Cocaine addiction is a chronic relapsing disorder characterized by compulsive cocaine use. Significant effort has been dedicated to reveal neurobehavioral factors responsible for promoting craving and drug seeking. Despite such effort, effective interventions to prevent cocaine relapse have yet to be established. An alternative research strategy may thus prove beneficial. For this premise, an omission cue-induced suppression (OCIS) paradigm was developed to investigate the relapse-suppressing potential of cues that signal cocaine omission (unavailability) in rats with a history of compulsiv cocaine intake. Preliminary results indicate a novel finding that, despite the history of compulsive cocaine intake, omission cues suppress cocaine seeking triggered by all major modes of relapse-promotion (drug cues, stress and cocaine priming) as well as cocaine intake. Additional results indicate that omission cues induce Fos (a marker of neural activation) in a discrete subpopulation of neurons localized within the medial prefrontal cortex (mPFC) - a region implicated in cognitive control of cocaine craving. Importantly, selective disruption of omission cue-activated neurons in mPFC blocked the subsequent expression of OCIS. Thus, 1) omission cue-induced neural activation in mPFC mediates OCIS. Because neural activation is a product of local excitatory neurotransmission, OCIS is likely controlled by 2) omission cue-activated excitatory neurotransmission in mPFC, as well as 3) omission cue- activated excitatory afferent innervations to mPFC - brain substrates known to provide the drive to induce neural activation in mPFC. Considering the above, this project will test the overarching hypothesis that OCIS of cocaine seeking is controlled by omission cue-activated excitatory neurotransmission and afferents driving distinct neural activation in mPFC.
Three Aims are proposed to establish the medial prefrontal cortical 1) neural phenotypes, 2) neurochemical signals and 3) neurocircuitry responsible for relapse-suppression by cocaine omission cues. Collectively, the expected results will establish brain mechanisms that actively suppress - rather than promote - cocaine relapse, and therefore present new insights for blocking relapse.

Public Health Relevance

Cocaine addiction is a chronic relapsing disorder characterized by compulsive cocaine use. The purpose of this grant is to combine a novel behavioral paradigm and advanced molecular, neurochemical, neuropharmacological, neuroanatomical as well as pharmacogenetic techniques to determine brain mechanisms that actively suppress 'addiction-like' cocaine seeking in rats. Since the majority of drug addiction research has focused on factors that promote relapse, our expected results could provide novel insights into the neurobiological underpinnings of cocaine craving and relapse, and aid to improve anti-relapse medication.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA037294-05
Application #
9618715
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Pariyadath, Vani
Project Start
2015-04-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037