Gabapentin blocks methamphetamine-induced sensitization and conditioned place preference via inhibition of α₂/δ-1 subunits of the voltage-gated calcium channels.

Our previous investigation demonstrated that repeated administration of morphine significantly enhanced α(2)/δ-1 subunit expression in the frontal cortex and limbic forebrain of mice as well as morphine-induced place preference. However, little is known about regulatory mechanisms of α(2)/δ-1 subunit expression in conditioned place preference by methamphetamine (METH). In the present study, we investigated the role of α(2)/δ-1 subunit of voltage-gated calcium channels (VGCCs) in the mouse brain under repeated treatment with METH. The level of α(2)/δ-1 subunit increased significantly in the limbic forebrain including the nucleus accumbens and the frontal cortex of mice showing METH-induced sensitization. Under these conditions, the development of behavioral sensitization induced by the intermittent administration of METH was significantly suppressed by the co-administration of gabapentin (GBP) with binding activity to an exofacial epitope of α(2)/δ-1 subunit. Furthermore, GBP administered i.c.v. caused a dose-dependent inhibition of the METH-induced place preference. Chronic GBP treatment at the dose alleviating sensitization and place preference significantly reduced the elevation of α(2)/δ-1 subunit of VGCC induced by the repeated administration of METH in the limbic forebrain and frontal cortex, whereas there were no changes in the increase of α(2)/δ-1 subunit mRNA. These findings indicate that α(2)/δ-1 subunit plays a critical role in the development of METH-induced place preference following neuronal plasticity, and that GBP, which significantly suppressed METH-induced place preference by its possible inhibitory action of α(2)/δ subunit to neuronal membrane, may possibly be used as an alternative drug to treat or prevent drug dependence.