Early-Life Stress Drives Increased Heroin Vulnerability: Role of D3 Receptors

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PROJECT SUMMARY Stress and addiction are intricately linked neural processes. Acute stress can serve as a stimulus for relapse to compulsive drug seeking following abstinence, and chronic stress can induce escalated drug intake to multiple classes of drugs. The Jones lab and others have shown that the chronic psychosocial stressor of adolescent social isolation (aSI) leads to impairments in dopamine (DA) function in the nucleus accumbens (NAc) and increased vulnerability to stimulant drug and alcohol taking that persists into adulthood. However, it is unknown how aSI affects consumption of opioids. In the current proposal, I have demonstrated that aSI leads to a robust increase in heroin self-administration, propensity for relapse, and heroin withdrawal-induced negative affect. This increase in vulnerability to heroin in aSI rats was coupled with data showing a greater reduction of dopamine function than aGH animals that may drive this increase in heroin behaviors in aSI animals. The F99 phase of this proposal will primarily examine the role dopamine D3 autoreceptor (D3autoR) in the NAc in driving increased heroin vulnerability and reduced dopamine transmission in aSI rats. I hypothesize that the combination of aSI stress and heroin self-administration synergistically increase D3autoR-mediated adaptations in the mesolimbic DA system producing hypodopaminergia and increasing heroin use vulnerability. The proposed project will also help the candidate, Ms. Brianna George, achieve her career goal of becoming an independent investigator at a research-intensive institution. This project provides training in valuable research techniques, including fast-scan cyclic voltammetry, RNAscope, and gene silencing. Further, the proposed studies will provide professional and technical training to prepare the candidate to successfully transition to a postdoctoral position (K00) in a laboratory that studies the neural-circuitry driving vulnerability to drug-seeking behavior. The complete plan proposed here for both the F99 and K00 phases has been designed to develop an independent neurobiologist prepared for a transition to a successful postdoctoral position and, ultimately, independent tenured investigator.