Discriminative stimulus effects in rats of SR-141716 (rimonabant), a cannabinoid CB1 receptor antagonist

Objective: To examine the discriminative stimulus effects of (i) the cannabinoid CB1 receptor antagonist SR-141716 (SR, 5.6 mg/kg) and vehicle, and (ii) the cannabinoid receptor agonist Delta(9)-THC (THC, 1.8 mg/kg) and vehicle using a discriminated taste aversion (DTA) procedure. Methods: Two groups of rats (n = 6) were trained to discriminate between these drugs and vehicle in DTA (t'= 20 min). The 30-min drinking bout of tap water following drug ( SR or THC) treatment was followed by an injection of lithium chloride (LiCl, 120 mg/kg) in the experimental animals. When offered water after vehicle pretreatment, experimental animals subsequently were given IP saline ( NaCl, 10 ml/ kg). Post-drinking treatment for controls (n=6) was NaCl, irrespective of the pretreatment condition ( SR, THC or vehicle). Additional water was provided during the afternoon ( 30 min) with no other manipulations. Food was available ad lib at all times. When the discriminations were established other doses and drugs were examined (t' = 20 min). In testing there were no post-drinking treatments. Results: The SR-related analog AM-251 ( dose range: 1 - 5.6 mg/kg) substituted for SR, whereas other drugs such as the cannabinoid CB2 receptor antagonist SR-144528 ( 3 and 10 mg/kg), THC ( 1 10 mg/kg), flumazenil ( 1 - 10 mg/kg), naloxone ( 1 10 mg/kg), morphine ( 10 and 18 mg/kg) and D-amphetamine ( 1 and 3 mg/kg) did not. There was a dose-related attenuation of SR-induced suppression of drinking when THC ( 1.8 - 10 mg/kg) was given together with SR (5.6 mg/animals. When offered water after vehicle pretreatment, experimental animals subsequently were given IP saline ( NaCl, 10 ml/ kg). Post-drinking treatment for controls (n = 6) was NaCl, irrespective of the pretreatment condition (SR, THC or vehicle). Additional water was provided during the afternoon ( 30 min) with no other manipulations. Food was available ad lib at all times. When the discriminations were established other doses and drugs were examined (t' = 20 min). In testing there were no post-drinking treatments. Results: The SR-related analog AM-251 ( dose range: 1 - 5.6 mg/kg) substituted for SR, whereas other drugs such as the cannabinoid CB2 receptor antagonist SR-144528 ( 3 and 10 mg/kg), THC ( 1 10 mg/kg), flumazenil ( 1 - 10 mg/kg), naloxone ( 1 10 mg/kg), morphine ( 10 and 18 mg/kg) and D-amphetamine ( 1 and 3 mg/kg) did not. There was a dose-related attenuation of SR-induced suppression of drinking when THC (1.8 - 10 mg/kg) was given together with SR ( 5.6 mg/kg). In the THC trained rats, SR ( 1 - 10 mg/kg), morphine ( 10 and 18 mg/kg) and D-amphetamine ( 1 and 3 mg/kg) did not substitute for THC. SR ( 1 mg/kg) attenuated the THC (1.8 mg/kg) induced suppression of drinking. Together with 3 mg/kg SR and 1.8 mg/kg THC, drinking was roughly equally suppressed in both the experimental group and the controls. Conclusion: SR-141716 induces a discriminative stimulus complex in DTA that shows potential for further examination of cannabinoid receptor antagonism.