Activation of Group II Metabotropic Glutamate Receptors in the Nucleus Accumbens Shell Attenuates Context-Induced Relapse to Heroin Seeking

Abstract

Using a rat relapse model, we previously reported that re-exposing rats to a drug-associated context, following extinction of operant responding in a different context, reinstates heroin seeking. In an initial pharmacological characterization, we found that the mGluR 2/3 agonist LY379268, which acts centrally to reduce evoked glutamate release, attenuates context-induced reinstatement of heroin seeking when injected systemically or into the ventral tegmental area, the cell body region of the mesolimbic dopamine system. Here, we tested whether injections of LY379268 into the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine system, would also attenuate context-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of responding, LY379268 was injected to different groups of rats into the NAc core or shell or into the caudate-putamen, a terminal region of the nigrastriatal dopamine system. Injections of LY379268 into the NAc shell (0.3 or 1.0 mg) dose-dependently attenuated context-induced reinstatement of heroin seeking. Injections of 1.0 mg of LY379268 into the NAc core had no effect, while a higher dose (3.0 mg) decreased this reinstatement. Injections of LY379268 (3.0 mg) 1.5 mm dorsal from the NAc core into the caudate-putamen were ineffective. Results suggest an important role of glutamate transmission in the NAc shell in context-induced reinstatement of heroin seeking.

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

“…In keeping with previous reports (Bossert et al, 2006Crombag et al, 2002), the present experiments showed that the context in which cocaine was initially self-administered was a strong stimulus for reinstating responding that had been extinguished in a different context. Thus, under control conditions rats that were returned to the selfadministration context, after extinction in a different context, showed an increase in responding compared to rats that remained in the extinction context.…”

“…This work has shown that the circuitry involved in mediating reinstatement induced by footshock overlaps substantially with that involved in mediating reinstatement induced by drug-associated cues and by drug priming (Shaham et al, 2003). Thus, regions such as the VTA, the PFC and the nucleus accumbens are all part of the circuitry involved in these different types of reinstatement (Bossert et al, 2006Capriles et al, 2003;Fuchs et al, 2005;McFarland et al, 2004;McFarland and Kalivas, 2001). Local infusion of a D1 receptor antagonist into the PFC blocked footshockinduced reinstatement suggesting that such reinstatement could result from enhanced dopaminergic activity in the PFC (Capriles et al, 2003).…”

“…This implies a role for dopamine in mediating this form of reinstatement. In terms of neuroanatomical substrates, both the VTA and the nucleus accumbens appear to be important elements of the circuitry mediating this behavior since microinfusion of the group II metabotropic glutamate receptor agonist LY379268 into these areas reduced context-induced reinstatement of heroin seeking (Bossert et al, , 2006. Previous work with 5-HT 2C receptor agonists including Ro60-0175 indicates that 5-HT 2C receptor activation reduces the activity of the mesolimbic dopamine system (Di Matteo et al, 2000a, b;Gobert et al, 2000) probably via an action at the VTA (Fletcher et al, 2004).…”

Rats with Extended Access to Cocaine Exhibit Increased Stress Reactivity and Sensitivity to the Anxiolytic-Like Effects of the mGluR 2/3 Agonist LY379268 during Abstinence

“…These findings also illustrate the importance of developing therapeutic interventions aimed at reducing stress as a strategy for reducing relapse risk. Consistent with recent reports showing a reduction in the response-reinstating effects of cocaine (Peters and Kalivas, 2006;Adewale et al, 2006), drug-associated stimuli (Baptista et al, 2004;Bossert et al, 2004Bossert et al, , 2006Zhao et al, 2006), and stressful stimuli (Zhao et al, 2006), the present data indicate that mGlu2/3 receptors may be promising treatment targets.…”

“…Recent animal studies have indicated pharmacotherapeutic potential of the mGlu2/3 receptor agonist LY379268 in treating relapse risk associated with cocaine (Peters and Kalivas, 2006;Adewale et al, 2006), drug-associated stimuli (Baptista et al, 2004;Bossert et al, 2004Bossert et al, , 2006Zhao et al, 2006), and stressful stimuli (Zhao et al, 2006). However, an important question is to what extent chronic drug use induces increased susceptibility to stress and thereby contributes to the maintenance or resumption of drug use.…”