Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats

Abstract

Although many studies have examined the acute behavioural effects of cannabinoids in rodents, few have examined the lasting effects of cannabinoids at different developmental ages. This study compared lasting effects of cannabinoid exposure occurring in adolescence to that occurring in early adulthood. Forty, 30-day old (adolescent) and 18, 56-day old (adult) female albino Wistar rats were injected with vehicle or incremental doses of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940) once per day for 21 consecutive days (150, 200 and 300 microg/kg i.p. for 3, 8 and 10 days, respectively). Following a 21-day drug-free period, working memory was assessed using an object recognition task. Locomotor activity was also measured in the object recognition apparatus via a ceiling-mounted passive infrared sensor. Three days later, anxiety was assessed using a social interaction test. In the object recognition task, significantly poorer working memory was observed in the adolescent but not adult CP 55,940-treated rats. Adolescent, but not adult CP 55,940-treated rats, also exhibited a significant decrease in social interaction with a novel conspecific. These results suggest that chronic exposure to a cannabinoid receptor agonist well after the immediate postnatal period, but before reaching sexual maturity, can lead to increased anxiety and a lasting impairment of working memory.

Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

“…Overall exploration times were not affected by prior D 9 -THC treatment, suggesting this deficit cannot be attributed to any nonspecific impairment or lack of exploration. This adolescent-specific deficit in object recognition memory is consistent with reports that cannabinoid administration in immature but not mature rats results in lasting impairments in learning (Stiglick and Kalant, 1985) and also more direct adolescent to adult comparisons showing adolescent-specific impaired object recognition memory after cannabinoid treatment (Schneider and Koch, 2003;O'Shea et al, 2004). This is also consistent with human studies showing persistent attentional deficits in early-but not late-onset cannabis users (Ehrenreich et al, 1999).…”

“…The residual decline in social interaction in D 9 -THCpretreated rats agrees with a recent report of long-lasting reductions in social interaction arising from prior cannabinoid (CP 55,940) exposure in male adolescent and adult rats (O'Shea et al, 2006). A different pattern of results may have been obtained in female rats however, as an earlier study by the same authors reported an adolescent-specific social interaction deficit in cannabinoid pretreated female rats (O'Shea et al, 2004).…”

“…More recently, administration of the synthetic cannabinoid agonist WIN 55,212-2 during the adolescent but not the adult period was reported to cause long-lasting deficits in sensorimotor gating, object recognition memory, and performance on an instrumental task (Schneider and Koch, 2003;Schneider et al, 2005). Residual working memory and social interaction deficits were also found in adolescent but not adult female rats treated with the synthetic cannabinoid agonist CP 55,940 (O'Shea et al, 2004). In a human study, early-but not late-onset human cannabis users exhibited longer reaction times in a visual scanning task suggestive of a persistent attentional deficit (Ehrenreich et al, 1999).…”

Abstinent adolescent marijuana users show altered fMRI response during spatial working memory

“…In particular, sex differences in cannabinoid receptor binding and interactions between cannabinoids and sex hormones have been observed (Rodriguez De Fonseca et al, 1993, raising the possibility of gender differences in neural response to cannabinoids. In support of this, previous studies have identified gender differences in the neurocognitive impact of marijuana use among humans (Skosnik et al, 2006) and rodents (O'Shea et al, 2004(O'Shea et al, , 2006. Gender differences in the rate and timing of neurodevelopment (Giedd et al, 1999(Giedd et al, , 2006 may also contribute to gender differences in sensitivity to marijuana in adolescence.…”

“…Similarly, adults who began using marijuana in early adolescence showed greater neural dysfunction during spatial attention (Chang et al, 2006) and poorer functioning on tests of attention (Ehrenreich et al, 1999), and verbal abilities and short-term memory (Pope et al, 2003). Animal models also indicate that cannabinoid exposure during adolescence is associated with greater impairments in working memory and spatial learning than adult exposure Kalant, 1982, 1985;O'Shea et al, 2004). Thus, evidence suggests that marijuana use during adolescence may influence the course of brain development, and those who begin using marijuana at a younger age may be more susceptible to dysfunction with continued use.…”