Cognitive dysfunction and impaired neuroplasticity following repeated exposure to the synthetic cannabinoid JWH-018 in male mice.

BACKGROUND AND PURPOSE: Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure. EXPERIMENTAL APPROACH: Male CD-1 mice were injected with vehicle, JWH-018 (6 mg·kg-1 ), the CB1 -antagonist NESS-0327 (1 mg·kg-1 ) or co-administration of NESS-0327 and JWH-018, every day for 7 days. After 15 or 16 days washout, we investigated the effects of JWH-018 on motor function, memory, social dominance and prepulse inhibition (PPI). We also evaluated glutamate levels in dialysates from dorsal striatum, striatal dopamine content and striatal/hippocampal neuroplasticity focusing on the NMDA receptor complex and the neurotrophin BDNF. These measurements were accompanied by in vitro electrophysiological evaluations in hippocampal preparations. Finally, we investigated the density of CB1 receptors and levels of the endocannabinoid anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and their main synthetic and degrading enzymes in the striatum and hippocampus. KEY RESULTS: The repeated treatment with JWH-018 induced psychomotor agitation while reducing social dominance, recognition memory and PPI in mice. JWH-018 disrupted hippocampal LTP and decreased BDNF expression, reduced the synaptic levels of NMDA receptor subunits and decreased the expression of PSD95. Repeated exposure to JWH-018, reduced hippocampal CB1 receptor density and induced a long-term alteration in AEA and 2-AG levels and their degrading enzymes, FAAH and MAGL, in the striatum. CONCLUSION AND IMPLICATIONS: Our findings suggest that repeated administration of a high dose of JWH-018 leads to the manifestation of psychotic-like symptoms accompanied by alterations in neuroplasticity and change in the endocannabinoid system.

Assay of GTPγS Binding in Autoradiography.

Autoradiography of radiolabeled GTPγS ([35S]GTPγS) binding is a relevant technique to study the function of G protein-coupled receptors (GPCRs) ex vivo. Here, we describe the protocol for such a method, suitable for investigating CB1 receptor functionality in tissue slices from rodent brains.

Long-Term Consequences of Adolescent Exposure to THC-Rich/CBD-Poor and CBD-Rich/THC-Poor Combinations: A Comparison with Pure THC Treatment in Female Rats.

Cannabis is the most-used recreational drug worldwide, with a high prevalence of use among adolescents. In animal models, long-term adverse effects were reported following chronic adolescent exposure to the main psychotomimetic component of the plant, delta-9-tetrahydrocannabinol (THC). However, these studies investigated the effects of pure THC, without taking into account other cannabinoids present in the cannabis plant. Interestingly, cannabidiol (CBD) content seems to mitigate some of the side effects of THC, at least in adult animals. Thus, in female rats, we evaluated the long-term consequences of a co-administration of THC and CBD at a 3:1 ratio, chosen based on the analysis of recently confiscated illegal cannabis samples in Europe. CBD content is able to mitigate some of the long-term behavioral alterations induced by adolescent THC exposure as well as long-term changes in CB1 receptor and microglia activation in the prefrontal cortex (PFC). We also investigated, for the first time, possible long-term effects of chronic administration of a THC/CBD combination reminiscent of "light cannabis" (CBD:THC in a 33:1 ratio; total THC 0.3%). Repeated administration of this CBD:THC combination has long-term adverse effects on cognition and leads to anhedonia. Concomitantly, it boosts Glutamic Acid Decarboxylase-67 (GAD67) levels in the PFC, suggesting a possible lasting effect on GABAergic neurotransmission.

Therapeutic potential of cannabidivarin for epilepsy and autism spectrum disorder.

Recent years have seen a renewed interest on the possible therapeutic exploitations of specific cannabinoids derived from the Cannabis sativa plant. Thus far, the most studied non-psychotomimetic cannabinoid is cannabidiol (CBD), which has shown promising therapeutic potential for relieving a variety of neurological diseases. However, also its propyl analogue, cannabidivarin (CBDV), has recently gained much attention as a potential therapeutic agent for the management of disabling neurological conditions. This review aims at providing a comprehensive and updated overview of the available animal and human data, which have investigated the possible therapeutic potential of CBDV for the management of epilepsy and autism spectrum disorder.

Neurobiological mechanisms underlying cannabis-induced memory impairment.

A growing body of literature suggests that cannabis intake can induce memory loss in humans and animals. Besides the recreational use, daily cannabis users may also belong to the ever-increasing population of patients who are administered cannabis as a medicine. As such, they also can experience impairments in memory as a negative side effect of their therapy. Comprehension of the neurobiological mechanisms responsible for such detrimental effects would be therefore of paramount relevance to public health. The investigation of neurobiological mechanisms in humans, despite the progress in the development of imaging technologies that allow the study of brain structure and function, still suffers substantial limitations. Animal models, instead, enable us to establish a causal relationship and thus to better elucidate the neurobiological mechanisms underlying the process under study. In this review, we will attempt to collect the insight coming from animal models about cannabis effects on memory, trying to depict a picture of the neurobiological mechanisms contributing to the development of cognitive deficits following cannabis use.

Cannabidivarin Treatment Ameliorates Autism-Like Behaviors and Restores Hippocampal Endocannabinoid System and Glia Alterations Induced by Prenatal Valproic Acid Exposure in Rats.

Autism spectrum disorder (ASD) is a developmental condition whose primary features include social communication and interaction impairments with restricted or repetitive motor movements. No approved treatment for the core symptoms is available and considerable research efforts aim at identifying effective therapeutic strategies. Emerging evidence suggests that altered endocannabinoid signaling and immune dysfunction might contribute to ASD pathogenesis. In this scenario, phytocannabinoids could hold great pharmacological potential due to their combined capacities to act either directly or indirectly on components of the endocannabinoid system and to modulate immune functions. Among all plant-cannabinoids, the phytocannabinoid cannabidivarin (CBDV) was recently shown to reduce motor impairments and cognitive deficits in animal models of Rett syndrome, a condition showing some degree of overlap with autism, raising the possibility that CBDV might have therapeutic potential in ASD. Here, we investigated the ability of CBDV treatment to reverse or prevent ASD-like behaviors in male rats prenatally exposed to valproic acid (VPA; 500 mg/kg i.p.; gestation day 12.5). The offspring received CBDV according to two different protocols: symptomatic (0.2/2/20/100 mg/kg i.p.; postnatal days 34-58) and preventative (2/20 mg/kg i.p.; postnatal days 19-32). The major efficacy of CBDV was observed at the dose of 20 mg/kg for both treatment schedules. CBDV in symptomatic rats recovered social impairments, social novelty preference, short-term memory deficits, repetitive behaviors and hyperlocomotion whereas preventative treatment reduced sociability and social novelty deficits, short-term memory impairments and hyperlocomotion, without affecting stereotypies. As dysregulations in the endocannabinoid system and neuroinflammatory markers contribute to the development of some ASD phenotypes in the VPA model, neurochemical studies were performed after symptomatic treatment to investigate possible CBDV's effects on the endocannabinoid system, inflammatory markers and microglia activation in the hippocampus and prefrontal cortex. Prenatal VPA exposure increased CB1 receptor, FAAH and MAGL levels, enhanced GFAP, CD11b, and TNFα levels and triggered microglia activation restricted to the hippocampus. All these alterations were restored after CBDV treatment. These data provide preclinical evidence in support of the ability of CBDV to ameliorate behavioral abnormalities resembling core and associated symptoms of ASD. At the neurochemical level, symptomatic CBDV restores hippocampal endocannabinoid signaling and neuroinflammation induced by prenatal VPA exposure.

Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male Mecp2 mutant mice.

BACKGROUND: Recent evidence suggests that 2-week treatment with the non-psychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of Rett syndrome (RTT). AIM: The aim of this study was to provide further insights into the efficacy of CBDV in Mecp2-null mice using a lifelong treatment schedule (from 4 to 9 weeks of age) to evaluate its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression. METHODS: CBDV 0.2, 2, 20 and 200 mg/kg/day was administered to Mecp2-null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wild-type and knockout mice to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system. RESULTS: CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in Mecp2 mutant mice at an advanced stage of the disease. Mecp2 deletion upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment. CONCLUSIONS: CBDV administration exerts an enduring rescue of memory deficits in Mecp2 mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.

Adult Cellular Neuroadaptations Induced by Adolescent THC Exposure in Female Rats Are Rescued by Enhancing Anandamide Signaling.

Background: In rodent models, chronic exposure to cannabis' psychoactive ingredient, Δ9-tetrahydrocannabinol, during adolescence leads to abnormal behavior in adulthood. In female rats, this maladaptive behavior is characterized by endophenotypes for depressive-like and psychotic-like disorders as well as cognitive deficits. We recently reported that most depressive-like behaviors triggered by adolescent Δ9-tetrahydrocannabinol exposure can be rescued by manipulating endocannabinoid signaling in adulthood with the anandamide-inactivating enzyme FAAH inhibitor, URB597. However, the molecular mechanisms underlying URB597's antidepressant-like properties remain to be established. Methods: Here we examined the impact of adult URB597 treatment on the cellular and functional neuroadaptations that occurred in the prefrontal cortex and dentate gyrus of the hippocampus upon Δ9-tetrahydrocannabinol during adolescence through biochemical, morphofunctional, and electrophysiological studies. Results: We found that the positive action of URB597 is associated with the rescue of Δ9-tetrahydrocannabinol-induced deficits in endocannabinoid-mediated signaling and synaptic plasticity in the prefrontal cortex and the recovery of functional neurogenesis in the dentate gyrus of the hippocampus. Moreover, the rescue property of URB597 on depressive-like behavior requires the activity of the CB1 cannabinoid receptor. Conclusions: By providing novel insights into the cellular and molecular mechanisms of URB597 at defined cortical and hippocampal circuits, our results highlight that positive modulation of endocannabinoid-signaling could be a strategy for treating mood alterations secondary to adolescent cannabis use.

Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex.

BACKGROUND: Increasing cannabis consumption among adolescents, studies that link its early use with mental illnesses, and the political debate on cannabis legalization together call for an urgent need to study molecular underpinnings of adolescent brain vulnerability. The emerging role of epigenetic mechanisms in psychiatric diseases led us to hypothesize that epigenetic alterations could play a role in causes and subsequent development of the depressive/psychotic-like phenotype induced by adolescent, but not adult, Δ9-tetrahydrocannabinol (THC) exposure in female rats. METHODS: We performed a time-course analysis of histone modifications, chromatin remodelling enzymes and gene expression in the prefrontal cortex of female rats after adolescent and adult THC exposure. We also administered a specific epigenetic drug (chaetocin) with THC to investigate its impact on THC-induced behavioural alterations. RESULTS: Adolescent THC exposure induced alterations of selective histone modifications (mainly H3K9me3), impacting the expression of genes closely associated with synaptic plasticity. Changes in both histone modifications and gene expression were more widespread and intense after adolescent treatment, suggesting specific adolescent susceptibility. Adolescent THC exposure significantly increased Suv39H1 levels, which could account for the enhanced H3K9me3. Pharmacological blockade of H3K9me3 during adolescent THC treatment prevented THC-induced cognitive deficits, suggesting the relevant role played by H3K9me3 in THC-induced effects. LIMITATIONS: Only female rats were investigated, and the expression studies were limited to a specific subset of genes. CONCLUSION: Through a mechanism involving SUV39H1, THC modifies histone modifications and, thereby, expression of plasticity genes. This pathway appears to be relevant for the development of cognitive deficits.

The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models.

Autism spectrum disorder (ASD) defines a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction with restricted or repetitive motor movements, frequently associated with general cognitive deficits. Although it is among the most severe chronic childhood disorders in terms of prevalence, morbidity, and impact to the society, no effective treatment for ASD is yet available, possibly because its neurobiological basis is not clearly understood hence specific drugs have not yet been developed. The endocannabinoid (EC) system represents a major neuromodulatory system involved in the regulation of emotional responses, behavioral reactivity to context, and social interaction. Furthermore, the EC system is also affected in conditions often present in subsets of patients diagnosed with ASD, such as seizures, anxiety, intellectual disabilities, and sleep pattern disturbances. Despite the indirect evidence suggestive of an involvement of the EC system in ASD, only a few studies have specifically addressed the role of the EC system in the context of ASD. This review describes the available data on the investigation of the presence of alterations of the EC system as well as the effects of its pharmacological manipulations in animal models of ASD-like behaviors.

New vistas on cannabis use disorder.

Cannabis sativa preparations are the most consumed illicit drugs for recreational purposes worldwide, and the number of people seeking treatment for cannabis use disorder has dramatically increased in the last decades. Due to the recent decriminalization or legalization of cannabis use in the Western Countries, we may predict that the number of people suffering from cannabis use disorder will increase. Despite the increasing number of cannabis studies over the past two decades, we have gaps of scientific knowledge pertaining to the neurobiological consequences of long-term cannabis use. Moreover, no specific treatments for cannabis use disorders are currently available. In this review, we explore new research that may help fill these gaps. We discuss and provide a solution to the experimental limitation of a lack of rodent models of THC self-administration, and the importance this model can play in understanding the neurobiology of relapse and in providing a biological rationale for potential therapeutic targets. We also focus our attention on glial cells, commenting on recent preclinical evidence suggesting that alterations in microglia and astrocytes might contribute to the detrimental effects associated with cannabis abuse. Finally, due to the worrisome prevalence rates of cannabis use during pregnancy, we highlight the associations between cannabis use disorders during pregnancy and congenital disorders, describing the possible neuronal basis of vulnerability at molecular and circuit level. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology".

Lifelong imbalanced LA/ALA intake impairs emotional and cognitive behavior via changes in brain endocannabinoid system.

Imbalanced dietary n-3 and n-6 PUFA content has been associated with a number of neurological conditions. Endocannabinoids are n-6 PUFA derivatives, whose brain concentrations are sensitive to modifications of fatty acid composition of the diet and play a central role in the regulation of mood and cognition. As such, the endocannabinoid system appears to be an ideal candidate for mediating the effects of dietary fatty acids on mood and cognition. Lifelong administration of isocaloric α-linolenic acid (ALA)-deficient and -enriched diets induced short-term memory deficits, whereas only dietary ALA enrichment altered emotional reactivity in adult male rats compared with animals fed a standard diet that was balanced in ALA/linoleic acid (LA) ratio. In the prefrontal cortex, both diets reduced 2-AG levels and increased MAG lipase expression, whereas only the enriched diet reduced AEA levels, simultaneously increasing FAAH expression. In the hippocampus, an ALA-enriched diet decreased AEA content and NAPE-PLD expression, and reduced 2-AG content while increasing MAG lipase expression. These findings highlight the importance of a diet balanced in fatty acid content for normal brain functions and to support a link between dietary ALA, the brain endocannabinoid system, and behavior, which indicates that dietary ALA intake is a sufficient condition for altering the endocannabinoid system in brain regions modulating mood and cognition.

The anabolic steroid nandrolone alters cannabinoid self-administration and brain CB1 receptor density and function.

Clinical and pre-clinical observations indicate that anabolic-androgenic steroids can induce neurobiological changes that alter the rewarding effects of drugs of abuse. In this study, we investigated the effect of the anabolic steroid nandrolone on the rewarding properties of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) in rats. Lister Hooded male rats were treated intramuscularly with nandrolone (15mg/kg) or vehicle for 14 consecutive days, and then allowed to self-administer WIN (12.5µg/kg/infusion) intravenously. After reaching stable drug intake, self-administration behavior was extinguished to examine drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Other behavioral parameters presumed to influence drug-taking and drug-seeking behaviors were examined to gain more insight into the behavioral specificity of nandrolone treatment. Finally, animals were sacrificed for analysis of CB1 receptor density and function in selected brain areas. We found that nandrolone-treated rats self-administered up to 2 times more cannabinoid than vehicle-treated rats, but behaved similarly to control rats when tested for drug- and cue-induced reinstatement of cannabinoid-seeking behavior. Enhanced cannabinoid intake by nandrolone-treated rats was not accompanied by changes in locomotor activity, sensorimotor gating, or memory function. However, our molecular data show that after chronic WIN self-administration nandrolone-treated rats display altered CB1 receptor density and function in selected brain areas. We hypothesize that increased cannabinoid self-administration in nandrolone-treated rats results from a nandrolone-induced decrease in reward function, which rats seem to compensate by voluntarily increasing their cannabinoid intake. Altogether, our findings corroborate the hypothesis that chronic exposure to anabolic-androgenic steroids induces dysfunction of the reward pathway in rats and might represent a potential risk factor for abuse of cannabis and other drugs in humans.

Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.

Cannabis use has been frequently associated with sex-dependent effects on brain and behavior. We previously demonstrated that adult female rats exposed to delta-9-tetrahydrocannabinol (THC) during adolescence develop long-term alterations in cognitive performances and emotional reactivity, whereas preliminary evidence suggests the presence of a different phenotype in male rats. To thoroughly depict the behavioral phenotype induced by adolescent THC exposure in male rats, we treated adolescent animals with increasing doses of THC twice a day (PND 35-45) and, at adulthood, we performed a battery of behavioral tests to measure affective- and psychotic-like symptoms as well as cognition. Poorer memory performance and psychotic-like behaviors were present after adolescent THC treatment in male rats, without alterations in the emotional component. At cellular level, the expression of the NMDA receptor subunit, GluN2B, as well as the levels of the AMPA subunits, GluA1 and GluA2, were significantly increased in hippocampal post-synaptic fractions from THC-exposed rats compared to controls. Furthermore, increases in the levels of the pre-synaptic marker, synaptophysin, and the post-synaptic marker, PSD95, were also present. Interestingly, KCl-induced [(3)H]D-ASP release from hippocampal synaptosomes, but not gliosomes, was significantly enhanced in THC-treated rats compared to controls. Moreover, in the same brain region, adolescent THC treatment also resulted in a persistent neuroinflammatory state, characterized by increased expression of the astrocyte marker, GFAP, increased levels of the pro-inflammatory markers, TNF-α, iNOS and COX-2, as well as a concomitant reduction of the anti-inflammatory cytokine, IL-10. Notably, none of these alterations was observed in the prefrontal cortex (PFC). Together with our previous findings in females, these data suggest that the sex-dependent detrimental effects induced by adolescent THC exposure on adult behavior may rely on its ability to trigger different region-dependent changes in glutamate synapse and glial cells. The phenotype observed in males is mainly associated with marked dysregulations in the hippocampus, whereas the prevalence of alterations in the emotional sphere in females is associated with profound changes in the PFC.

Assay of GTPγS Binding in Autoradiography.

Autoradiography of radiolabeled GTPγS ([(35)S]GTPγS) binding is a relevant method to study the function of G protein-coupled receptors (GPCRs), in tissue sections. Here, we describe the protocol for such a binding autoradiography, suitable to investigate the functionality of CB1 receptor in tissue slices from rodent brain.

MeCP2 Related Studies Benefit from the Use of CD1 as Genetic Background.

MECP2 mutations cause a number of neurological disorders of which Rett syndrome (RTT) represents the most thoroughly analysed condition. Many Mecp2 mouse models have been generated through the years; their validity is demonstrated by the presence of a broad spectrum of phenotypes largely mimicking those manifested by RTT patients. These mouse models, between which the C57BL/6 Mecp2tm1.1Bird strain probably represents the most used, enabled to disclose much of the roles of Mecp2. However, small litters with little viability and poor maternal care hamper the maintenance of the colony, thus limiting research on such animals. For this reason, past studies often used Mecp2 mouse models on mixed genetic backgrounds, thus opening questions on whether modifier genes could be responsible for at least part of the described effects. To verify this possibility, and facilitate the maintenance of the Mecp2 colony, we transferred the Mecp2tm1.1Bird allele on the stronger CD1 background. The CD1 strain is easier to maintain and largely recapitulates the phenotypes already described in Mecp2-null mice. We believe that this mouse model will foster the research on RTT.

The Impact of Exposure to Cannabinoids in Adolescence: Insights From Animal Models.

The regular use of cannabis during adolescence is of particular concern because use by this age group seems to be associated with an increased likelihood of deleterious consequences, as reported by several epidemiologic studies. However, despite their unquestionable value, epidemiologic data are inconclusive. Modeling the adolescent phase in animals appears to be a useful approach to investigate the impact of cannabis use on the adolescent brain. In these models, adolescent cannabinoid exposure has been reported to cause long-term impairment in specific components of learning and memory and to have differential effects on anxiety, social behavior, and depressive-like signs. These findings suggest that it may represent, per se or in association with other hits, a risk factor for developing psychotic-like symptoms in adulthood. The neurobiological bases of this association include the induction of alterations in the maturational events of the endocannabinoid system occurring in the adolescent brain. Alterations in the endocannabinoid system may profoundly dysregulate developmental processes in some neurotransmitter systems, such as gamma-aminobutyric acid and glutamate, mainly in the cortex. The resulting picture strongly resembles the one present in schizophrenic patients, highlighting the translational value of this experimental approach.

Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats.

Over 180 million people consume cannabis globally. Cannabis use peaks during adolescence with a trend for continued consumption by adults. Notably, several studies have shown that long-term and heavy cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders, although the neurobiological mechanisms underlying this association remain largely unknown. In this study, we evaluated whether, in female rats, chronic administration of increasing doses of the psychotropic plant-derived cannabis constituent, delta-9-tetrahydrocannabinol (THC), during adolescence (PND 35-45) could affect microglia function in the long-term. Furthermore, we explored a possible contribution of microglia to the development of THC-induced alterations in mood and cognition in adult female rats. Present data indicate that adolescent THC administration induces a persistent neuroinflammatory state specifically localized within the adult prefrontal cortex (PFC), characterized by increased expression of the pro-inflammatory markers, TNF-α, iNOS and COX-2, and reduction of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with down-regulation of CB1 receptor on neuronal cells and up-regulation of CB2 on microglia cells, conversely. Interestingly, blocking microglia activation with ibudilast during THC treatment significantly attenuates short-term memory impairments in adulthood, simultaneously preventing the increases in TNF-α, iNOS, COX-2 levels as well as the up-regulation of CB2 receptors on microglia cells. In contrast, THC-induced depressive-like behaviors were unaffected by ibudilast treatment. Our findings demonstrate that adolescent THC administration is associated with persistent neuroinflammation within the PFC and provide evidence for a causal association between microglial activation and the development long-term cognitive deficits induced by adolescent THC treatment.

Endocannabinoids and Mental Disorders.

Preclinical and clinical data fully support the involvement of the endocannabinoid system in the etiopathogenesis of several mental diseases. In this review we will briefly summarize the most common alterations in the endocannabinoid system, in terms of cannabinoid receptors and endocannabinoid levels, present in mood disorders (anxiety, posttraumatic stress disorder, depression, bipolar disorder, and suicidality) as well as psychosis (schizophrenia) and autism. The arising picture for each pathology is not always straightforward; however, both animal and human studies seem to suggest that pharmacological modulation of this system might represent a novel approach for treatment.

Sex-dependent vulnerability to cannabis abuse in adolescence.

The goal of this review is to summarize current evidence for sex differences in the response to cannabinoid compounds, focusing mainly on a specific age of exposure, i.e., adolescence. Preclinical as well as clinical studies are examined. Among the different possible underlying mechanisms, the consistent dimorphism in the endocannabinoid system and delta9-tetrahydrocannabinol metabolism may play a part. All the collected data point to the need of including females in basic research as well as of analyzing results for sex differences in epidemiological studies.