Repeated Δ⁹-Tetrahydrocannabinol Exposure in Adolescent Monkeys: Persistent Effects Selective for Spatial Working Memory

Abstract

Objective Epidemiological findings suggest that, relative to adults, adolescents are more vulnerable to the adverse persistent effects of cannabis on working memory. However, the potential confounds inherent in human studies preclude direct determination of a cause-and-effect relationship between adolescent cannabis use and heightened susceptibility to persistent working memory impairments. Consequently, the authors examined the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) on performance of spatial and object working memory tasks in adolescent monkeys. Method Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 6 months. Performance on spatial and object memory tasks was assessed 23 or 71 hours after drug administration throughout the study. In addition, acute effects on working memory were also assessed at the beginning and end of the 6-month period. Results Relative to the vehicle-exposed control animals, those with repeated THC exposure had a blunted trajectory of accuracy improvements on the spatial working memory task in a delay-dependent manner. Accuracy improvements on the object working memory task did not differ between groups. Relative to the acute effects of THC on working memory at the beginning of the study, neither sensitivity nor tolerance was evident after 6 months of THC exposure. Conclusions Because maturation of performance is later for spatial than for object working memory, these findings suggest that persistent effects of THC on cognitive abilities are more evident when exposure coincides with the developmental stage during which the underlying neural circuits are actively maturing.

Altered cortical maturation in adolescent cannabis users with and without schizophrenia

“…Differences in test performance in nonpsychotic adolescents with CUD were noted at study endpoint, but not at baseline. These data support a hypothesis that adolescent exposure to cannabis may have an adverse effect on cognitive development (Verrico et al, 2014). In HC, greater cortical thinning in the left SFG was related to improved performance on the D-KEFS Tower Test.…”

“…The D-KEFS Tower Test was chosen to examine the relationship between change in cortical thickness within the left SFG and change in planning and problem solving ability. This test was selected for comparison to a study in non-human primates demonstrating an adverse effect of cannabis on the development of spatial working memory (a process also thought to be subserved by the superior frontal cortex) (Verrico et al, 2014).…”

“…There are increasing data suggesting that the effects of delta-9-tetrahydrocannabinol (THC) may be more deleterious in adolescents, whose cognitive development and brain maturation are still ongoing, than in adults (Lisdahl et al, 2013). Recently, a primate study found that exposure to THC for six months during adolescence selectively impaired development of a spatial working memory task that preferentially activates the still-developing superior frontal cortex (Verrico et al, 2014). The primary target of exogenous cannabinoids in the brain is the cannabinoid-1 (CB-1) receptor.…”

Alcohol Use in Adolescence and Later Working Memory: Findings From a Large Population-Based Birth Cohort

“…This is perhaps unsurprising as there is substantial evidence from animal studies linking cannabis use in adolescent with deficits in WM performance (Rubino et al , 2009; Renard et al , 2014; Verrico et al , 2014). The association is further complicated as nicotine withdrawal has been shown to be associated with reductions in WM efficiency in animal studies (Levin et al , 1990; Levin et al , 2006).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Both Δ 9 -THC and WIN 55,212-2 decrease PFC DA turnover for up to 2 weeks, suggesting that persistent cognitive disturbances after cannabinoid exposure are possible and perhaps Drug-Induced Neuroplasticity at least partly related to the reduction in the DA transmission in the PFC (Verrico et al, 2003). Repeated Δ 9 -THC administration in adolescent rhesus monkeys impaired age-and practice-related improvements in accuracy on a spatial working memory task and neither tolerance nor sensitization developed to the acute effects after 6 months (Verrico et al, 2014). This result is consistent with the acute impairment of cognition by cannabis in adolescent humans.…”