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Repeated Δ9-Tetrahydrocannabinol Exposure in Adolescent Monkeys: Persistent Effects Selective for Spatial Working Memory
Christopher D. Verrico, Ph.D.; Hong Gu, M.S.; Melanie L. Peterson, B.S.; Allan R. Sampson, Ph.D.; David A. Lewis, M.D.
Am J Psychiatry 2014;171:416-425. doi:10.1176/appi.ajp.2013.13030335
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Dr. Sampson is a consultant in statistical design to Janssen Pharmaceutical Research and Development, a Janssen Pharmaceutical Company. Dr. Lewis currently receives investigator-initiated research support from Bristol-Myers Squibb, Curridium, and Pfizer and in 2011–2013 served as a consultant in the areas of target identification and validation and new compound development to Bristol-Myers Squibb and Concert Pharmaceuticals. Dr. Verrico, Ms. Gu, and Ms. Peterson report no financial relationship with commercial interests.

Supported by National Institute on Drug Abuse grant DA-023109 and by a NARSAD Distinguished Investigator award to Dr. Lewis.

The authors thank Elizabeth Bitler and Lisa Nieman-Vento for technical support.

From the Departments of Psychiatry, Statistics, and Neuroscience, University of Pittsburgh.

Presented in part at the 2010 annual meeting of the Society for Neuroscience, San Diego, Oct. 13–17, 2010, and the 49th annual meeting of the American College of Neuropsychopharmacology, Miami Beach, Fla., Dec. 5–9, 2010.

Address correspondence to Dr. Verrico (verrico@bcm.edu) or Dr. Lewis (lewisda@upmc.edu).

Copyright © 2014 by the American Psychiatric Association

Received March 11, 2013; Revised November 02, 2013; Accepted November 18, 2013.

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.

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FIGURE 1. Spatial and Object Working Memory Tasks Performed by Adolescent Monkeys Exposed Repeatedly to THC or Vehicle

a In the spatial working memory trials (part A, top), a sample stimulus appeared at one of the four corners of the touch screen. The monkey had to touch it. Immediately following this response, a fixation cue stimulus appeared at the center of the screen. The monkey had to touch the fixation cue stimulus and thus could not remember the target location by continuing to touch it. A randomly selected delay (1, 4, 8, or 16 seconds) ensued. At the end of the delay period, choice probes appeared at each corner of the screen. The monkey had to touch the probe at the location occupied by the sample stimulus appearing earlier in the trial. Spatial memory control trials (part A, bottom) were distinguished by the appearance of a single probe at the same location occupied by the sample stimulus appearing earlier in the trial.

b In the object working memory trials (part B, top), a sample stimulus appeared at the center of the touch screen. The monkey had to touch it. A randomly selected delay (1, 4, 8, or 16 seconds) ensued. At the end of the delay period, choice probes appeared at the corners of the screen, distinct in color and shape. The monkey had to touch the probe that matched the sample stimulus appearing earlier in the trial. Object memory control trials (part B, bottom) were distinguished by the reappearance of the sample stimulus at the center of the screen. In an effort to offset a potential order effect, the object memory task had two reinforcement conditions, distinguished by color. The animals were paired to counterbalance assignments to THC or vehicle; therefore, blue or yellow objects indicated double reinforcement for three pairs of monkeys while red or green objects indicated double reinforcement for the other four pairs of monkeys.

c For all trials and both tasks, the monkeys were allowed 20 seconds to respond to the sample stimulus and 20 seconds to respond to the choice probes. If a monkey failed to respond during the allotted times, the trial was recorded as an omission.

FIGURE 2. Number of Weeks in Each Study Period for Pairs of Adolescent Monkeys in Comparison of THC and Vehicle Exposure

a Within each pair, one monkey received THC and the other received vehicle.

b Acute effects were determined by assessing performance immediately before and 30 minutes after administration of THC or vehicle.

c Persistent effects were determined by assessing performance 23 or 71 hours after administration of THC or vehicle.

FIGURE 3. Observed and Estimated Mean Rates of Working Memory Accuracy in Adolescent Monkeys Repeatedly Exposed to THC or Vehicle

a Left panels show the mean observed working memory accuracy rates by week and delay for the vehicle and THC groups on the spatial task (panel A) and on the double-reinforcement (panel C) and single-reinforcement (panel E) trials of the object task.

b Right panels show the mean estimated working memory accuracy rates derived from the two-phase statistical models of the observed data for the spatial task (panel B) and for the double-reinforcement (panel D) and single-reinforcement (panel F) trials of the object task.

c For both groups on both tasks and both object reinforcement conditions, accuracy rates increased for an initial period of time (phase 1) and then reached a point (change point) before the rate of increase substantially slowed, flattened, or slightly declined (phase 2).

FIGURE 4. Observed and Estimated Mean Rates of Working Memory Accuracy, Expressed as Area Under the Curve (AUC), in Adolescent Monkeys Repeatedly Exposed to THC or Vehicle

a Left panels show the mean observed area under the delay curves by week for the vehicle and THC groups on the spatial task (panel A) and on the double-reinforcement (panel C) and single-reinforcement (panel E) trials of the object task.

b Right panels show the mean estimated area under the delay curves derived from the two-phase statistical models of the observed data for the spatial task (panel B) and the double-reinforcement (panel D) and single-reinforcement (panel F) trials of the object task.

c For both groups on both tasks and both object reinforcement conditions, accuracy rates increased for an initial period of time (phase 1) and then reached a point (change point) before the rate of increase substantially slowed, flattened, or slightly declined (phase 2).

FIGURE 5. Mean Acute Change in Working Memory Accuracy From Pre- to Postinjection of THC or Vehicle in Adolescent Monkeys Before and After 6 Months of Repeated Exposurea

a During the first acute period, increasing doses of THC (or vehicle) were administered in order to determine the dose at which each monkey in the THC group became acutely intoxicated, as reflected by a marked decline of performance across tasks. Acute period 1 preceded the 6-month repeated-dosing study, which used stable doses, and acute period 2 came after the repeated-dosing study. During the second acute period, performance (measured as the percentage change in accuracy from pre- to post-drug administration) of monkeys in the THC group was assessed following administration of the same THC doses used throughout the repeated-dosing study, either 120 μg/kg of THC (three monkeys) or 240 μg/kg of THC (four monkeys).

b Panel A: independent of delay, performance on the spatial task during the first acute period was similar to performance during the second acute period for both the THC and vehicle groups.

c Panel B: performance on the double-reinforcement trials of the object task during the first acute period was similar to performance during the second acute period for both the THC and vehicle groups.

d Panel C: performance on the single-reinforcement trials of the object task during the first acute period was similar to performance during the second acute period for both the THC and vehicle groups.

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