Hippocampal and amygdalar increased BDNF expression in the extinction of opioid-induced place preference

Abstract

The opioid crisis was exacerbated during the COVID-19 pandemic in the United States with alarming statistics about overdose-related deaths (Ahmad et al., 2022). Current treatment options, such as medication assisted treatments, have been unable to prevent relapse in many patients, whereas cue-based exposure therapy have had mixed results in human trials. To improve patient outcomes, it is imperative to develop animal models of addiction to understand molecular mechanisms and identify potential therapeutic targets. We previously found increased brain derived neurotrophic factor (bdnf) transcript in the ventral striatum/nucleus accumbens (VS/NAc) of rats that extinguished morphine-induced place preference. Here, we expand our study to determine whether BDNF protein expression was modulated in mesolimbic brain regions of the reward system in animals exposed to extinction training. Drug conditioning and extinction sessions were followed by Western blots for BDNF in the hippocampus (HPC), amygdala (AMY) and VS/NAc. Rears, as a measure of withdrawal-induced anxiety were also measured to determine their impact on extinction. Results showed that animals who received extinction training and successfully extinguished morphine CPP significantly increased BDNF in the HPC when compared to animals deprived of extinction training (sham-extinction). This increase was not significant in animals who failed to extinguish (extinction-resistant). In AMY, all extinction-trained animals showed increased BDNF, regardless of behavior phenotype. No BDNF modulation was observed in the VS/NAc. Finally, extinction-trained animals showed no difference in rears regardless of extinction outcome, suggesting that anxiety elicited by drug withdrawal did not significantly impact extinction of morphine CPP. Our results suggest that BDNF expression in brain regions of the mesolimbic reward system could play a key role in extinction of opioid-induced maladaptive behaviors and represents a potential therapeutic target for future combined pharmacological and extinction-based therapies.