Effects of calcium channel blockers on behaviors induced by the N-methyl-D-aspartate receptor antagonist, dizocilpine, in rats.

ABSTRACT

The present study assessed the ability of voltage-sensitive calcium channel (VSCC) blockers to affect the behavioral effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine, in male Wistar rats. Dizocilpine produced dose-dependent increases in locomotor activity. Nimodipine, verapamil, and flunarizine suppressed dizocilpine-facilitated vertical activity, while horizontal activity was attenuated by verapamil and nimodipine but not flunarizine. Repeated dizocilpine injections resulted in the development of sensitization to its locomotor stimulating properties. Development of sensitization was not context specific, and was observed following repeated exposures to 0.1 but not 0.056 or 0.3 mg/kg of dizocilpine. Nimodipine retarded the development of sensitization to dizocilpine's stimulating effects on horizontal activity, while verapamil suppressed sensitization to the vertical stimulating effects of dizocilpine. Flunarizine had no significant effects on sensitization to dizocilpine's locomotor stimulating properties. In rats trained to discriminate between injections of 0.056 mg/kg of dizocilpine and vehicle, none of the tested VSCC blockers was able to completely antagonize the discriminative stimulus properties of dizocilpine. Nimodipine, when administered in combination with the training dose of dizocilpine, modestly decreased the dizocilpine-lever selection. Dizocilpine dose dependently decreased the self-determined stimulation threshold implanted in rats with electrodes into the ventral tegmental area. Nimodipine exhibited some tendency to block the facilitating effects of dizocilpine, while verapamil and flunarizine had no effects. In summary, in the present experiments VSCC blockers exerted only modest interactions with the behavioral effects of dizocilpine, and it is unlikely that VSCC blockers have remarkable potential as adjunct treatment aimed at correcting the negative side effects of NMDA receptor antagonists (e.g., dizocilpine).