Comparisons of  9-Tetrahydrocannabinol and Anandamide on a Battery of Cognition-Related Behavior in Nonhuman Primates

Abstract

The primary psychoactive ingredient of marijuana, D 9-tetrahydrocannabinol (D 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 D 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)-(1)-arachidonyl-19-hydroxy-29-propylamide]. The effects of D 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) D 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 matchingto-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 D 9 -THC, possibly offering a therapeutic advantage in clinical settings.

Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats

“…We hypothesized that enhancing anandamide levels with URB597 would increase the pleasurable aspects of social play without affecting responding for social play (Adamcyk et al, 2009; Forget et al, 2009; Justinova et al, 2008; Kangas et al, 2016; Oleson et al, 2012; Scherma et al, 2008; Solinas et al, 2005), whereas treatment with the CB1 cannabinoid receptor antagonist rimonabant would decrease both the motivational (Economidou et al, 2006; Hernandez and Cheer, 2012; Maccioni et al, 2010; Rasmussen and Huskinson, 2008; Solinas and Goldberg, 2005; Ward and Dykstra, 2005) and pleasurable aspects (Chaperon et al, 1998; Forget et al, 2004; Hu et al, 2014; Méndez-Diaz et al, 2012; Singh et al, 2004; Thanos et al, 2005; Yu et al, 2011) of social play.…”

“…Place conditioning was used to assess the pleasurable aspects of social play (Calcagnetti and Schechter, 1992; Crowder and Hutto, 1992; Douglas et al, 2004; Thiel et al, 2008; Trezza et al, 2009b). Since treatment with URB597 was previously found not to affect responding for food and drug rewards in rats and non-human primates (Adamcyk et al, 2009; Forget et al, 2009; Justinova et al, 2008; Kangas et al, 2016; Oleson et al, 2012; Scherma et al, 2008; Solinas et al, 2005), we hypothesized that enhancing anandamide levels with URB597 would increase the pleasurable aspects of social play without affecting responding for social play. Conversely, since genetic and pharmacological blockade of CB1 cannabinoid receptors decreases the motivation to respond for food (Hernandez and Cheer, 2012; Rasmussen and Huskinson, 2008; Solinas and Goldberg, 2005; Ward and Dykstra, 2005) and drugs of abuse (Economidou et al, 2006; Maccioni et al, 2010), and affect food- (Chaperon et al, 1998; Méndez-Diaz et al, 2012) and drug-induced (Forget et al, 2004; Hu et al, 2014; Singh et al, 2004; Thanos et al, 2005; Yu et al, 2011) conditioned place preference, we hypothesized that treatment with the CB1 cannabinoid receptor antagonist rimonabant would decrease both the motivational and pleasurable aspects of social play.…”

Touchscreen assays of learning, response inhibition, and motivation in the marmoset (Callithrix jacchus)

“…In progressive ratio experiments, average break point values were also not statistically different ( F[7] =1.52, P =.26) between marmosets and squirrel monkeys responding for 0.15 mL milk delivery (cf. Kangas et al in press). In addition, the effects of varying reinforcer magnitude on break points are generally similar between primates (unpublished findings).…”

Touchscreen technology in the study of cognition-related behavior

“…This is especially valuable in pharmacological research because the ability to assess multiple endpoints in the same session can provide a highly powerful within-subject evaluation of a drug’s relative potency on different dimensions of cognitive function (cf. Kangas et al, 2016b). …”

“…Harlow termed this phenomenon learning set (or learn-to-learn). An automated version of this task designed for touchscreen chambers was recently developed to examine some basic parameters of this animal model of learning (Kangas and Bergman, 2012; 2014; Kangas et al, 2016a), and to refine its ability to serve as a component of a larger battery of cognitive tasks for the examination of both commonly abused drugs and candidate medications (e.g., Kangas and Bergman, 2016; Kangas et al, 2016b). …”