Behavioral Mechanisms of Δ9-THC in Nonhuman Primates

A comprehensive understanding of the reinforcing effects and cognitive consequences of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent in marijuana, is critical for developing treatments in cannabis dependent patients. Despite the fact that marijuana is the most commonly abused illicit substance in the U.S., self-administration (SA) of THC has only been established in one laboratory using New World primates (squirrel monkeys). In Chapter 2, THC and the synthetic cannabinoid agonist CP55,940 were made available for SA in Old World monkeys, a species more closely related to humans, by using similar parameters deemed successful in squirrel monkeys. CP55,940 functioned as a reinforcer in a subset (3 of 8) of rhesus monkeys, with an inverse relationship between magnitude of SA and sensitivity to rate-decreasing effects. On the other hand, THC did not function as a reinforcer in any monkey. To test the hypothesis that attenuating the rate-decreasing effects of THC would increase the likelihood THC would function as a reinforcer, monkeys were administered THC daily until tolerance developed. When THC SA was reexamined, it functioned as a reinforcer in a subset (3 of 8) of subjects. Further, the reinforcing effects of THC were noted in two of four cynomolgus monkeys responding under a second-order schedule of reinforcement in which behavior was maintained by conditioned stimuli. These studies indicate that sensitivity to rate-decreasing effects and schedule of reinforcement are important determinants for cannabinoid-maintained behavior. In Chapter 3, monkeys were chronically treated with THC and the residual effects (22 hrs after THC administration) were assessed on cognitive performance. Impairments were found in working memory (WM) but not in other aspects of executive function. These cognitive deficits were independent of changes in dopamine D2/3 receptor availability as measured with PET and [11C]-raclopride. THC-induced impairments to WM recovered during abstinence. Moreover, chronic THC treatment resulted in tolerance to the acute impairments in compound discrimination learning but only to impairments in working memory when the cognitive demand was low.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2016

Author dc:creator

• John, William

• Addiction

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/64196

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/64196