SR141716A ANTAGONIZES THE DISRUPTIVE EFFECTS OF CANNABINOID LIGANDS ON LEARNING IN RATS

The effects of cannabinoid ligands were studied in rats responding und er a repeated acquisition procedure. Each session rats were required t o learn a different three-response sequence; every third correct compl etion of the sequence resulted in the presentation of a food pellet. E rrors produced a brief timeout but did not reset the chain. Neither in jections of the centrally inactive cannabinoid, cannabidiol (3.2-100 m g/kg i.p.), nor the endogenous ligand, anandamide (0.01-18 mg/kg i.p.) , affected rate or accuracy of responding. In contrast, Delta(9)-tetra hydrocannabinol (3.2-18 mg/kg i.p.) and the long-acting analog of the endogenous ligand, R-methanandamide (1-18 mg/kg i.p.), produced dose-r elated increases in the total percentage of errors and decreases in th e rate of responding. The brain cannabinoid receptor antagonist SR1417 16A (1-32 mg/kg) did not affect either accuracy or rate of responding when administered alone. A low dose of SR141716A (1 mg/kg), which had no effect when administered alone, antagonized the disruptive effects of Delta(9)-tetrahydrocannabinol and R-methanandamide on rate and accu racy of responding and produced an estimated 3-fold shift to the right in the dose-effect curves. However, administration of SR141716A did n ot alter the effects of morphine. These results suggest that cannabino id agonists produce disruptions of learning in rats through stimulatio n of the cannabinoid receptor. The data further suggest that whereas c annabimimetic agents can disrupt learning, the anandaminergic system m ay not be tonically involved in learning.