Effects of L-745,870, a dopamine D4 receptor antagonist, on naloxone-induced morphine dependence in mice

We examined whether dopamine D4 receptor is involved in morphine dependence in mice. Mice pretreated with morphine (10 mg/kg, s.c.) twice a day for 5 days showed withdrawal syndromes such as jumping, rearing, and forepaw tremors after the administration of naloxone (2 mg/kg, i.p.) on the sixth day. Such mice exhibited significant elevation of cAMP levels in the thalamus compared with the control mice. L-745,870 (1 mg/kg, i.p.), a selective dopamine D4 receptor antagonist, pretreated with morphine on the sixth day, significantly attenuated the severity of withdrawal syndromes and the increase in cAMP levels after the administration of naloxone. These results suggest that (1) the elevation of cAMP levels is involved in the expression of morphine-induced withdrawal syndromes, and (2) dopamine D4 receptor antagonists inhibit the expression of morphine-induced withdrawal syndromes accompanied with biochemical changes in mice. Furthermore, dopamine D4 receptor antagonists may be useful drugs for attenuating the expression of morphine dependence.