title: Gabapentin blocks methamphetamine-induced sensitization and conditioned place preference via inhibition of α₂/δ-1 subunits of the voltage-gated calcium channels.
abstract: 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.
authors.affiliation: Department of Pharmacology, Kawasaki Medical School, Matsushima 577, Kurashiki, Okayama 701-0192, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kurokawa
authors.forename: M
authors.initials: M
authors.lastname: Shibasaki
authors.forename: K
authors.initials: K
authors.lastname: Mizuno
authors.forename: S
authors.initials: S
authors.lastname: Ohkuma
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015220:Calcium Channels / Q000096:biosynthesis*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D000077206:Gabapentin; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D021122:Protein Subunits / Q000096:biosynthesis; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019966:Substance-Related Disorders / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D000697:Central Nervous System Stimulants; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D021122:Protein Subunits; D012333:RNA, Messenger; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin