To characterize the role of CB1 receptors in mediating the acquisition of n
ew behavior or learning, Delta(9)-THC (ag-tetrahydrocannabinol), WIN 55,212
-2 (R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpho-linyl)methyl]pyrol-(1,2,3-de]-
1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate), SR141
716A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-
1H-pyrazole-3-carboxamide hydrochloride) and cannabidiol were administered
to monkeys responding under a multiple schedule of repeated acquisition and
performance of conditional discriminations. SR141716A, a putative antagoni
st at CB1 receptors, was also administered in combination with Delta(9)-THC
. In one component of the multiple schedule, subjects acquired a different
complex discrimination each session (acquisition component), whereas in the
other component the discrimination remained the same each session (perform
ance component). Correct responding in each component was maintained by foo
d presentation under a variable-ratio (VR) schedule, whereas incorrect resp
onding (errors) produced a time-out. Administered prior to the start of the
session, Delta(9)-THC and WIN 55,212-2 dose-dependently decreased overall
response rate in both the acquisition and performance components. Both drug
s also selectively increased the percentage errors in the acquisition compo
nent, but only at higher doses. SR141716A and cannabidiol also dose-depende
ntly decreased overall response rate in both schedule components, but neith
er drug increased the percentage of errors. Decreases in response rate were
also observed 24 hours after administration of SR141716A at doses greater
than 1 mg/kg. When lower doses of SR141716A (0.1-1 mg/kg) were administered
in combination with Delta(9)-THC, there was a dose-dependent antagonism of
the rate-decreasing and error-increasing effects of Delta(9)-THC (i.e. the
dose-effect curves for Delta(9)-THC-induced disruptions in responding were
shifted rightward). In summary, CBI-receptor agonists such as Delta(9)-THC
and WIN 55,212-2 were more disruptive to the rate and accuracy of learning
in old-world monkeys than the CB1-receptor antagonist SR141716A or cannabi
diol. (C) 1999 Lippincott Williams & Wilkins.