Behavioral tolerance and sensitization to CGS 19755, a competitive N-methyl-D-aspartate receptor antagonist

Competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including CGS 19755, have the ability to antagonize NMDA-induced convulsions, to cause ataxia and, at high doses, to increase spontaneous locomotor activity. It was of interest to determine whether or not repeated treatment with CGS 19755 would induce tolerance to some or all of these effects. CGS 19755 was administered to mice twice daily for 14 days at 54 mg/kg i.p. per injection. One day after the last repeated injection, mice were challenged with vehicle or one of several doses of CGS 19755 (10, 30, 54 and 100 mg/kg) and were tested for evidence of motor impairment (using righting reflex and traction tests), for spontaneous locomotor activity and for the threshold dose of NMDA required to induce convulsions. When challenged with CGS 19755, mice that had previously received only vehicle showed reduced motor activity in response to doses of 54 and 100 mg/kg. In contrast, mice that had received the repeated treatment regimen of CGS 19755 increased motor activity in response to challenge doses of 30 and 54 mg/kg. These effects resembled those reported previously by some investigators for phencyclidine. However, repeated treatment with CGS 19755 induced only slight tolerance to the ability of this drug to cause ataxia. In mice treated repeatedly with CGS 19755, the threshold dose of NMDA to induce convulsions did not differ significantly from that in mice treated repeatedly with vehicle, indicating no demonstrable tolerance to the apparent anticonvulsant effects of CGS 19755 over this time period.(ABSTRACT TRUNCATED AT 250 WORDS)