Program Director/Principal Investigator (Last, First, Middle): Barreto-Estrada JL SUMMARY DBS Mechanisms of Morphine Extinction 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 therefore propose to use DBS as treatment for drug-seeking behaviors in a rat model. We previously 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). In other experiments (in the absence of DBS), we demonstrated that animals showing good rate of morphine extinction exhibited an increase in brain derived neurotrophic factor (BDNF) mRNA in the VS/NAc. In the present study, Aim 1 will examine whether LF-DBS of the VS/NAc increases BDNF expression in key regions of the brain reward circuit (i.e. PFC, amygdala, hippocampus and VS/NAc). In brief, rats expressing morphine-CPP will receive extinction sessions, together with LF-DBS (20 Hz). After the extinction test day, rats will be sacrificed and brains will be collected for Neu-N/BDNF immunohistochemistry.
Aim 1. 2 will test a cohort of animals to determine whether LF-DBS is effective in female rats for morphine extinction.
In Aim 2, the retrograde tracer cholera toxin subunit B, conjugated to Alexa Fluor-555 (CTB) will be injected in the VS/NAc and tested in Morphine/fast-extinction animals.
This aim will be done in the absence of DBS (2.1-baseline) or in the presence of DBS (2.2-tracer injected in IL) to determine the connectivity between brain regions associated with morphine extinction.
In Aim 3. 1 we will centrally infuse to IL, ANA-12, a BDNF receptor antagonist, while in Aim 3.2, systemic injections of 7,8DHF, a Trk B receptor agonist will be performed to behaviorally determine whether LF-DBS extinction enhancement is mediated by BDNF signaling. Future interventions of treatment-resistant patients will benefit of the characterization of the cellular and behavioral domains underlying morphine extinction after LF-DBS. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page
Barreto-Estrada, JL NARRATIVE The study will characterize a reliable methodology for drug extinction in animal models. This might establish the biological basis for future translational studies in humans that might allow addicted refractory patients to facilitate drug extinction and/or strengthen extinction memory. Protein molecules associated to DBS-induced drug extinction will be studied for the future establishment of surgical and/or pharmacological treatments. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page
