This review summarizes the evidence for the potential involvement of metabotropic glutamate receptor 5 (mGluR5) in the development of nicotine addiction. Nicotine is consumed worldwide and is highly addictive. Previous research has extensively investigated the role of dopamine in association with reward learning and addiction, which has provided strong evidence for the involvement of dopaminergic neuronal circuitry in nicotine addiction. More recently, researchers focused on glutamatergic transmission after nicotine abuse, and its involvement in the reinforcing and rewarding effects of nicotine addiction. A number of robust preclinical and clinical studies have shown mGluR5 signaling as a facilitating mechanism of nicotine addiction and nicotine withdrawal. Specifically, clinical studies have illustrated lower cortical mGluR5 density in smokers compared to nonsmokers in the human brain. In addition, mGluR5 might selectively regulate craving and withdrawal. This suggests that mGluR5 could be a key receptor in the development of nicotine addiction and therefore clinical trials to examine the therapeutic potential of mGluR5 agents could help to contribute to reduce nicotine addiction in society.

Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.

Recent studies have demonstrated that metabotropic glutamate receptor 5 (mGluR5) antagonists decrease alcohol self-administration and suggest that the anti-craving medication, acamprosate, may also act to decrease mGluR5 function. To address the role of mGluR5 in behavioural actions of ethanol and acamprosate, we compared mutant mice with deletion of the mGluR5 gene and mice treated with a mGluR5 antagonist (MPEP) or acamprosate. Lack of mGluR5 or administration of MPEP reduced the severity of alcohol-induced withdrawal (AW), increased the sedative effect of alcohol (duration of loss of righting reflex; LORR), and increased basal motor activity. The motor stimulation produced by ethanol was blocked by deletion of mGluR5, but not by injection of MPEP. Both acamprosate and MPEP increased ethanol-induced LORR and reduced AW. Importantly, the protective effects of both MPEP and acamprosate on AW were found when the drugs were injected before, but not after, injection of ethanol. This indicates that the drugs prevented development of dependence rather than merely producing an anticonvulsant action. No effects of acamprosate or MPEP on ethanol-induced LORR and AW were found in mGluR5 knockout mice, demonstrating that mGluR5 is required for these actions. mGluR5 null mutant mice showed decreased alcohol consumption in some, but not all, tests. These data show the importance of mGluR5 for several actions of alcohol and support the hypothesis that some effects of acamprosate require mGluR5 signalling.