A DETAILED CHARACTERIZATION OF THE EFFECTS OF 4 CANNABINOID AGONISTS ON OPERANT LEVER PRESSING

The present experiments were conducted to investigate the effects of f our cannabimimetics on detailed temporal parameters of operant respond ing. In this study, the behavioral output during performance of a fixe d ratio 5 schedule of reinforcement was recorded by a computer program that measured the response initiation time (IT; time interval between the offset of one lever press and the onset of the next) and the resp onse duration (the amount of time that elapses from the onset to the o ffset of one lever press) of each lever press. ITs were further partit ioned into fast responses (IT=0.0-1.0 s), short pauses (IT=1.0-2.5 s), and long pauses (IT>2.5 s). Four cannabimimetic agents were assessed in this study: (R)-methanandamide (AM 356), a hydrolytically stable an alog of arachidonylethanolamide, an endogenous ligand for the CB1 rece ptor; CP-55,940, a potent non-classical synthetic ligand; (-)-Delta(8) -tetrahydrocannabinol (Delta(8)-THC), an isomer of the naturally occur ring Delta(9)-THC; and WIN 55,212-2, a synthetic aminoalkylindole. All four of the cannabimimetic drugs tested significantly suppressed oper ant lever pressing in a dose dependent manner. The rank order of poten cies observed in the present study was CP-55,940>>WIN-55,212-2 Delta(8 )-THC>AM 356, which is consistent with the rank order of affinities fo r the CB 1 receptor shown by these drugs. All of the cannabimimetics s ubstantially increased average IT, and also increased duration time. T here was a substantial increase in average length of long pauses, and statistically significant but very small changes in the local rate of responding as measured by the average length of fast ITs. Cannabinoid- treated rats were largely immobile during pauses in responding, and th ese animals showed several signs of ataxia and catalepsy at the doses that suppressed lever pressing. Together with other data, the present results suggest that CBI stimulation: leads to motor effects that are associated with a suppression of lever pressing.