Enhancement by chlordiazepoxide of catalepsy induced in rats by intravenous or intrapallidal injections of enantiomeric cannabinoids.

The cataleptic response of rats to (-)-delta-9-tetrahydrocannabinol (delta-9-THC), measured using a bar test, was enhanced by subcutaneous pretreatment with chlordiazepoxide (10 mg/kg). Significant potentiation was observed when the cannabinoid was administered peripherally (0.1-1.0 mg/kg i.v.) and when it was injected bilaterally into sites in or very near the posterior medial region of the globus pallidus (30 micrograms). Similar results were obtained with (-)-11-hydroxy-delta-8-dimethylheptyl-THC (0.005 to 0.02 mg/kg i.v. and 3, 10 or 30 micrograms intracerebrally). However, the (+) isomer of the 11-hydroxy compound was inactive in the presence and absence of chlordiazepoxide. It was also found that chlordiazepoxide (10 mg/kg s.c.) enhanced the cataleptic response to the GABA agonist, THIP (0.25 microgram), injected bilaterally into sites located in or very near the globus pallidus and that the cataleptic response to delta-9-THC (1 mg/kg i.v.) could be potentiated by chlordiazepoxide (50 micrograms), when this was injected into similar sites in the brain. The results support the hypothesis that the cataleptic response to cannabinoids is mediated by gamma-aminobutyric acid. They also provide evidence that cannabinoids can produce catalepsy by interacting with tissue in the vicinity of the globus pallidus and that the ability to interact in this way depends on the conformation of the cannabinoid molecule.