Diazepam-induced locomotor sensitization and increased cell surface AMPA receptors: Involvement of GABAA α1 subunit.

Benzodiazepines (BDZs) are widely used clinically to treat anxiety and insomnia, but the risk of addiction after chronic treatment was a concern. It was reported that BDZs were capable of elevating the dopamine level in the nucleus accumbens (NAc) by positively regulating the γ-aminobutyric acid type A (GABAA) receptor α1 subunit. However, the neuroadaptation changes and underlying mechanism after chronic BDZs treatment have not been clearly elucidated. In this study, behavioral sensitization, an animal model of addiction, along with AMPA receptor trafficking in the NAc and the ventral tegmental area (VTA) were evaluated. It was found that Diazepam, a classic BDZ drug, produced locomotor sensitization in mice after repeated injection at dose of 0.06 mg/kg. Cell surface AMPA receptors in NAc, especially GluA1 subunits, were significantly increased in diazepam-sensitized mice. The GluA2 subunits in VTA were also elevated. Moreover, repeated i.p. injection of Zolpidem (selective GABAA α1 subunit agonist) produced sensitized behavioral response to subsequent diazepam injection. Local activation of GABAA α1 subunit in VTA also produced behavioral response to diazepam, associated with significantly increased surface AMPA receptors in NAc. These findings emphasized the enhancement of behavioral and neural responsiveness following long-term exposure to diazepam, and the involvement of GABAA α1 subunit in this process.