Abstract

The influence of the 5-hydroxytryptamine_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) on locomotor hyperactivity induced by the acute and chronic administration of cocaine was assessed. Horizontal activity was measured in the periphery and center of an open field test enclosure equipped with photobeams; vertical activity was also recorded. Peripheral hyperactivity induced by an acute administration of cocaine (10 or 20 mg/kg) was significantly enhanced by 0.2 mg/kg DPAT. In contrast, central and vertical activities were reduced in a dose-related manner by DPAT (0.1 and 0.2 mg/kg); DPAT also suppressed central (0.2 mg/kg) and vertical (0.1 and 0.2 mg/kg) activities when administered alone. Similar observations were made on day 1 of chronic treatment with DPAT (0, 0.1, or 0.2 mg/kg) injected 15 min before an injection of cocaine (0, 10, or 15 mg/kg) administered twice daily for 7 days. By day 7 of repeated DPAT treatment, sensitization of DPAT-evoked peripheral activity developed, which contrasted with tolerance to the central and vertical hypoactivity evoked by DPAT. Sensitization developed to the repeated treatment with 15 mg/kg cocaine but not 10 mg/kg cocaine. Interestingly, enhancements of all activity measures were observed between days 1 and 7 in rats cotreated with DPAT plus either dose of cocaine. This sensitization to DPAT plus cocaine was expressed on challenge with DPAT and cocaine but not with cocaine alone. The present study implies that the stimulation of 5-hydroxytryptamine_1A receptors is capable of modulating the hyperactivity evoked by cocaine, possibly via modulation of the mesoaccumbens dopamine circuit thought to mediate the behavioral effects of cocaine.