Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice

Abstract

Use of exogenous cannabinoids disrupts the fine-tuned endocannabinoid receptor system, possibly leading to alterations in cognition, memory, and emotional processes that endure long after cannabinoid use has stopped. Long-term adolescent use may uniquely disrupt these behaviors when compared to adult use. The current study explored the acute and long-term behavioral effects of six 10 mg/kg Δ9-tetrahydrocannabinol (THC) injections across the adolescent or early adult period in male inbred C57Bl/6J and DBA/2J mice. The acute and prolonged effects of THC on object memory using the novel object recognition task, unconditioned anxiety in the elevated plus maze and open field, and sedative effects in the open field were examined. Acute THC treatment resulted in anxiogenic activity in both strains, but only caused sedation in B6 mice. Repeated THC treatment resulted in a protracted effect on object recognition, but not unconditioned anxiety, assessed 4 weeks later. In both strains, an adolescent history of THC treatment disrupted later object recognition. Interestingly, in B6 mice an adult history of THC exposure appeared to rescue a deficit in object recognition observed in vehicle-treated adults. Repeated THC administration also produced a protracted effected on CB1R protein expression. Animals treated with THC in adolescence maintained increased levels of CB1R protein expression compared to their adult THC-treated counterparts at five weeks following the last injection. These results indicate that THC use may have long-lasting effects with adolescence being a unique period of susceptibility.

Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain

“…Memory performance was also assessed the third week after starting the THC treatment. As expected, mice exposed to the chronic nociceptive manifestations of endometriosis showed a pronounced cognitive impairment, as well as sham mice exposed to THC, in accordance with previous reports in naïve males (Kasten et al, 2017; Puighermanal et al, 2013). Surprisingly, endometriosis mice repeatedly treated with natural THC showed intact discrimination indices (Figure 3c) suggesting protective effects of THC in this chronic inflammatory condition.…”

Sex and Strain Variation in Initial Sensitivity and Rapid Tolerance to Δ9–Tetrahydrocannabinol

“…26 Initial response to cannabis, THC, and other cannabinoid receptor 1 (CB1R) agonists has been measured across a range of doses among several inbred and outbred mouse strains (Table 1). [27][28][29][30][31][32][33][34][35] However, few of these studies have directly compared strain differences in response and most do not include females, thus preventing analysis of sex differences. Despite marked variation among individuals in the acute response to cannabis in humans, 36 little is known about the genetic factors mediating differential response or how initial sensitivity and tolerance may contribute to risk of CUD.…”

Assessment of Acute Motor Effects and Tolerance Following Self‐Administration of Alcohol and Edible ∆9‐Tetrahydrocannabinol in Adolescent Male Mice

“…Increased activity following repeated periods of voluntary EtOH intake in adolescent mice has been previously reported (Quoilin and Boehm, ) and appears to be an age‐related phenomenon, as adult mice show a decrease in activity to EtOH intake over days (Linsenbardt et al., ; Quoilin and Boehm, ). Administration of THC typically decreases activity (Lichtman et al., ; McMahon and Koek, ), except at low doses in novel environments (Kruse et al., ; Sañudo‐Peña et al., ), and although there is evidence for age‐related differences in the locomotor response to THC (Kasten et al., ; Schramm‐Sapyta et al., ), the decreases in activity seen here in adolescent mice are similar to those seen in adult mice following edible THC consumption (Smoker et al., ). While these EtOH‐ and THC‐induced locomotor effects were most pronounced during the 2 hours of DID, the effect of THC persisted post‐DID on some days, consistent with the extended duration of action of THC following oral administration (Grotenhermen, ; Hložek et al., ).…”

“…Blood samples were centrifuged, and plasma was separated and stored at −80°C until analyzed for BEC using gas chromatography as previously described (Lumeng et al., ). Whole‐brain CB1R expression was determined via Western blot as previously described (Kasten et al., ). Briefly, whole‐brain samples were homogenized in 2 ml of RIPA buffer, protein concentration was determined using a Bio‐Rad protein assay kit (Bio‐Rad, Hercules, CA), and 20 μ g of protein in 20 μ l of 4× loading buffer was loaded.…”