Comparisons of Δ9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates

Abstract

The primary psychoactive ingredient of marijuana, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), has medicinal value but also produces unwanted deleterious effects on cognitive function, promoting the search for improved cannabinergic therapeutics. The present studies used a battery of touchscreen procedures in squirrel monkeys to compare the effects of different types of cannabinergic drugs on several measures of performance including learning (repeated acquisition), cognitive flexibility (discrimination reversal), short-term memory (delayed matching-to-sample), attention (psychomotor vigilance), and motivation (progressive ratio). Drugs studied included the cannabinoid agonist Δ(9)-THC, fatty acid amide hydrolase (FAAH) inhibitor cyclohexylcarbamic acid 3-carbamoylbiphenyl-3-yl ester (URB597), and endocannabinoid anandamide and its stable synthetic analog methanandamide [(R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide]. The effects of Δ(9)-THC and anandamide after treatment with the cannabinoid receptor type 1 inverse agonist/antagonist rimonabant [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1Hpyrazole-3-carboxamide] and the FAAH inhibitor URB597, respectively, also were examined. The results showed the following: 1) Δ(9)-THC produced dose-related impairments of discrimination-based cognitive behavior with potency that varied across tasks (discriminative capability < learning < flexibility < short-term memory); 2) anandamide alone and URB597 alone were without effect on all endpoints; 3) anandamide following URB597 pretreatment and methanandamide had negligible effects on discriminative capability, learning, and reversal, but following large doses affected delayed matching-to-sample performance in some subjects; 4) all drugs, except anandamide and URB597, disrupted attention; and 5) progressive ratio breakpoints were generally unaffected by all drugs tested, suggesting little to no effect on motivation. Taken together, these data indicate that metabolically stable forms of anandamide may have lesser adverse effects on cognitive functions than Δ(9)-THC, possibly offering a therapeutic advantage in clinical settings.

Fig. 1.

Dose-effect functions for Δ⁹-THC alone (black symbols) and following treatment of 1.0 mg/kg of rimonabant (shaded symbols) on repeated acquisition (RA) trials (circles), discrimination reversal (DR) trials (triangles), and discriminative capability (DC) trials (diamonds). Abscissa, cumulative dose, log scale; ordinate, mean percent correct. Symbols left of abscissa break indicate performance during noninjection control (C) and saline (S) sessions. Points represent averages (±S.E.M.) for the groups of subjects; n = 5, *P < 0.05, **P < 0.01.

Fig. 2.

Dose-effect functions for anandamide (A), URB597 (B), anandamide following treatment of 3.2 mg/kg of URB597 (C), and methanandamide (D) on repeated acquisition (RA) trials (circles), discrimination reversal (DR) trials (triangles), and discriminative capability (DC) trials (diamonds). Abscissae, cumulative dose, log scale; ordinate, mean percent correct. Symbols left of abscissae breaks indicate performance during noninjection control (C) and saline (S) sessions. Points represent averages (±S.E.M.) for the groups of subjects; n = 5.

Fig. 3.

DMTS forgetting functions across several doses of Δ⁹-THC (A), Δ⁹-THC following treatment of 1.0 mg/kg rimonabant (B), anandamide (C), URB597 (D), anandamide following treatment of 3.2mg/kg URB597 (E), and methanandamide (F). Abscissae, delay value (s); ordinate, mean percent correct. Noninjection control (open triangles) and saline (open circles) values are represented in all graphs. Points represent averages (±S.E.M.) for the groups of subjects. A larger dose of Δ⁹-THC (0.32 mg/kg) was tested, but performance was abolished making accuracy indeterminate; n = 3, *P < 0.05.

Fig. 4.

Dose-effect functions for Δ⁹-THC (A), methanandamide (B), URB597 (C), and anandamide alone (open inverted-triangle) or following treatment of 3.2mg/kg URB597 (filled inverted-triangle) (D) on titrated duration values. Abscissae, cumulative dose, log scale; ordinate, mean titrated duration (s). Symbols left of abscissae breaks indicate performance during noninjection control (C) and saline (S) sessions. Points represent averages (±S.E.M.) for the groups of subjects; n = 5, *P < 0.05, **P < 0.01.

Fig. 5.

Dose-effect functions for Δ⁹-THC (A), methanandamide (B), URB597 (C), and anandamide alone (open inverted-triangle) or following treatment of 3.2mg/kg URB597 (filled inverted-triangle) (D) on progressive ratio. Abscissae, cumulative dose, log scale; ordinate, mean change in breakpoint. Points represent averages (±S.E.M.) for the groups of subjects. A larger dose of Δ⁹-THC (1.0 mg/kg) was tested, but performance was abolished making breakpoints indeterminate; n = 6.