Susceptibility of the adolescent brain to cannabinoids: long-term hippocampal effects and relevance to schizophrenia

Abstract

Clinical studies report associations between cannabis use during adolescence and later onset of schizophrenia. We examined the causal relationship between developmental cannabinoid administration and long-term behavioral and molecular alterations in mice. Mice were administered either WIN 55,212-2 (WIN), a cannabinoid receptor 1 (CB1) agonist or vehicle (Veh) during adolescence (postnatal day 30–35) or early adulthood (postnatal day 63–70). Behavioral testing was conducted after postnatal day 120 followed by biochemical assays. Adolescent cannabinoid treatment (ACU) leads to deficits in prepulse inhibition and fear conditioning in adulthood. Metabotropic glutamate receptors type 5 (mGluR5), a receptor critically involved in fear conditioning and endocannabinoid (eCB) signaling, is significantly reduced in the ACU mouse hippocampus. Next, we examined expression profiles of genes involved in eCB synthesis (diacylglycerol lipase (DGL)) and uptake (monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH)) in the experimental mice. We find evidence of increased MGL and FAAH in ACU mice, reflecting increases in eCB uptake and degradation. These data suggest that administration of cannabinoids during adolescence leads to a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations in sensorimotor gating and hippocampal-dependent learning and memory deficits. Further, these deficits are associated with a reduction in hippocampal mGluR5 and a sustained change in eCB turnover, suggesting reduced eCB signaling in the ACU hippocampus. These data suggest that significant cannabis use during adolescence may be a contributory causal factor in the development of certain features of schizophrenia and may offer mGluR5 as a potential therapeutic target.

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

“…(55)). Echoing these limited findings in humans, preclinical studies showed that mice treated with cannabinoids during adolescence have sustained, markedly increased FAAH protein concentrations in the hippocampus in adulthood (33); as well, THC-tolerant rats have significantly decreased AEA concentrations in the striatum and midbrain although opposite findings were observed in the limbic forebrain and no change was observed in other brain regions including hippocampus, suggesting possible regionally specific FAAH modulation following chronic CB1 stimulation (31, 32). …”

“…Although it may be expected that development of tolerance to cannabinoids is also associated with changes in AEA concentrations and FAAH activities (26–28), few studies addressed this question in THC-dependent animals or humans. In this regard, studies by Leweke and colleagues of human cannabis users reported lower levels of AEA in cerebral spinal fluid (CSF) of frequent versus occasional users and healthy controls (a trend, (29, 30)), which is supported by some preclinical data (31, 32) and suggests that heavy chronic cannabis exposure might be associated with elevated brain FAAH activities (33, 34) and that targeting FAAH might be useful for cannabis withdrawal. Indeed, the FAAH inhibitor URB597 reduced rimonabant-precipitated withdrawal in THC-dependent mice (17).…”

Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

“…Several recent genome-wide association studies confirmed the involvement putative SNPs in GRM5 (Matosin et al, 2015b). In animal models, administration of cannabinoids during adolescence were shown to a reduction in hippocampal mGluR5, which was associated with learning deficits (Gleason et al, 2012). In contrast, postmortem studies have found only minimal changes in mGluR5 mRNA and mGluR5 protein in schizophrenia (Corti et al, 2011;Gupta et al, 2005;Volk et al, 2010).…”

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

“…Cognitive deficits in associative fear memory have been reported in mice displaying schizophrenic-like phenotypes (Arguello and Gogos, 2006;Gleason et al, 2012). Fear conditioning was assessed in computer-controlled operant chambers (Imetronic), as previously described (Blundell et al, 2010;Cai et al, 2006;Powell et al, 2004).…”