Modification of d-amphetamine-induced responses by baclofen in rats

Abstract.

Rationale:d-Amphetamine is known to have effects on heart rate, body temperature and locomotor activity. However, it is not known if GABA_B receptor stimulation modifies these actions of d-amphetamine. Objectives: Using telemetry recordings, this study examined the interactions between the GABA_B receptor agonist baclofen and d-amphetamine, on heart rate responses, body temperature and locomotor activity, and whether these effects could be blocked by the GABA_B receptor antagonist SCH 50911. Methods: Rats were prepared with telemetry implants, which allowed continuous monitoring of heart rate, core temperature and spontaneous locomotor activity. Drugs were subsequently administered subcutaneously to the animals for simultaneous recording over a period of 180 min. Results:d-Amphetamine alone (0.3, 1.0 and 3.0 mg/kg) produced a dose-related increase in heart rate, but was without any effect on body temperature, whilst at 1.0 mg/kg, it significantly increased locomotor activity. Baclofen increased heart rate without affecting locomotor activity, and, at the highest dose of 10.0 mg/kg, it induced a significant reduction in body temperature. Graded doses of baclofen (3.0–10.0 mg/kg), when co-administered with d-amphetamine (1.0 mg/kg), did not modify the d-amphetamine-induced increase in heart rate, but the combination produced significant reductions of body temperature. The latter was only partially reversed by the GABA_B receptor antagonist SCH 50911 (10.0 mg/kg). By contrast, the increase in locomotor activity by d-amphetamine was markedly blocked by baclofen in a dose-related manner, and this effect was abolished by SCH 50911 (10.0 mg/kg). SCH 50911 alone at doses of 3.0, 6.0 and 10.0 mg/kg had no effect on temperature or locomotor activity. Heart rate was increased significantly, but the magnitude of change was small. Conclusions: The results of the present study suggest that stimulation of GABA_B receptors by baclofen completely blocks the locomotor stimulatory effects of d-amphetamine. Baclofen did not significantly modify the increase in heart rate produced by d-amphetamine and decreased body temperature, both alone and in combination with d-amphetamine. GABA_B receptor ligands may well have potential as pharmacotherapies in the treatment of amphetamine abuse and dependence.