Abstract
Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlies MPEP-induced glutamate release. This interpretation was further supported by our findings that genetic deletion of CB1 receptors in CB1-knockout mice blocked both MPEP-enhanced extracellular glutamate and MPEP-induced reductions in cocaine self-administration. Together, these results indicate that the therapeutic anti-cocaine effects of mGluR5 antagonists are mediated by elevation of extracellular glutamate in the NAc via an endocannabinoid-CB1 receptor disinhibition mechanism.
Highlights
Drug addiction is a chronic brain disease characterized by drug-induced euphoria, craving and relapse to drug-seeking behavior after abstinence
We have recently reported that the Metabotropic glutamate receptor 5 (mGluR5) antagonists MTEP, fenobam and MFZ 10−7 are effective in attenuation of cocaine self-administration and relapse to drug-seeking behavior in rats[7,8]
We found that mGluR5-immunostaining was detected mainly in cell bodies of striatal neurons, not in GFAP-labeled astrocytes (Fig. 4A,B), suggesting that mGluR5s are located mainly on postsynaptic medium-spiny neurons in the nucleus accumbens (NAc) and MPEP-enhanced glutamate release may be derived from neuronal, not glial, sources
Summary
Drug addiction is a chronic brain disease characterized by drug-induced euphoria, craving and relapse to drug-seeking behavior after abstinence. Recent studies suggest that the metabotropic glutamate receptor 5 (mGluR5) is involved in cocaine reward and addiction[1,2], as genetic deletion or pharmacological blockade of mGluR5 inhibits cocaine self-administration[1,3,4,5,6,7,8] and cocaine-induced reinstatement of drug-seeking behavior[7,8,9,10,11]. We hypothesized that mGluR5s may modulate cocaine self-administration and reinstatement of cocaine-seeking behaviors by regulating presynaptic glutamate release via a retrograde eCB-CB1 receptor mechanism To test this hypothesis, we used multiple animal models of drug self-administration, combined with in vivo brain microdialysis and transgenic CB1 receptor knockout approaches, to study the interaction of cocaine, mGluR5 and CB1 receptors on drug-taking and drug-seeking behavior and on extracellular DA and glutamate levels in the NAc
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