In abstinent drug users, environmental cues associated with prior drug use are powerful triggers for relapse. This project focuses on mechanisms that maintain methamphetamine (Meth) craving and vulnerability to relapse even after prolonged periods of abstinence. In a rat model of persistent vulnerability to relapse, cue- induced drug craving progressively intensifies (`incubates') during abstinence from self-administration of many drugs of abuse, including Meth. Despite recent interest in the incubation of Meth craving, studies at the synaptic level are lacking. Such studies have the potential to identify novel therapeutic targets. Recently, we found that strengthening of synapses in the core subregion of the nucleus accumbens (NAc), via incorporation of high conductance Ca2+-permeable AMPARs (CP-AMPARs), underlies incubation of Meth craving after >40 days of abstinence. We also showed that positive allosteric modulators of mGluR1 remove these CP-AMPARs from NAc synapses and thereby reduce `incubated Meth craving'. These findings parallel our previous results on the incubation of cocaine craving. Importantly, however, incubation of craving and CP-AMPAR plasticity occur much more rapidly after discontinuing Meth (1 week) than cocaine (1 month). The narrower time-frame will facilitate identification of underlying synaptic mechanisms. However, first it is necessary to define fundamental parameters of the `incubation model' as it pertains to Meth. The main objective of this proposal is to determine how alterations in ionotropic glutamate receptor transmission in the NAc and its modulation by group I mGluRs contribute to the development and expression of `incubated Meth craving'. Our central hypothesis, formulated based on our cocaine studies and our recently published Meth work, is that incubation- related plasticity in the NAc begins with decreased mGluR1 function, enabling persistent changes in AMPAR and NMDAR transmission, which then maintain incubation of Meth craving. We propose 4 Aims that combine behavioral measures, biochemistry, and whole-cell patch-clamp recordings: 1) Define the time course (rising and falling phases) of incubation of Meth craving and accompanying CP-AMPAR plasticity in female and male rats. 2) Determine the subunit composition of CP-AMPARs that accumulate in the NAc core during incubation of Meth craving and test a potential underlying mechanism. 3) Determine the roles of group I mGluRs in the development and expression of Meth incubation, focusing on mGluR-LTD in the NAc core and on allosteric modulation of group I mGluRs as a potential therapeutic strategy. 4) Determine if NMDAR transmission in the NAc core is altered during the incubation of Meth craving, and if mGluR1 stimulation normalizes NMDAR plasticity. We expect our studies to define fundamental features of the incubation of Meth craving and its relationship to alterations in AMPAR, NMDAR and group I mGluR transmission in the NAc core. This in turn will enable novel research in a number of areas, including sex differences in relapse vulnerability, group I mGluR-based treatment strategies, and consequences of Meth-induced synaptic plasticity for NAc function.
In abstinent methamphetamine users, environmental cues associated with prior drug use are powerful triggers for relapse. The proposed research is relevant to NIH's mission of reducing the burden of illness because it explores, using male and female rats, the mechanisms that maintain persistent methamphetamine craving and vulnerability to relapse even after prolonged periods of abstinence. Because we are studying previously unexplored mechanisms for methamphetamine-induced plasticity, our results may lead to novel strategies for treating methamphetamine addiction.
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