Brain
glutamate has been shown to play an important role in reinstatement to
drug seeking, a behavior considered to be of relevance to relapse to
drug taking in humans. Therefore,
glutamate receptors, in particular metabotropic
glutamate (mGlu) receptors, have become important targets for medication development for the treatment of
drug dependence. In this review article, we focus on the mGlu7 receptor subtype, and discuss recent findings with
AMN082, a selective mGlu7 receptor allosteric agonist, in animal models with relevance to
drug dependence. Systemic or local administration of
AMN082 into the nucleus accumbens (NAc), a critical brain region involved in reward and
drug dependence processes, inhibited the reinforcing and motivational effects of
cocaine,
heroin and
ethanol, as assessed by the intravenous
drug self-administration procedure. In addition,
AMN082 inhibited the reward-enhancing effects induced by
cocaine, as assessed in the intracranial self-stimulation procedure, and
cocaine- or cue-induced reinstatement of drug-seeking behavior. In vivo microdialysis studies indicated that systemic or intra-NAc administration of
AMN082 significantly decreased extracellular γ-
aminobutyric acid (
GABA) and elevated extracellular
glutamate, but had no effect on extracellular
dopamine in the NAc, suggesting that a non-dopaminergic mechanism underlies the effects of
AMN082 on the actions of
cocaine. Further, data indicated that AMN082-induced changes in
glutamate were the net effect of two actions: one is the direct inhibition of
glutamate release by activation of mGlu7 receptors on glutamatergic neurons; another is the indirect increases of
glutamate release mediated by decreases in
GABA transmission. These increases in extracellular
glutamate functionally antagonized
cocaine-induced inhibition of NAc-ventral pallidum GABAergic neurotransmission, and therefore, the rewarding effects of
cocaine. In addition, elevated extracellular
glutamate activated presynaptic mGlu2/3
autoreceptors which in turn inhibited
cocaine priming- or cue-induced enhancement of
glutamate release and reinstatement of drug-seeking behavior. Taken together, these findings suggest that the mGlu7 receptor is an important target for medication development for the treatment of
drug dependence.
AMN082 or other mGlu7 receptor allosteric agonists may have potential as novel
pharmacotherapies for
cocaine addiction. This article is part of a Special Issue entitled '
Metabotropic Glutamate Receptors'.