The role of benzodiazepine receptors in the acquisition and expression of behavioral sensitization to methamphetamine.

The GABA-benzodiazepine neurotransmission has been reported to be implicated in various forms of plasticity such as kindling and learning. In a previous study, we have shown that clonazepam (CZP), a GABA-benzodiazepine agonist, prevents the acquisition of behavioral sensitization to methamphetamine (MA). The present study was conducted to extend this finding by examining the effect of flumazenil (Flu), a GABA-benzodiazepine antagonist on the prevention by CZP. Rats (male Wistar-King rats) treated with MA (1 mg/kg, SC) for 10 days showed significantly enhanced motor activity compared to those treated with saline when tested with MA (1 mg/kg) after a 7-8-day withdrawal, indicating the acquisition of behavioral sensitization. Representing the previous finding, pretreatment with CZP (0.5 mg/kg) prior to MA administration prevented the acquisition of the phenomenon. Pretreatment with Flu (10 mg/kg) prior to MA administration has no influence on the acquisition of sensitization. However, pretreatment with Flu prior to CZP administration reversed the inhibitory effect of CZP. CZP showed no effect on the expression of sensitization in the sensitized rats when given prior to the MA readministration. These results strengthen the suggestion that stimulation of GABA-benzodiazepine receptors plays a role in the acquisition but not in the expression of behavioral sensitization to MA.