Effect of serotonin (5-HT)(1B) receptor ligands on cocaine sensitization in rats

Recent studies have shown that antagonists of serotonin (5-HT)(1B) receptor s attenuate cocaine-induced locomotor hyperactivity, whereas agonists enhan ce reinforcing and discriminative stimulus effects of the psychostimulant. The present study was designed to determine how 5-HT1B receptor ligands aff ected the development or the expression phase of sensitization to the cocai ne-induced locomotor response in rats, In Experiment 1, rats were treated r epeatedly (for 5 days) with cocaine (10 mg/kg) in combination with either s aline, GR 127935 (5-HT1B antagonist), CP 94,253 (5-HT1B agonist) or GR 1279 35 + CP 94,253, On day 10, they received a challenge dose of cocaine (10 mg /kg), In Experiment 2, animals received either saline or cocaine (10 mg/kg) for 5 days, and were then challenged with cocaine (10 mg/kg) in combinatio n with saline, GR 127935, CP 94,253 or GR 127935 + CP 94,253, on day 10, In Experiment 3, rats received either saline, cocaine or CP 94,253 for 5 days ; on day 10 they received challenge doses of CP 94,253 or cocaine, In rats treated repeatedly with cocaine, the locomotor hyperactivity induced by a c hallenge dose of the psychostimulant was about twice as high as that observ ed after its first administration, The effect evoked by cocaine challenge w as further increased in animals treated repeatedly with CP 94,253 + cocaine , but not with GR 127935 + CP 94,253 + cocaine, No difference was observed in the response to cocaine challenge in rats treated repeatedly with cocain e or GR 127935 + cocaine (Experiment 1), In animals treated repeatedly with the psychostimulant, the behavioral response to a challenge dose of cocain e was dose-dependently increased when that drug was combined with CP 94,253 , but not with GR 127935 + CP 94,253, No difference was observed in the loc omotor response of rats challenged with cocaine or CR 127935 + cocaine (Exp eriment 2). When rats were treated repeatedly with cocaine, a challenge dos e of CP 94,253 produced an about threefold increase in the locomotor effect compared to the animals treated likewise with saline (Experiment 3). Our r esults indicate that 5-HT1B receptors are involved in neither the developme nt nor the expression of sensitization to cocaine-induced locomotor hyperac tivity. On the other hand, they also show that pharmacological activation o f 5-HT1B receptors enhances both phases of this phenomenon, and that repeat ed administration of cocaine leads to an increased functional reactivity of these receptors, (C) 2001 Lippincott Williams & Wilkins.