The dopamine antagonist Sch 23390 reverses dizocilpine-induced blockade ofcocaine sensitization

The present work examined the effects of pre-treatment with Sch 23390, a se lective D-1 receptor antagonist, on the dizocilpine-induced blockade of sen sitization to the locomotor-stimulating effect of cocaine. Rats were given either cocaine [15 mg kg(-1) day(-1) intraperitoneally (i.p.)] from day 1 t o day 5 (cocaine-experienced rats) or vehicle (cocaine-naive rats). From da y 6 to day 15, animals remained drug-free in their home cages. On day 16 ra ts received a challenge injection of cocaine (15 mg kg(-1)) or vehicle, and were tested for sensitization to the locomotor-stimulating effect of cocai ne. In cocaine-naive rats the acute effect of cocaine was a 1.5 times incre ase in locomotor activity. In cocaine-experienced rats, the acute effects o f cocaine were considerably more pronounced than in cocaine-naive rats; the stimulating effect of cocaine in these animals was a doubling in locomotor activity. In cocaine-naive rats, pre-treatment with dizocilpine (100 mu g kg(-1)), Sch 23390 (100 mu g kg(-1)) or a combination of the two drugs from day 1 to day 5 changed neither spontaneous locomotor activity nor cocaine stimulant activity. By contrast, cocaine-experienced animals that had been given 100 mu g kg-(1) dizocilpine from day 1 to day 5 failed to show the in crease in locomotor activity when challenged with cocaine on day 16. Pre-tr eatment with Sch 23390 (100 mu g kg(-1)day(-1), i.p.) from day 1 to day 5 w as found to prevent completely the cocaine anti-sensitization properties of 100 mu g kg(-1) dizocilpine, but failed to prevent cocaine sensitization. On the other hand, horizontal activity in cocaine-experienced rats that had been given dizocilpine (100 mu g kg(-1)) 15 min before cocaine challenge o n day 16 was higher than in corresponding controls. It is concluded that pr evention of cocaine sensitization by dizocilpine may be related to the even ts set into motion by the NMDA antagonist at the level of dopaminergic tran smission involving D-1 receptors. (C) 2000 Elsevier Science Ltd. All rights reserved.