Ketanserin reverses dizocilpine-suppression of morphine dependence but nottolerance in mice

The present study investigated the effect of co-administration of ketanseri n, a 5-HT2A receptor antagonist and dizocilpine, a non-competitive NMDA rec eptor antagonist on the development of tolerance and dependence to morphine in mice. Animals developed tolerance to the antinociceptive effect of morp hine (10 mg/kg, twice daily) on day 3 and the degree of tolerance was furth er enhanced on day 9 and 10. Dizocilpine (0.2 m/kg, twice daily for 9 days) prevented the development of tolerance to the antinociceptive effect of mo rphine. Dizocilpine (0.2 mg/kg) or combination of dizocilpine (0.2 mg/kg) a nd ketanserin (0.5, and 2 mg/kg) acutely on day 10 did not affect morphine tolerance. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) pre-trea tment failed to reverse the effect of dizocilpine on morphine tolerance. Di zocilpine (0.2 mg/kg, twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdra wal jumps and diarrhea on day 10 of testing. Similarly, dizocilpine (0.2 mg /kg) acutely on day 10 suppressed the development of morphine dependence. K etanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days and acutely on day 10 ) pre-treatment reversed the effect of dizocilpine on morphine dependence. Ketanserin (0.5, 1 and 2 mg/kg, twice daily for 9 days) did not affect deve lopment of morphine tolerance and dependence. The present study demonstrate d that ketanserin, a 5-HT2A receptor antagonist reversed the effect of dizo cilpine on morphine dependence. This study gives behavioral evidence to the hypothesis that 5-HT2A receptor antagonists facilitate NMDA neurotransmiss ion. (C) 2000 Elsevier Science B.V. All rights reserved.