Ketanserin reverses dizocilpine-suppression of morphine dependence but not tolerance in mice

The present study investigated the effect of co-administration of ketanserin, a 5-HT(2A) receptor antagonist and dizocilpine, a non-competitive NMDA receptor antagonist on the development of tolerance and dependence to morphine in mice. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg, twice daily) on day 3 and the degree of tolerance was further enhanced on day 9 and 10. Dizocilpine (0.2 mg/kg, twice daily for 9 days) prevented the development of tolerance to the antinociceptive effect of morphine. Dizocilpine (0.2 mg/kg) or combination of dizocilpine (0.2 mg/kg) and ketanserin (0.5, 1 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-treatment failed to reverse the effect of dizocilpine on morphine tolerance. Dizocilpine (0.2 mg/kg, twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg)-precipitated withdrawal jumps and diarrhea on day 10 of testing. Similarly, dizocilpine (0.2 mg/kg) acutely on day 10 suppressed the development of morphine dependence. Ketanserin (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 development of morphine tolerance and dependence. The present study demonstrated that ketanserin, a 5-HT(2A) receptor antagonist reversed the effect of dizocilpine on morphine dependence. This study gives behavioral evidence to the hypothesis that 5-HT(2A) receptor antagonists facilitate NMDA neurotransmission.