The dopamine antagonist sch 23390 reverses dizocilpine-induced blockade of cocaine sensitization.
The present work examined the effects of pre-treatment with Sch 23390, a selective D(1) receptor antagonist, on the dizocilpine-induced blockade of sensitization to the locomotor-stimulating effect of cocaine. Rats were given either cocaine [15mgkg(-1)day(-1), intraperitoneally (i.p.)] from day 1 to day 5 (cocaine-experienced rats) or vehicle (cocaine-naïve rats). From day 6 to day 15, animals remained drug-free in their home cages. On day 16 rats received a challenge injection of cocaine (15mgkg(-1)) or vehicle, and were tested for sensitization to the locomotor-stimulating effect of cocaine. In cocaine-naïve rats the acute effect of cocaine was a 1.5 times increase in locomotor activity. In cocaine-experienced rats, the acute effects of cocaine were considerably more pronounced than in cocaine-naïve rats; the stimulating effect of cocaine in these animals was a doubling in locomotor activity. In cocaine-naïve rats, pre-treatment with dizocilpine (100microgkg(-1)), Sch 23390 (100microgkg(-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 100microgkg(-1) dizocilpine from day 1 to day 5 failed to show the increase in locomotor activity when challenged with cocaine on day 16. Pre-treatment with Sch 23390 (100microgkg(-1)day(-1), i.p.) from day 1 to day 5 was found to prevent completely the cocaine anti-sensitization properties of 100microgkg(-1) dizocilpine, but failed to prevent cocaine sensitization. On the other hand, horizontal activity in cocaine-experienced rats that had been given dizocilpine (100microgkg(-1)) 15min before cocaine challenge on day 16 was higher than in corresponding controls. It is concluded that prevention of cocaine sensitization by dizocilpine may be related to the events set into motion by the NMDA antagonist at the level of dopaminergic transmission involving D(1) receptors.
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Department of Research and Development, BIAL, 4785, S. Mamede do Coronado, Portugal.
Soares-da-Silva
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D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors
D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D016291:Dizocilpine Maleate; D003042:Cocaine