Inhibition by diazepam of ketamine-induced hyperlocomotion and dopamine turnover in mice.

Abstract

To investigate the effects of the benzodiazepine diazepam on ketamine-induced hyperlocomotion and dopamine turnover. Adult male ddY mice were used (n = 218). Locomotor activity was measured with four circular activity cages equipped with three photocell sensor units. Interruptions by a mover of the infrared light Peams were recorded on electromechanical counters, and automatically printed every 10 min for three hours after the ketamine injection. All drugs were administered intraperitoneally (i.p.). The concentrations of dopamine and its metabolites in discrete brain regions were measured by high performance liquid chromatography with electrochemical detection. Ketamine (30 mg.kg-1) increased total locomotor activity counts for three hours to 442% of control in mice (P = 0.0001). Diazepam, 3 and 10 mg.kg-1, inhibited, in a dose-dependent fashion, this ketamine-induced hyperlocomotion by 26% (P = 0.0111) and 59% (P = 0.0001), respectively. Regional brain dopamine assays revealed that ketamine (30 mg.kg-1) increased the homovanillic acid:dopamine ratio (one indicator of dopamine turnover) to 121% of control in the nucleus accumbens (P = 0.0065) and to 111% in the striatum (P = 0.0135) at peak locomotion. Diazepam, 3 and 10 mg.kg-1, returned this increase in dopamine turnover produced by ketamine to control levels both in the nucleus accumbens (P = 0.0061 and P = 0.0117, respectively) and in the striatum (P = 0.0004 and P = 0.0047, respectively). These results suggest that the inhibition by diazepam of ketamine-induced hyperlocomotion may be related to its ability to suppress the activation of dopamine neurons in the nucleus accumbens and striatum.