Effects of Adolescent Cannabinoid Self-Administration in Rats on Addiction-Related Behaviors and Working Memory

Abstract

Use of marijuana (Cannabis sativa) often begins in adolescence, and heavy adolescent marijuana use is often associated with impaired cognitive function in adulthood. However, clinical reports of long-lasting cognitive deficits, particularly in subjects who discontinue use in adulthood, are mixed. Moreover, dissociating innate differences in cognitive function from cannabis-induced deficits is challenging. Therefore, the current study sought to develop a rodent model of adolescent cannabinoid self-administration (SA), using the synthetic cannabinoid receptor agonist WIN55,212-2 (WIN), in order to assess measures of relapse/reinstatement of drug seeking and long-term effects on cognitive function assessed in a delay-match-to-sample working memory task and a spatial recognition task. Adolescent male rats readily self-administered WIN in 2-h or 6-h sessions/day, but did not demonstrate an escalation of intake with 6-h access. Rats exhibited significant cue-induced reinstatement of WIN seeking that increased with 21 days of abstinence (ie, 'incubation of craving'). Cognitive testing occurred in adulthood under drug-free conditions. Both 2-h and 6-h adolescent WIN SA groups exhibited significantly better working memory performance in adulthood relative to sucrose SA controls, and performance was associated with altered expression of proteins regulating GABAergic and glutamatergic signaling in the prefrontal cortex. Self-administered WIN did not produce either acute or chronic effects on short-term memory, but experimenter administration of WIN in adolescence, at doses previously reported in the literature, produced acute deficits in short-term memory that recovered with abstinence. Thus, SA of a rewarding cannabinoid in adolescence does not produce long-term cognitive dysfunction.

A Population-Based Analysis of the Relationship Between Substance Use and Adolescent Cognitive Development

“…Over and above the effect of being prone to cannabis use during adolescence, when increases in cannabis use frequency were observed in a given year, reductions in delayed recall memory and perceptual reasoning were observed in that same year, and these effects were independent of any changes in alcohol quantity3frequency. The transient effects of cannabis on episodic memory have been reported in animal (32) and human studies investigating long-term cognitive outcomes of cannabis-exposed subjects who later achieved abstinence (4). The ability to encode and retrieve memories is regulated by the circuitry of the medial-temporal lobe, including the hippocampus, which is rich in endocannabinoid receptors (17).…”

Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure

“…Fattore et al (2001) extended WIN 55,212-2 self-administration procedures to use rats over multiple sessions, allowing study of the acquisition of the behavior, its maintenance over time, and its extinction when drug delivery was discontinued. This procedure has been used in subsequent studies (see Table 1 for details) to investigate subject variables (strain and sex of the rats), procedural variables (dose of the cannabinoid), treatment drugs (potential therapeutics), and specific aspects of addiction (relapse) (Deiana et al, 2007;Fattore et al, 2007Fattore et al, , 2010Justinova et al, 2013;Kirschmann et al, 2017;Lefever et al, 2014;Mendizabal et al, 2006;Scherma et al, 2016a;Struik et al, 2017). However, compared with selfadministration of classical drugs of abuse such as cocaine and heroin, self-administration of WIN 55,212-2 by rodents tends to be more sensitive to variables such as training conditions and genetic strain, and it is generally harder to obtain.…”

Effect of N‐acetylcysteine on motivation, seeking and relapse to ethanol self‐administration

“…Time‐dependent increases in cue‐induced ethanol craving during abstinence were recently reported in AUD patients (Li et al ), demonstrating an ‘incubation of craving’ in the context of AUD. In rats, the ‘incubation of craving’ phenomenon was also observed for cannabinoid (Kirschmann et al ) and for heroin, nicotine, methamphetamine and ethanol self‐administration (for a review, see Pickens et al ). Moreover, extinction training alone can reduce drug‐seeking behavior (McNally ).…”