The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning

Abstract

Cocaine addiction is a chronic, relapsing disease characterized by an inability to regulate drug-seeking behavior. Here we investigated the role of mGluR5 in the ventral and dorsal striatum in regulating cocaine-seeking following both abstinence and extinction. Animals underwent 2 weeks of cocaine self-administration followed by 3 weeks of home-cage abstinence. Animals were then reintroduced to the operant chamber for a context-induced relapse test, followed by 7–10 days of extinction training. Once responding was extinguished, cue-primed reinstatement test was conducted. Both drug-seeking tests were conducted in the presence of either the mGluR5 negative allosteric modulator, MTEP or vehicle infused into either the nucleus accumbens (NA) core or dorsolateral striatum (dlSTR). We found that MTEP infused in the NA core attenuated both context-induced relapse following abstinence and cue-primed reinstatement following extinction training. Blocking dlSTR mGluR5 had no effect on context- or cue-induced cocaine-seeking. However, the intra-dlSTR MTEP infusion on the context-induced relapse test day attenuated extinction learning for 4 days after the infusion. Furthermore, mGluR5 surface expression was reduced and LTD was absent in dlSTR slices of animals undergoing 3 weeks of abstinence from cocaine but not sucrose self-administration. LTD was restored by bath application of VU-29, a positive allosteric modulator of mGluR5. Bath application of MTEP prevented the induction of LTD in dSTR slices from sucrose animals. Taken together, this data indicates that dlSTR mGluR5 plays an essential role in extinction learning but not cocaine relapse, while NA core mGluR5 modulates drug-seeking following both extinction and abstinence from cocaine self-administration.

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…Recent data suggest that in vitro induction of mGluR5-dependent LTD in NAc shell slices from cocaine-treated animals is disrupted, rather than facilitated (Huang et al, 2014;Huang et al, 2011). These data match a broader pattern of disruption of mGluR5-dependent LTD in other striatal regions and the bed nucleus of the stria terminalis in brain slices from cocaine-treated animals (Grueter et al, 2006;Grueter et al, 2008;Knackstedt et al, 2014) that may be related to reduced mGluR5 expression (Huang et al, 2011) or decreased presence on the cell surface (Knackstedt et al, 2010). These studies have employed the useful strategy of applying trains of electrical stimulation or directly activating mGluRs with agonist (eg, DHPG) to induce plasticity ex vivo.…”

Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

“…Current findings are reminiscent of the loss of (glutamatedependent) LTD seen following chronic exposure to psychostimulant drugs of abuse that occurs in the DS as well as the nucleus accumbens (31)(32)(33)(34). By limiting synaptic rescaling, drug-induced loss of LTD has been posited to impair the responsivity of accumbal circuits to new (e.g., cortically derived) environmental information, and thereby contribute to behavioral inflexibility in addiction (33).…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…(S)-3,5-Dihydroxyphenylglycine infusion into the NAshell also promotes cocaine seeking (Schmidt et al, 2015). Infusion of the mGluR5 antagonist MTEP into the NAcore inhibited cue-and drug-induced cocaine seeking (Knackstedt et al, 2014) and cue-induced reinstatement of ethanol seeking (Sinclair et al, 2012). These data suggest that blockade of mGluR5 prevents synaptic potentiation of MSNs in response to glutamate overflow occurring during cue-and drug-primed drug seeking (Fig.…”