The Role of Prefrontal Glutamate to Ventral Tegmental Area Gaba Neural Circuitry on Extinction of Methamphetamine Addiction

Drug addiction accounts as a phenomenon of compulsive drug use, which is accompanied by a high rate of relapse even after prolonged period of abstinence, however current treatment regimens remain relatively ineffective. To manage drug abuse, strengthening the extinction of drug memory in order to prevent drug relapse would be practical and essential. Previously, we reported that in methamphetamine conditioned place preference (METH-CPP) mice, lesion of medial prefrontal cortex (mPFC) disrupts the METH-CPP extinction and decreases GluR1/S845 phosphorylation. From the last grant period, we further found photo-inactivation of GABA interneuron, but not the projection GABA from the nucleus accumben-shell (NAc-shell), in the ventral tegmental area (VTA) abolishes the METH-CPP extinction. These results let us to speculate that mPFC glutamate sends out an extinction signal and targets on the VTA GABA interneuron, in turn suppresses neighboring dopamine (DA) activity and results in drug extinction. Considering there are different forebrain glutamate efferents that play a role upon aversion stimulus, we wonder these novel neural pathways might participate in drug extinction. To test this working hypothesis, we propose a 3-year grant period to conduct following experiments: (1) adopt optogenetic technique and the use of vGluT2::Cre mice with AAV-ChR2 or –eNpHR3.0 to test the significance of VTA micro-circuit and LHb-RMTg during the extinction of METH-CPP; (2) test if manipulation of GluR1/S845A or GluR1/S831A/S845A in the VTA would block the extinction signal derived from the vmPFC or LHb; (3) investigate if VTA-to-NAc glutamate projection would play a role during METH-CPP extinction and reinstatement; and (4) explore the role of orbital frontal cortex (OFC) glutamate on extinction and reinstatement of METH-CPP. All the behavioral experiment, after the last CPP re-test, will be subjected to anatomical and electrophysiological (in vitro brain slice recording) verification to validate the opto-manipulation. We believe through these experiments, in particular the novel brain structure and neural pathway in drug extinction research, we are able to dissect the cellular mechanism underlying context-associated appetitive extinction for its relationship with particular projection pathway. Therefore, we could have better chance to develop effective drug treatment program in strengthening the drug extinction hence prevent the drug relapse.

Project ID:PC10901-0048
External Project ID:MOST107-2320-B182-019-MY3