The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats

Abstract

Background Given the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats. Methods Rats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6 h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule. Results Animals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose. Conclusions LY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…For instance, mGlu 5 receptor antagonists produce a dose-dependent decrease in METH SA without affecting food reinforcement, suggesting that mGlu 5 receptors are involved in the reinforcing effects of METH, but not natural rewards (Osborne and Olive, 2008). Similar effects have been reported with the mGlu 2/3 antagonist LY379268 (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid) (Crawford et al, 2013;Kufahl et al, 2013). The mGlu 5 receptor is also involved in extinction learning, because administration of an mGlu 5 -positive allosteric modulator resulted in more rapid extinction of responding on the active SA lever.…”

Effect of the Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 2 AZD8529 on Incubation of Methamphetamine Craving After Prolonged Voluntary Abstinence in a Rat Model

“…LY379268 and related compounds decrease reinstatement induced by re-exposure to discrete, discriminative, or contextual cues that were previously associated with alcohol (71), heroin (72, 73), cocaine (74, 75), and methamphetamine (76) self-administration. LY379268 also decreases cocaine priming-induced reinstatement in squirrel monkeys (77) and nicotine and methamphetamine self-administration in rats (78, 79). We also found that systemic and central amygdala LY379268 injections decrease incubation of cocaine craving after forced abstinence (80).…”

The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine

“…For example, LY379268 reduces anxiety-like behavior only in animals with a history of extended access cocaine self-administration (Aujla et al, 2008). Additionally, studies have shown that mGluR2/3 activation attenuates cue-induced reinstatement of cocaine seeking (Baptista et al., 2004; Adewale et al, 2006) and decreases breakpoints on PR reinforcement schedules in animals with escalated cocaine (Hao et al 2010) and methamphetamine intake (Crawford et al, 2013). The current findings are consistent with these previous studies given our observation of reduced breakpoints at both the lower (0.03 mg/kg) and higher (0.30 mg/kg) doses of LY379268 used in the current study.…”

“…The current findings are consistent with these previous studies given our observation of reduced breakpoints at both the lower (0.03 mg/kg) and higher (0.30 mg/kg) doses of LY379268 used in the current study. Interestingly, LY379268 failed to affect responding for food on a PR, suggesting the possibility of a specific effect on cocaine-maintained responding (Crawford et al, 2013). …”

“…The doses used for LY379268 in the current study were selected because these doses do not affect feeding behavior in our experimental environment (Crawford et al, 2013), but show effects on other schedules of cocaine self-administration in other laboratories (Peters and Kalivas, 2006; Justinova et al, 2015). On subsequent days, breakpoints were recorded until they again reached a stable baseline with no treatment, following which, rats were administered with the second dose of LY379268 that they had not yet received (Phase One dose order counterbalanced).…”