Treatment of cocaine addiction beyond the period of acute withdrawal must be pursued in order to effectively mitigate the risk of relapse in recovering addicts, as cue-induced drug craving may increase as withdrawal progresses. Similarly, rats show a progressive increase in cue-induced cocaine craving after withdrawal from extended access cocaine self-administration, a phenomenon termed "incubation of cocaine craving." My lab's prior work has shown that high conductance calcium-permeable AMPA receptors (CP-AMPARs) accumulate in nucleus accumbens (NAc) synapses during incubation and mediate the expression of "incubated" cocaine craving. Furthermore, mGluR1, which normally exerts little effect on synaptic transmission in the NAc, decreases CP-AMPAR function after "incubation" through a form of mGluR1-LTD and thus reduces cocaine craving. Thus mGluR1 is a potential target for the development of pharmacotherapies for cocaine addiction. Other adaptations also occur in the NAc during "incubation" in addition to CP-AMPAR accumulation and gain of mGluR1-LTD, including loss of mGluR5-mediated synaptic depression and the development of type 1 cannabinoid receptor (CB1R) supersensitivity. Despite the potential relevance of these changes for regulating cue-induced cocaine craving, little is known about the sequence in which they emerge, the mechanisms that promote their development, or the relationship that might exist between them. The objective of this proposal is to fill these gap and thus obtain mechanistic information which can be used to develop pharmacotherapies for cocaine craving.
In Aim 1, I will use whole-cell patch-clamp electrophysiology and immunoblotting to determine the time-course of adaptations in CP-AMPAR, mGluR1, mGluR5 and CB1R transmission in the NAc during incubation of cocaine craving. My working hypotheses are: (i) gain of mGluR1-LTD occurs in tandem with increased expression of CP-AMPARs and (ii) loss of mGluR5-mediated synaptic depression and development of CB1R supersensitivity develop in tandem at a later withdrawal time.
In Aim 2, I will use whole-cell patch- clamp electrophysiology to determine mechanisms underlying the mGluR1-mediated decrease in CP-AMPAR transmission in the NAc of "incubated rats". My working hypotheses are: i) mGluR1-LTD is mediated by the internalization of high conductance CP-AMPARs, which are in turn replaced by lower conductance GluA2- containing calcium-impermeable AMPARs, leading to synaptic depression, ii) this process requires the trafficking protein PICK1, and iii) protein synthesis is required for maintenance of CP-AMPARs in NAc synapses from "incubated rats" and thus protein-synthesis inhibition occludes mGluR1-mediated CP-AMPAR removal from synapses. While these studies are underway, I will participate in a Training Plan that employs individual mentoring, collaborative interactions, and coursework in research skills and ethical conduct of research to develop the skills needed to reach my goal of becoming a principal investigator in an academic setting.
Environmental cues previously associated with drug use are powerful triggers for relapse in abstinent cocaine users. The proposed research is relevant to NIH's mission of reducing the burden of illness because it characterizes neuronal plasticity underlying enhanced cue-induced cocaine craving during withdrawal and mechanisms for reversal of this plasticity. The results have translational significance because this reversal can be achieved using a class of drugs currently under development for human use.
|Loweth, Jessica A; Scheyer, Andrew F; Milovanovic, Mike et al. (2014) Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. Nat Neurosci 17:73-80|
|Scheyer, Andrew F; Wolf, Marina E; Tseng, Kuei Y (2014) A protein synthesis-dependent mechanism sustains calcium-permeable AMPA receptor transmission in nucleus accumbens synapses during withdrawal from cocaine self-administration. J Neurosci 34:3095-100|