The metabotropic glutamate receptor antagonist (RS)-MCPG produces hyperlocomotion in amphetamine pre-exposed rats.

It is known that, over a wide range of doses, the selective metabotropic glutamate receptor (mGluR) agonist, 1-aminocyclopentane-trans-1,3-dicarboxylic acid [(1S,3R)-ACPD], increases locomotion whereas the selective mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) [(RS)-MCPG], is without effect when microinjected into the nucleus accumbens (NAcc) of drug-naive rats. The present experiments determined whether these responses are altered by pre-exposing rats to a regimen of systemic amphetamine (AMPH) injections known to produce locomotor sensitization. Rats in different groups were administered four injections of saline or AMPH (1.0 mg/kg, i.p.), one injection every third day. Two weeks after the last injection, rats were challenged with microinjections of either saline, (RS)-MCPG (2.5 nmole/side) or (1S,3R)-ACPD (0.5 nmole/side) into the NAcc. While (1S,3R)-ACPD increased locomotor activity when injected into the NAcc, no significant difference between saline and AMPH pre-exposed rats was observed. However, and interestingly, (RS)-MCPG which had no effect on locomotor activity when given to saline pre-exposed rats induced significantly higher locomotor activity in AMPH compared to saline pre-exposed rats. These results indicate that glutamatergic neurotransmission mediated by mGluRs in the NAcc is altered by repeated systemic injections of AMPH. Such changes may ultimately position the mGluR to contribute to the expression of sensitization by AMPH as well as other psychomotor stimulant drugs.