Cannabis is the most widely used illicit substance in the United States and worldwide, and its use is expected to increase with recent and pending changes in its legal and medical status. Cannabis use during adolescence is of particular concern because of its association with enduring cognitive impairments and overall worse life outcomes. Whether these deleterious outcomes are a direct result of cannabis use, however, remains controversial (Curran et al, 2016). Indeed, many of the genetic and environmental factors that increase the likelihood of drug experimentation (eg, impulsivity, low socioeconomic status, and chronic stress) also predispose individuals to adverse outcomes, even in the absence of drug use. Animal studies to date, however, also show that cannabinoid administration during adolescence can induce cognitive deficits that persist into adulthood. While directly addressing causality, these prior animal studies also have limitations, as they have employed passive drug administration, which fails to model the volitional nature of human drug use. This is an important distinction as passive versus active drug administration can result in unique neural and behavioral consequences. Self-administration models (in which a response is required in order to receive a drug) better mimic human drug use, but cannabinoid self-administration can be challenging to establish. In this issue of NPP, Kirschmann et al. report the first animal model of adolescent cannabinoid self-administration. Rats in this study were trained to intravenously self-administer the synthetic CB1 receptor agonist WIN55,212-2 (WIN) in daily sessions over several weeks during mid- to-late adolescence. The rats acquired robust WIN self-administration at levels comparable to those shown previously in adult rats (Fattore et al, 2007).
A primary goal of these studies was to evaluate the effects of adolescent cannabinoid self-administration on adult cognitive outcomes. Rats that self-administered WIN during adolescence, together with control rats that had comparable experience self-administering a food reward, were assessed under drug-free conditions on several tests of prefrontal cortex (PFC)-dependent mnemonic function (delayed-response working memory and spatial/object recognition memory tasks). Somewhat surprisingly, cannabinoid self-administration had no adverse effects on performance across a range of adult time points, and working memory performance was actually enhanced. These findings stand in sharp contrast to the cognitively impairing effects of passive adolescent cannabinoid exposure reported previously, and suggest that the route of administration has a critical role in behavioral consequences of cannabinoids. It is also important to acknowledge, however, that the cumulative doses of self-administered WIN were markedly lower than doses used in prior passive administration studies. Indeed, Kirschmann et al. replicated a previous demonstration of impaired spatial and object recognition memory following passive administration of higher WIN doses (Abush and Akirav, 2012). It is possible that these and similar impairments are due to the increased anxiety reported to follow passive, high dose cannabinoid administration. It remains to be determined whether passive administration of doses more akin to those achieved through self-administration produces such deleterious behavioral effects.
