Interactions between dopamine and GABA in the control of ambulatory activity and neophobia in the mouse

Ambulatory activity in a familiar and novel environment as well as the time spent in a novel environment were evaluated using the free exploratory paradigm. Male mice treated with D-amphetamine, 2 mg/kg, displayed enhanced ambulatory activity in the familiar environment. The time spent in the novel environment was reduced by amphetamine, 1 and 2 mg/kg. The GABA transaminase inhibitor gamma-acetylen GABA (GAG) reduced ambulatory activity and rearing as well as the time spent in the novel environment. The mixed GABA(A)/GABA(B) agonist progabide, 200 mg/kg, reduced rearing both in the familiar and novel environments without affecting the time spent in the novel environment. Amphetamine, 1 mg/kg, was then combined with ineffective doses of GAG and progabide (50 and 100 mg/kg, respectively). The GABAergics did not reliably modify the effects of amphetamine on the time spent in the novel environment. Ambulatory activity and rearing were reduced both in comparison to amphetamine + saline and to control. These data show that GABAergic drugs are potentiated by enhanced dopaminergic neurotransmission with regard to their actions on ambulatory activity and rearing. The effects of progabide + amphetamine were then evaluated after treatment with the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 35348. Neither bicuculline, 1 mg/kg, nor CGP 35348, 100 mg/kg, blocked the actions of progabide. The combined treatment with both antagonists was also unable to reduce the effects of progabide. These data suggest that the interaction between amphetamine and progabide with regard to motor effects depends on a non-GABA(A), non-GABA(B) receptor.