Treatments to prevent cue-induced relapse in abstinent cocaine users are urgently needed. In a rat model of persistent relapse vulnerability, extended access cocaine self-administration leads to a withdrawal-dependent "incubation" of cue-induced cocaine craving. After >1 month of withdrawal, incubation depends on increased synaptic strength in the nucleus accumbens (NAc) mediated by a very persistent elevation of high conductance Ca2+-permeable AMPARs (CP-AMPARs) and by related changes in group I metabotropic glutamate receptor (mGluR) function. Our objective is to determine if maintenance of these long-lasting adaptations depends on dysregulation of protein translation in the NAc. It is well established that dendrites contain mRNAs for AMPAR subunits and other synaptic proteins, and dendritic translation of these mRNAs (controlled by NMDARs and mGluRs) is critical for plasticity. However, nothing is known about whether synaptic transmission regulates translation in the NAc under normal conditions or if drugs of abuse produce persistent alterations in translation in the NAc or in any brain region. By focusing on these fundamental yet unexplored questions, we will advance our understanding of normal NAc function as well as cocaine addiction. Our central hypothesis is: 1) synaptic adaptations in the NAc of "incubated rats" depend upon dysregulated translation;2) this dysregulation is due to loss of inhibitory tone on protein translation normally provided by spontaneous NMDAR transmission (minis) and the resulting Ca2+ influx;and 3) loss of this inhibitory tone reflects increased levels of GluN3-containing NMDARs, which have very low Ca2+ permeability. We have 3 Aims. First, we will use metabolic labeling in brain slices to determine if the overall basal rate of protein translatio or the translation of key proteins (GluA1 or Arc) increases after incubation, and if NMDAR and mGluR1/5 regulation of translation is altered. Related questions will be studied in cultured NAc neurons, a system in which dendritic translation can be unequivocally measured. Second, array tomography and postembedding immunogold electron microscopy will be used to define expression and colocalization at the single synapse level of AMPAR subunits, NMDAR subunits, and group I mGluRs. We hypothesize that NAc synapses in "incubated rats" that are enriched for GluA1 relative to GluA2, indicative of CP-AMPARs, will also be enriched for GluN3. Third, whole-cell patch clamp recordings will determine if incubation is associated with an increased contribution of GluN3-containing NMDARs to synaptic transmission in the NAc, and whether mGluR1 stimulation, which removes CP-AMPARs from synapses, also removes GluN3-NMDARs. Overall, we are testing innovative hypotheses using state-of-the-art methods, several of which have never been applied to addiction research. Furthermore, given that fragile X research has identified aberrant protein translation as a viable therapeutic target, and given intriguing recent evidence that altered protein translation underlies the rapid antidepressant effect of ketamine, our findings will have broad significance for research aimed at normalizing aberrant protein translation in a variety of brain disorders.
In abstinent cocaine 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 the mechanisms that maintain persistent cocaine craving and vulnerability to relapse even after prolonged periods of abstinence. Because we are studying previously unexplored mechanisms for cocaine-induced plasticity, our results may lead to novel strategies for treating cocaine addiction.
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