder of chronic drug-seeking relapse; caused by aberrant learning patterns that induce neuroplasticity damage in the circuits of the mesocorticolimbic system. Understanding the role of brain plasticity in addiction is essential for mitigating the current public health crisis.

Methods: To elucidate the neurobiological role of BDNF, a pro-extinction protein that increases neuroplasticity in the reward mesolimbic system, we applied a conditioned place preference (CPP) protocol, followed by a forced extinction protocol. Withdrawal-related symptoms (rearings, grooming), and exploratory-based anxiety (side changes) were also assessed during morphine conditioning and extinction test days. Finally, Western Blot analysis were done to evaluate the BDNF expression in the amygdala and hippocampus.

Results: Previously, we showed that three distinctive behavioral phenotypes were observed after morphine CPP: the sham-extinction, extinction, and extinction resistant groups. In addition, the neuroplasticity transcript bdnf was upregulated within the ventral striatum/nucleus accumbens (VS/Nac) of males that extinguished morphine-conditioned place preference (CPP) after extinction training. Using the same methods, we found that although BDNF protein expression showed no significant difference in the VS/Nac, both males and females showed an upregulation within the hippocampus (HPC). In contrast, BDNF expression in the amygdala (AMY) was increased in both extinction and extinction-resistant groups, only in males. Furthermore, females show a higher likeability to extinguish their morphine CPP without extinction training as compared to males. On the other hand, withdrawal-related symptoms were significantly reduced in males that received extinction training, compared to sham-extinction animals. Although female withdrawal were unaffected by training, they showed significantly less withdrawal symptoms than males in their baseline trials.

Conclusion: Results demonstrate that although increased BDNF expression in the AMY might be responsible for contextual learning during extinction training, the increased BDNF expression in the HPC plays a crucial role in the successful extinction of opioid seeking behavior.

Support: Supported by: MBRS-SCORE-1SC2DA047809, NIGMS-RISE-R25GM061838 and NeuroID. IACUC Number: 9940112