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

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.