Cellular Mechanism Underlying the Methamphetamine Extinction: Neuroplasticity Alteration in Mesolimbic Circuitry

[Of note, this project extends from our last year proposal, however was only approved by MOST for one year. We took reviewers suggestions and made significant modifications for this submission.] Drug addiction is viewed as a phenomenon of compulsive drug use, which is accompanied by a high rate of relapse even after prolonged abstinence while current treatment regimens remain relatively ineffective. To manage drug abuse, strengthening the extinction of drug memory (engram) in order to prevent drug relapse would be practical and essential. Previously, we found (a) in methamphetamine conditioned place preference (METH-CPP) mice, glutamate receptor GluR1/S845 phosphorylation enhanced in the ventral tegmental area (VTA) during METH-CPP extinction along with an increase in numbers of dendritic spine, while lesion of medial prefrontal cortex (mPFC) interrupts the METH-CPP extinction and decreases GluR1/S845 phosphorylation and numbers of VTA dendritic spine, and (b) mTOR signaling of nucleus accumbens (NAc) enhanced in behaviorally METH-sensitized mice, whiles mTORC1 inhibitor, rapamycin not only suppressed METH sensitization but prevented stress-induced METH-CPP relapse. These results let us to hypothesize that mPFC glutamate projection to the VTA consolidates the cue-associated drug extinction. Additionally, mTOR-mediated signaling in addiction pathway (VTA-NAc) reflects an altered neuroplasticity that involves in drug craving. To test this working hypothesis, we propose a 3-year research proposal to conduct following experiments: (1) adopt optogenetic technique via the use of specific Cre mice in combination with AAV-ChR2 or –eNpHR3.0 to manipulate VTA GABA interneuron or projection neuron (originates from NAc) and mPFC glutamate neuron and test the effect on METH-CPP extinction, verified by stress-induced METH-CPP relapse; (2) test if administration of glutamate receptor (NMDA, AMPA or mGluR5) (ant)agonists, GluR1(S845A) mutant or LV-shRNA would affect the extinction of METH-CPP, verified by stress-induced METH-CPP relapse; (3) biochemical analyses of above-mentioned behavioral animals for changes in glutamate receptor-mediated signalplex, mTOR signaling and dendritic arborization in the VTA; and (4) in METH-sensitized animals (represents stage of ‘drug craving’), obtain a comprehensive profiling of mTOR-dependent or synaptic proteins and test if manipulation of these targeted protein(s) would affect behavioral sensitization. We believe through these experiments, from molecule to systemic and focusing on drug extinction and craving, we are able to dissect the molecular mechanism of cue-associated appetitive (abuse drug) extinction for its relationship with mTOR-dependent synaptic alteration and explore effective drug therapeutic program in strengthening the drug addiction extinction.

Project ID:PC10507-0282
External Project ID:MOST105-2320-B182-012-MY2