Tolerance and cross-tolerance to the activating effects of 3,4-methylenedioxymethamphetamine and a 5-hydroxytryptamine1B agonist.

Previous studies indicate that 3,4-methylenedioxymethamphetamine (MDMA) produces locomotor hyperactivity in rats by increasing the presynaptic release of serotonin (5-HT). Interactions between MDMA and 5-HT receptor antagonists suggest that the activating effects of MDMA are mediated via 5-HT1-like receptors. In order to assess the contribution of particular 5-HT receptor subtypes to the behavioral effects of MDMA, the present studies examined the development of tolerance and cross-tolerance to the behavioral effects of MDMA and selective 5-HT receptor agonists. In the first study, rats were pretreated with saline, a 5-HT1A receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 1.0 mg/kg), a 5-HT1B receptor agonist [5-methoyx-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole butane dioate (RU24969), 2.5 mg/kg] or a 5-HT1C/5-HT2 receptor agonist (2,5-dimethoxy-4-iodoamphetamine, 1.0 mg/kg) twice daily for 3 days. The behavioral response to S-MDMA (3.0 mg/kg) was assessed 36 hr after the last pretreatment injection. Pretreatment with RU24969 antagonized the activating effects of S-MDMA. In contrast, pretreatment with 2,5-dimethoxy-4-iodoamphetamine did not alter the response to S-MDMA, and pretreatment with 8-hydroxy-2-(di-n-propylamino)tetralin reduced the activity of both control and S-MDMA-treated animals. In the second study, rats were pretreated with saline or RS-MDMA (10 mg/kg), twice daily for 4 days. The behavioral response to saline, S-MDMA (3.0 mg/kg), RU24969 (2.5 mg/kg) or S-amphetamine (1.0 mg/kg) was assessed 36 hr after the last pretreatment injection.(ABSTRACT TRUNCATED AT 250 WORDS)