Adolescent self-administration of the synthetic cannabinoid receptor agonist JWH-018 induces neurobiological and behavioral alterations in adult male mice

Abstract

Rationale The use of synthetic cannabinoid receptor agonists (SCRAs) is growing among adolescents, posing major medical and psychiatric risks. JWH-018 represents the reference compound of SCRA-containing products. Objectives This study was performed to evaluate the enduring consequences of adolescent voluntary consumption of JWH-018. Methods The reinforcing properties of JWH-018 were characterized in male CD1 adolescent mice by intravenous self-administration (IVSA). Afterwards, behavioral, neurochemical, and molecular evaluations were performed at adulthood. Results Adolescent mice acquired operant behavior (lever pressing, Fixed Ratio 1–3; 7.5 µg/kg/inf); this behavior was specifically directed at obtaining JWH-018 since it increased under Progressive Ratio schedule of reinforcement, and was absent in vehicle mice. JWH-018 IVSA was reduced by pretreatment of the CB1-antagonist/inverse agonist AM251. Adolescent exposure to JWH-018 by IVSA increased, at adulthood, both nestlet shredding and marble burying phenotypes, suggesting long-lasting repetitive/compulsive-like behavioral effects. JWH-018 did not affect risk proclivity in the wire-beam bridge task. In adult brains, there was an increase of ionized calcium binding adaptor molecule 1 (IBA-1) positive cells in the caudate-putamen (CPu) and nucleus accumbens (NAc), along with a decrease of glial fibrillary acidic protein (GFAP) immunoreactivity in the CPu. These glial alterations in adult brains were coupled with an increase of the chemokine RANTES and a decrease of the cytokines IL2 and IL13 in the cortex, and an increase of the chemokine MPC1 in the striatum. Conclusions This study suggests for the first time that male mice self-administer the prototypical SCRA JWH-018 during adolescence. The adolescent voluntary consumption of JWH-018 leads to long-lasting behavioral and neurochemical aberrations along with glia-mediated inflammatory responses in adult brains.

Adolescent exposure to the Spice/K2 cannabinoid JWH-018 impairs sensorimotor gating and alters cortical perineuronal nets in a sex-dependent manner

“…Notably, adolescent JWH-018 exposure induced an activation of microglia and astrocytes in the prefrontal cortex of adult male mice. In agreement, a recent study showed a long-term microglia activation in several brain areas such as the nucleus accumbens and caudate-putamen following adolescent self-administration of JWH-018 [ 43 ]. Taken together, it is tempting to hypothesize that exposure to JWH-018 to adolescent mice induces changes in glial cells reactivity and PNNs density in the prefrontal cortex, leading to the appearance of sensorimotor gating deficits in adulthood.…”

“…By using the EPM, most of the studies have not shown differences in anxiety in adult male [ 24 , 40 , 41 ] or female [ 40 , 41 ] rodents due to adolescent ∆ 9 -THC exposure, although an anxiogenic-like effect was observed in adult male mice in another report [ 42 ]. A recent study revealed an increase of repetitive/compulsive behaviors at adulthood in adolescent male mice exposed to JWH-018, as shown in the nestlet shredding and marble burying tests [ 43 ]. Although marble burying test can be used to assess anxiety-like behavior, the heightened marble burying activity of JWH-018 treated male mice could reflect compulsive-like rather than anxiety-like states considering that in a previous study adult male rats showed increased burying scores, but not anxiety alterations in the EPM test, 7 days after JWH-018 discontinuation [ 16 ].…”

Deletion of Cryab increases the vulnerability of mice to the addiction-like effects of the cannabinoid JWH-018 via upregulation of striatal NF-κB expression

“…Our results contradict some previous studies, given that cannabinoids are understood to be anti-inflammatory and JWH-018 seemed to potentially induce inflammation in Cryab KO mice. However, according to previous studies (Pintori et al, 2021;Margiani et al, 2022), JWH-018 may potentially promote neuroinflammation in mice following previous repeated exposures. Thus, the absence of CRYAB might have exacerbated the neuroinflammatory effect of JWH-018 in Cryab KO mice, resulting in the observed alterations in NF-κB, GFAP, and IL-6 expressions, given also that CRYAB, possessing an anti-inflammatory function, might have rendered the Cryab KO mice susceptible to inflammatory insults.…”

“…The results of the SA and CPP tests were consistent with this hypothesis, as WT mice did not exhibit significant preference or tendency for self-administering JWH-018 at 0.03 mg/kg/infusion or 0.3 mg/kg, unlike with previous studies. This discrepancy among studies investigating intravenous JWH-018 SA in WT mice might be attributed primarily to methodological differences, given that some studies required long-term exposure of mice in JWH-018 SA ( de Luca et al, 2015 ), with some using adolescent mice with potentially different drug sensitivity ( Margiani et al, 2022 ). However, the fact that Cryab KO mice exhibited modest SA responses and place preference for JWH-018 indicated cannabinoid-induced addiction-like behaviors, suggesting cannabinoid abuse susceptibility.…”

Repeated exposure to the synthetic cannabinoid JWH-018 induces enduring immune and glial alterations in the rat brain

“…Kevin and colleagues [24] reported decreased IL-1α and IL-12 plasma levels in rats after adolescent treatment with AB-FUBINACA. Recently, our group demonstrated that adolescent voluntary consumption of JWH-018 leads to long-lasting behavioral and neurochemical aberrations along with changes in glial cells (i.e., astrocytopathy and microgliosis) [25]. These glial alterations in adult brains were coupled with an increase in the chemokine regulated on activation normal T cells expressed and secreted (RANTES), a decrease in the cytokines IL-2 and IL-13 in the cortex, and an increase in the chemokine monocyte chemoattractant protein-1 (MCP-1) in the striatum [25].…”