BDNF in the Reward Circuit for DBS-Induced Opioid Extinction

Abstract/Summary
Deep brain stimulation (DBS) is a neurosurgical procedure that is used to treat neurologic and
psychiatric disorders. Recent research in both animals and humans has shown that DBS may be
an effective procedure for refractory addiction. We previously propose to use DBS as treatment
for drug-seeking behaviors in a rat animal model, and found that high frequency DBS (HF-DBS)
of the ventral striatum/nucleus accumbens (VS/NAc) impaired extinction of morphine-induced
conditioned place preference (CPP), whereas low frequency DBS (LF-DBS) enhanced extinction
memory (reducing drug seeking behavior). Interestingly, we also found that LF-DBS
significatively shortens the persistency of the drug (LF-DBS~10 days vs sham-DBS~40 days). At
the molecular level, we found that DBS-treated animals increased BDNF expression in the
hippocampus (HPC). However, drug reinstatement was not significatively prevented in LF-DBS-
treated animals when stimulation was applied only during extinction sessions. In this transition
between the SCORE-SuRE grant cycle, we propose to further advance the knowledge in drug-
seeking behavior, and in the underlying DBS’ mechanisms of action, by using pharmacological
and chemogenetic approaches. Therefore, in the present study, Aim 1a-c will determine whether
LF-DBS applied during extinction, in addition to provide electrical stimulation in the phase of
drug reinstatement prevents drug seeking in a higher percentage of animals. Also, BDNF
expression will be measured in the HPC, as well as in other brain regions, i.e., amygdala, VS/NAc,
and medial prefrontal cortex (mPFC). Aim 2a will use a pharmacological approach by infusing
BDNF and TrkB antagonist (ANA-12) in the VS/NAc to determine their effects in extinction of
morphine CPP. Since glutamatergic neurons in the HPC encompass a subpopulation of neurons
expressing BDNF, the approach in Aim 2b is to use the chemogenetic tool, known as designer
receptors exclusively activated by designer drugs (DREADDs) to activate HPC glutamatergic
neurons in the presence of ANA-12, to prevent extinction of morphine CPP. Activation of
DREADDs will be done with clozapine N-oxide (CNO). Aim 2c will inactivate HPC-NAc
glutamatergic/BDNFergic projections that will prevent the beneficial effects of LF-DBS. Our
study represents a circuit-based approach to better understand the action mechanisms of drug-
seeking and extinction. Because rodent models of drug extinction resemble exposure-based
therapies in humans, it is possible that targeted electrical stimulation and the DBS-increased
expression of pro-extinction molecules might represent an effective future approach to reduce the
symptoms of addiction and opioid use disorders (OUD).

Grant Number: 5R16GM149491-04
NIH Institute/Center: NIH
Principal Investigator: Jennifer Barreto Estrada