Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy

Abstract

The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg-1 sc-20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg-1 sc. The number of intertrial crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg-1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg-1 sc, or by 8-OH-DPAT, 0.1 mg kg-1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in "immobility" (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg-1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg-1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg-1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg-1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects.