Activation of group II mGlu receptors blocks the enhanced drug taking induced by previous exposure to amphetamine

Abstract

Repeated exposure to amphetamine (AMPH) leads to the development of behavioural sensitization that can be demonstrated in rats as enhanced locomotor responding to and self-administration of the drug. Glutamate systems are known to participate in the induction and expression of sensitization by psychostimulants. Group II metabotropic glutamate receptors (mGluRs), because they negatively regulate both vesicular and nonvesicular glutamate release, are thus well positioned to gate its expression. Here we report that the expression of locomotor sensitization by AMPH is completely prevented by a systemic injection of the selective group II mGluR agonist LY379268 at a dose that produced no effects when administered alone. The activation of group II mGluRs in AMPH-sensitized rats also reduced the enhanced overflow of both dopamine and glutamate normally observed in the nucleus accumbens, a brain region critical for the generation of locomotor and drug self-administration behaviours. To directly determine the effect of group II mGluR activation on enhanced drug self-administration, AMPH-sensitized rats were allowed to self-administer a mixture of LY379268 and AMPH. These rats continued to self-administer but did not exhibit the enhanced work output and drug intake observed in AMPH-sensitized rats self-administering AMPH alone. Thus, activating group II mGluRs prevents the expression of different manifestations of AMPH sensitization including enhanced self-administration of the drug. These receptors may represent a potentially important target for therapeutic intervention directed at drugs of abuse.

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

“…The higher LY379268 dose (3 mg/kg), when tested on its own in nicotine-naïve rats, decreased NAcc shell dopamine levels at some time-points postadministration compared with baseline dopamine levels (Figure 2a). This LY379268-induced dose-dependent decrease in basal NAcc shell dopamine levels in nicotine-naïve rats is consistent with previously published results (Greenslade and Mitchell, 2004;Hu et al, 1999;Kim et al, 2005;Xi et al, 2010a, b). Taken together, these findings reflect the fact that activation of mGlu2/3 receptors on presynaptic glutamate terminals decreases glutamate release, which in turn results in lower activation of dopamine neurons in areas such as the VTA and consequently decreases in dopamine release in terminal areas such as the NAcc.…”

“…Because mGlu2/3 receptor activation negatively regulates glutamatergic neurotransmission (Cartmell and Schoepp, 2000), we hypothesized that LY379268 decreases the reinforcing effects of nicotine by attenuating nicotineinduced increases in NAcc shell dopamine. This hypothesis is supported by the observation that mGlu2/3 receptors are expressed in the NAcc shell (Testa et al, 1998), and these receptors regulate both basal and psychostimulantinduced NAcc dopamine neurotransmission (Greenslade and Mitchell, 2004;Hu et al, 1999;Karasawa et al, 2006;Kim et al, 2005;Manzoni et al, 1997;Uslaner et al, 2009;Xi et al, 2002aXi et al, , 2010a. Furthermore, activation of mGlu2/3 receptors attenuated the dopamine-dependent psychostimulant-induced enhancement of locomotor activity (Kim et al, 2005;Riegel et al, 2003).…”

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

“…Finally, the present findings on the effect of intra-NAc LY379268 injections in a rat relapse model extend those from our previous study on the effect of systemic and intra-VTA injections of the drug on context-induced reinstatement of heroin seeking (Bossert et al, 2004). It was also reported that systemic injections of LY379268 attenuate (1) discrete cue-induced reinstatement of heroin seeking , (2) discriminative cue-induced reinstatement of cocaine seeking (Baptista et al, 2004), (3) cocaine priming-induced reinstatement (Peters et al, 2004), (4) enhanced amphetamine-taking behavior by prior sensitizing exposure to the drug (Kim et al, 2005), and (5) other behavioral effects of abused drugs (Kenny and Markou, 2004). Together, these results from preclinical studies suggest that pharmacological manipulations that target group II metabotropic glutamate receptors should be considered in the treatment of drug addiction.…”

“…The physical environments that provided Contexts A and B were counterbalanced. Drugs LY379268 (0.3, 1.0, and 3.0 mg) was dissolved in 1.2 M NaOH solution (pH adjusted to 7.4) (Kim and Vezina, 2002;Kim et al, 2005). The bilateral intracranial doses of LY379268 were based on our previous report (Bossert et al, 2004).…”

“…Systemic injections of LY379268 attenuate amphetamine-induced dopamine release (Kim et al, 2005) and agonist activation of NAc mGluR 2/3 decreases dopamine release (microdialysis probes were aimed at both the NAc core and shell). In addition, and potentially highly relevant to our results, local infusions of LY379268 reduce dopamine levels in the NAc shell, but not in the core (Greenslade and Mitchell, 2004).…”