Publications by authors named "Tiziana Rubino"

63 Publications

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.

Int J Mol Sci 2021 Aug 18;22(16). Epub 2021 Aug 18.

Department of Biotechnology and Life Sciences (DBSV) and Neuroscience Center, University of Insubria, 21052 Busto Arsizio, Italy.

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.
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http://dx.doi.org/10.3390/ijms22168899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396365PMC
August 2021

Therapeutic potential of cannabidivarin for epilepsy and autism spectrum disorder.

Pharmacol Ther 2021 Oct 22;226:107878. Epub 2021 Apr 22.

Dept. of Biotechnology and Life Sciences (DBSV) and Neuroscience Center, University of Insubria, Busto Arsizio, Italy; Zardi-Gori Foundation, Milan, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107878DOI Listing
October 2021

Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping.

Int J Mol Sci 2020 Aug 29;21(17). Epub 2020 Aug 29.

Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano-Via Fratelli Cervi 93, 20090 Segrate (MI), Italy.

There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive. Environmental stress challenges individuals' equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety. A relevant homeostatic pathway is the endocannabinoid system (ECS). In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism. As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization. In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1. We here emphasize a remarkable example of stress-coping network where homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences.
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http://dx.doi.org/10.3390/ijms21176252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504015PMC
August 2020

Impact of Endocannabinoid System Manipulation on Neurodevelopmental Processes Relevant to Schizophrenia.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 06 1;6(6):616-626. Epub 2020 Jul 1.

Department of Biotechnology and Life Sciences and Neuroscience Center, University of Insubria, Busto Arsizio, Varese, Italy. Electronic address:

The neurodevelopmental hypothesis of schizophrenia has received much support from epidemiological and neuropathological studies and provides a framework to explain how early developmental abnormalities might manifest as psychosis in early adulthood. According to this theory, the onset of schizophrenia is likely the result of a complex interplay between a genetic predisposition and environmental factors whose respective influence might contribute to the etiology and progression of the disorder. The two most sensitive windows for neurodevelopment are the prenatal/perinatal and the adolescent windows, both of which are characterized by specific processes impinging upon brain structure and functionality, whose alterations may contribute to the onset of schizophrenia. An increasing number of articles suggest the involvement of the endocannabinoid system in the modulation of at least some of these processes, especially in the prenatal/perinatal window. Thus, it is not surprising that disturbing the physiological role of endocannabinoid signaling in these sensitive windows might alter the correct formation of neuronal networks, eventually predisposing to neuropsychiatric diseases later in life. We review the most recent preclinical studies that evaluated the impact of endocannabinoid system modulation in the two sensitive developmental windows on neurodevelopmental processes that possess a specific relevance to schizophrenia.
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http://dx.doi.org/10.1016/j.bpsc.2020.06.013DOI Listing
June 2021

Termination of acute stress response by the endocannabinoid system is regulated through lysine-specific demethylase 1-mediated transcriptional repression of 2-AG hydrolases ABHD6 and MAGL.

J Neurochem 2020 10 30;155(1):98-110. Epub 2020 Mar 30.

Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Segrate, MI, Italy.

Acute environmental stress rarely implies long-lasting neurophysiological and behavioral alterations. On the contrary, chronic stress exerts a potent toxic effect at the glutamatergic synapse whose altered physiology has been recognized as a core trait of neuropsychiatric disorders. The endocannabinoid system (ECS) plays an important role in the homeostatic response to acute stress. In particular, stress induces synthesis of endocannabinoid (eCB) 2-arachidonyl glycerol (2-AG). 2-AG stimulates presynaptic cannabinoid 1 (CB1) receptor contributing to stress response termination through inhibition of glutamate release, restraining thereafter anxiety arousal. We employ mouse models of stress response coupled to gene expression analyses, unravelling that in response to acute psychosocial stress in the mouse hippocampus, ECS-mediated synaptic modulation is enhanced via transcriptional repression of two enzymes involved in 2-AG degradation: α/β-hydrolase domain containing 6 (ABHD6) and monoacylglycerol lipase (MAGL). Such a process is orchestrated by the epigenetic corepressor LSD1 who directly interacts with promoter regulatory regions of Abhd6 and Magl. Remarkably, negative transcriptional control of Abhd6 and Magl is lost in the hippocampus upon chronic psychosocial stress, possibly contributing to trauma-induced drift of synapse physiology toward uncontrolled glutamate transmission. We previously showed that in mice lysine-specific demethylase 1 (LSD1) increases its hippocampal expression in response to psychosocial stress preventing excessive consolidation of anxiety-related plasticity. In this work, we unravel a nodal epigenetic modulation of eCB turn over, shedding new light on the molecular substrate of converging stress-terminating effects displayed by ECS and LSD1.
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http://dx.doi.org/10.1111/jnc.15000DOI Listing
October 2020

Neurobiological mechanisms underlying cannabis-induced memory impairment.

Eur Neuropsychopharmacol 2020 07 2;36:181-190. Epub 2020 Mar 2.

Department of Biotechnology and Life Sciences, and Neuroscience Center, University of Insubria, Busto Arsizio VA, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.euroneuro.2020.02.002DOI Listing
July 2020

Adolescent drug exposure: A review of evidence for the development of persistent changes in brain function.

Brain Res Bull 2020 03 8;156:105-117. Epub 2020 Jan 8.

Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. Electronic address:

Over the past decade, many studies have indicated that adolescence is a critical period of brain development and maturation. The refinement and maturation of the central nervous system over this prolonged period, however, makes the adolescent brain highly susceptible to perturbations from acute and chronic drug exposure. Here we review the preclinical literature addressing the long-term consequences of adolescent exposure to common recreational drugs and drugs-of-abuse. These studies on adolescent exposure to alcohol, nicotine, opioids, cannabinoids and psychostimulant drugs, such as cocaine and amphetamine, reveal a variety of long-lasting behavioral and neurobiological consequences. These agents can affect development of the prefrontal cortex and mesolimbic dopamine pathways and modify the reward systems, socio-emotional processing and cognition. Other consequences include disruption in working memory, anxiety disorders and an increased risk of subsequent drug abuse in adult life. Although preventive and control policies are a valuable approach to reduce the detrimental effects of drugs-of-abuse on the adolescent brain, a more profound understanding of their neurobiological impact can lead to improved strategies for the treatment and attenuation of the detrimental neuropsychiatric sequelae.
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http://dx.doi.org/10.1016/j.brainresbull.2020.01.007DOI Listing
March 2020

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

Front Cell Neurosci 2019 9;13:367. Epub 2019 Aug 9.

Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy.

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.
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http://dx.doi.org/10.3389/fncel.2019.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696797PMC
August 2019

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

J Psychopharmacol 2019 07 14;33(7):894-907. Epub 2019 May 14.

1 Department of Biotechnology and Life Sciences (DBSV), University of Insubria, Varese, Italy.

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 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 -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 -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 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 mutant mice at an advanced stage of the disease. 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 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.
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http://dx.doi.org/10.1177/0269881119844184DOI Listing
July 2019

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

Int J Neuropsychopharmacol 2018 11;21(11):1014-1024

Department of Biotechnology and Life Sciences, and Neuroscience Center, University of Insubria, Busto Arsizio VA, Italy.

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.
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http://dx.doi.org/10.1093/ijnp/pyy057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209859PMC
November 2018

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

J Psychiatry Neurosci 2018 03 12;43(2):87-101. Epub 2017 Oct 12.

From the Department of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio VA, Italy (Prini, Zamberletti, Gabaglio, Penna, Parolaro, Rubino); the Neuroscience Center, University of Insubria, Busto Arsizio VA, Italy (Prini, Zamberletti, Gabaglio, Fasano, Parolaro, Rubino); the Department of Medical Biotecnology and Translational Medicine, University of Milan, Milano, Segrate MI, Italy (Rusconi, Battaglioli); and the Department of Science and High Technology, University of Insubria, Busto Arsizio VA, Italy (Fasano).

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837889PMC
March 2018

Chronic Δ⁸-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain.

Int J Mol Sci 2017 Oct 4;18(10). Epub 2017 Oct 4.

Department of Biotechnology and Life Sciences, University of Insubria, 21052 Busto Arsizio, VA, Italy.

Adolescence represents a vulnerable period for the psychiatric consequences of delta9-tetrahydrocannabinol (Δ⁸-THC) exposure, however, the molecular underpinnings of this vulnerability remain to be established. Histone modifications are emerging as important epigenetic mechanisms involved in the etiopathogenesis of psychiatric diseases, thus, we investigated the impact of chronic Δ⁸-THC exposure on histone modifications in different brain areas of female rats. We checked histone modifications associated to both transcriptional repression (H3K9 di- and tri-methylation, H3K27 tri-methylation) and activation (H3K9 and H3K14 acetylation) after adolescent and adult chronic Δ⁸-THC exposure in the hippocampus, nucleus accumbens, and amygdala. Chronic exposure to increasing doses of Δ⁸-THC for 11 days affected histone modifications in a region- and age-specific manner. The primary effect in the adolescent brain was represented by changes leading to transcriptional repression, whereas the one observed after adult treatment led to transcriptional activation. Moreover, only in the adolescent brain, the primary effect was followed by a homeostatic response to counterbalance the Δ⁸-THC-induced repressive effect, except in the amygdala. The presence of a more complex response in the adolescent brain may be part of the mechanisms that make the adolescent brain vulnerable to Δ⁸-THC adverse effects.
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http://dx.doi.org/10.3390/ijms18102094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666776PMC
October 2017

New vistas on cannabis use disorder.

Neuropharmacology 2017 Sep 31;124:62-72. Epub 2017 Mar 31.

Dept. of Biotechnology and Life Sciences, University of Insubria, Busto Arsizio (VA), Italy; Zardi Gori Foundation, Milan, Italy. Electronic address:

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".
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http://dx.doi.org/10.1016/j.neuropharm.2017.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865400PMC
September 2017

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

J Lipid Res 2017 02 30;58(2):301-316. Epub 2016 Nov 30.

Department of Biotechnology and Life Sciences (DBSV), University of Insubria, Busto Arsizio (VA), Italy

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.
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http://dx.doi.org/10.1194/jlr.M068387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282947PMC
February 2017

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

Pharmacol Res 2017 01 24;115:209-217. Epub 2016 Nov 24.

Centre of Excellence "Neurobiology of Dependence", University of Cagliari, Cittadella Universitaria di Monserrato, SS 554 Km 4,500, 09042 Monserrato, CA, Italy; CNR Institute of Neuroscience-Cagliari, National Research Council, Italy. Electronic address:

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 CB 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 CB 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 CB 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.
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http://dx.doi.org/10.1016/j.phrs.2016.11.031DOI Listing
January 2017

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

Pharmacol Res 2016 09 12;111:459-470. Epub 2016 Jul 12.

Dept. of Biotechnology and Life Sciences (DBSV), University of Insubria, Busto Arsizio, VA, Italy; Zardi Gori Foundation, Milan, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.phrs.2016.07.008DOI Listing
September 2016

Assay of GTPγS Binding in Autoradiography.

Methods Mol Biol 2016 ;1412:95-101

Department of Biotechnology and Life Sciences, University of Insubria, Via Manara 7, 21052, Busto Arsizio (VA), Italy.

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.
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http://dx.doi.org/10.1007/978-1-4939-3539-0_10DOI Listing
December 2017

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

Eur Neuropsychopharmacol 2015 Dec 21;25(12):2404-15. Epub 2015 Oct 21.

Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio (VA), Italy; Zardi Gori Foundation, Milan, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.euroneuro.2015.09.021DOI Listing
December 2015

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

Eur Neuropsychopharmacol 2015 Dec 21;25(12):2404-15. Epub 2015 Oct 21.

Department of Theoretical and Applied Sciences, University of Insubria, Busto Arsizio (VA), Italy; Zardi Gori Foundation, Milan, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.euroneuro.2015.09.021DOI Listing
December 2015

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

Biol Psychiatry 2016 Apr 7;79(7):578-85. Epub 2015 Aug 7.

Department of Theoretical and Applied Sciences, Biomedical Research Division, and Neuroscience Center, University of Insubria, Busto Arsizi, Italy.

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.
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http://dx.doi.org/10.1016/j.biopsych.2015.07.024DOI Listing
April 2016

Sex-dependent vulnerability to cannabis abuse in adolescence.

Front Psychiatry 2015 20;6:56. Epub 2015 Apr 20.

Department of Theoretical and Applied Sciences, and Neuroscience Center, University of Insubria , Busto Arsizio , Italy.

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.
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http://dx.doi.org/10.3389/fpsyt.2015.00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403248PMC
May 2015

Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex.

Neurobiol Dis 2015 Jan 2;73:60-9. Epub 2014 Oct 2.

Department of Theoretical and Applied Science, Biomedical Research Division, and Neuroscience Center, University of Insubria, 21052 Busto Arsizio, VA, Italy; Zardi Gori Foundation, 21100 Milan, Italy.

Current concepts suggest that exposure to THC during adolescence may act as a risk factor for the development of psychiatric disorders later in life. However, the molecular underpinnings of this vulnerability are still poorly understood. To analyze this, we investigated whether and how THC exposure in female rats interferes with different maturational events occurring in the prefrontal cortex during adolescence through biochemical, pharmacological and electrophysiological means. We found that the endocannabinoid system undergoes maturational processes during adolescence and that THC exposure disrupts them, leading to impairment of both endocannabinoid signaling and endocannabinoid-mediated LTD in the adult prefrontal cortex. THC also altered the maturational fluctuations of NMDA subunits, leading to larger amounts of gluN2B at adulthood. Adult animals exposed to THC during adolescence also showed increased AMPA gluA1 with no changes in gluA2 subunits. Finally, adolescent THC exposure altered cognition at adulthood. All these effects seem to be triggered by the disruption of the physiological role played by the endocannabinoid system during adolescence. Indeed, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses. These results suggest that vulnerability of adolescent female rats to long-lasting THC adverse effects might partly reside in disruption of the pivotal role played by the endocannabinoid system in the prefrontal cortex maturation.
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http://dx.doi.org/10.1016/j.nbd.2014.09.015DOI Listing
January 2015

Chronic nandrolone decanoate exposure during adolescence affects emotional behavior and monoaminergic neurotransmission in adulthood.

Neuropharmacology 2014 Aug 8;83:79-88. Epub 2014 Apr 8.

Department of Theoretical and Applied Sciences, Biomedical Research Division, Neuroscience Center, University of Insubria, Busto Arsizio, VA, Italy. Electronic address:

Nandrolone decanoate, an anabolic androgen steroid (AAS) illicitly used by adult and adolescent athletes to enhance physical performance and body image, induces psychiatric side effects, such as aggression, depression as well as a spectrum of adverse physiological impairments. Since adolescence represents a neurodevelopmental window that is extremely sensitive to the detrimental effects of drug abuse, we investigated the long-term behavioral and neurophysiological consequences of nandrolone abuse during adolescence. Adolescent rats received daily injections of nandrolone decanoate (15 mg/kg, i.m.) for 14 days (PND 40-53). At early adulthood (PND 68), forced swim, sucrose preference, open field and elevated plus maze tests were performed to assess behavioral changes. In vivo electrophysiological recordings were carried out to monitor changes in electrical activity of serotonergic neurons of the dorsal raphe nucleus (DRN) and noradrenergic neurons of the locus coeruleus (LC). Our results show that after early exposure to nandrolone, rats display depression-related behavior, characterized by increased immobility in the forced swim test and reduced sucrose intake in the sucrose preference test. In addition, adult rats presented anxiety-like behavior characterized by decreased time and number of entries in the central zone of the open field and decreased time spent in the open arms of the elevated plus maze. Nandrolone decreased the firing rate of spontaneously active serotonergic neurons in the DRN while increasing the firing rate of noradrenergic neurons in the LC. These results provide evidence that nandrolone decanoate exposure during adolescence alters the emotional profile of animals in adulthood and significantly modifies both serotonergic and noradrenergic neurotransmission.
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http://dx.doi.org/10.1016/j.neuropharm.2014.03.015DOI Listing
August 2014

Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect.

PLoS One 2013 21;8(10):e76918. Epub 2013 Oct 21.

Department of Theoretical and Applied Sciences, Biomedical Research Division, Centre of Neuroscience, University of Insubria, Busto Arsizio, Varese, Italy.

In the present study, we found that CBD inhibited U87-MG and T98G cell proliferation and invasiveness in vitro and caused a decrease in the expression of a set of proteins specifically involved in growth, invasion and angiogenesis. In addition, CBD treatment caused a dose-related down-regulation of ERK and Akt prosurvival signaling pathways in U87-MG and T98G cells and decreased hypoxia inducible factor HIF-1α expression in U87-MG cells. Taken together, these results provide new insights into the antitumor action of CBD, showing that this cannabinoid affects multiple tumoral features and molecular pathways. As CBD is a non-psychoactive phytocannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anti-cancer drug in the management of gliomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076918PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804588PMC
August 2014

Alterations of prefrontal cortex GABAergic transmission in the complex psychotic-like phenotype induced by adolescent delta-9-tetrahydrocannabinol exposure in rats.

Neurobiol Dis 2014 Mar 4;63:35-47. Epub 2013 Nov 4.

Dept. of Theoretical and Applied Sciences, Biomedical Division and Center of Neuroscience, Univ. of Insubria, Busto Arsizio (VA), Italy; Zardi-Gori Foundation, Milan, Italy. Electronic address:

Although several findings indicate an association between adolescent cannabis abuse and the risk to develop schizophrenia later in life, the evidence for a causal relationship is still inconclusive. In the present study, we investigated the emergence of psychotic-like behavior in adult female rats chronically exposed to delta-9-tetrahydrocannabinol (THC) during adolescence. To this aim, female Sprague-Dawley rats were treated with THC during adolescence (PND 35-45) and, in adulthood (PND 75), a series of behavioral tests and biochemical assays were performed in order to investigate the long-term effects of adolescent THC exposure. Adolescent THC pretreatment leads to long-term behavioral alterations, characterized by recognition memory deficits, social withdrawal, altered emotional reactivity and sensitization to the locomotor activating effects of acute PCP. Moreover, since cortical disinhibition seems to be a key feature of many different animal models of schizophrenia and GABAergic hypofunction in the prefrontal cortex (PFC) has been observed in postmortem brains from schizophrenic patients, we then investigated the long-lasting consequences of adolescent THC exposure on GABAergic transmission in the adult rat PFC. Biochemical analyses revealed that adolescent THC exposure results in reduced GAD67 and basal GABA levels within the adult PFC. GAD67 expression is reduced both in parvalbumin (PV)- and cholecystokinin (CCK)-containing interneurons; this alteration may be related to the altered emotional reactivity triggered by adolescent THC, as silencing PFC GAD67 expression through a siRNA-mediated approach is sufficient to impact rats' behavior in the forced swim test. Finally, the cellular underpinnings of the observed sensitized response to acute PCP in adult THC-treated rats could be ascribed to the increased cFos immunoreactivity and glutamate levels in the PFC and dorsal striatum. The present findings support the hypothesis that adolescent THC exposure may represent a risk factor for the development of a complex psychotic-like behavior in adulthood.
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http://dx.doi.org/10.1016/j.nbd.2013.10.028DOI Listing
March 2014

Sex-dependent changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of maternal deprivation and adolescent cocaine exposure.

Pharmacol Res 2013 Aug 14;74:23-33. Epub 2013 May 14.

Departamento de Fisiología (Fisiología Animal II), Facultad de Ciencias Biológicas, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.

Early life stress has been associated with several psychiatric disorders, including drug addiction. Actually, maternal deprivation (MD) alters the endocannabinoid system, which participates in motivation and reward for drugs, including cocaine. At youth, the rate of cocaine abuse is alarmingly increasing. Herein, we have investigated the consequences of MD and/or adolescent cocaine exposure in brain CB1Rs and CB2Rs in immune tissues. Control and maternally deprived (24h on postnatal day, pnd, 9) male and female Wistar rats were administered cocaine (8mg/kg/day) or saline during adolescence (pnd 28-42). At adulthood, [(3)H]-CP-55,940 autoradiographic binding was employed for the analysis of CB1R density and CP-55,940-stimulated [(35)S]-GTPgammaS binding for CB1R functionality; CB2R expression was analyzed by Western blotting. Sex differences in CB1R expression and functionality were found, and MD induced important and enduring sex-dependent changes. In addition, the plastic changes induced by adolescent cocaine administration in brain CB1Rs were differentially influenced by early life events. MD increased spleen CB2R expression while adolescent cocaine administration attenuated this effect; cocaine exposure also diminished CB2R expression in bone marrow. Present findings provide evidence for changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of early life stress and adolescent cocaine exposure, and indicate functional interactions between both treatments, which in many regions differ between males and females.
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http://dx.doi.org/10.1016/j.phrs.2013.05.001DOI Listing
August 2013

The endocannabinoid system and schizophrenia: integration of evidence.

Curr Pharm Des 2012 ;18(32):4980-90

Department of Theoretical and Applied Sciences, Biomedical Division, and Neuroscience Center, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy.

Cannabis derivatives produce their CNS effect through activation of the endocannabinoid system, a recently discovered signalling system comprising specific receptors, their intrinsic lipid ligands and the associated enzymatic machinery (transporters, biosynthetic and degradative enzymes). This review provides the latest preclinical and clinical breakthroughs on the endocannabinoid system's role in psychotic disorders such as schizophrenia. Data reported so far clearly indicate the presence of a dysregulation in the endocannabinoid system (both in term of cannabinoid receptors and endocannabinoid ligands) in animal models of psychosis as well as in schizophrenic patients. Based on these observations, the pharmacological modulation of the endocannabinoid system has been taken into account as a new therapeutic possibility for psychotic disorders. However, preclinical studies have not provided straightforward results, with both agonists and antagonists exhibiting positive, negative or even no effect. At human level, only cannabidiol, a non psychotropic phytocannabinoid, and the antagonist/inverse agonist rimonabant were tested, however additional controlled trials are required to confirm the therapeutic exploitation of these compounds. Another important aspect in studying the relationship between the endocannabinoid system and schizophrenia is the impact of Cannabis consumption on psychotic disorders, especially when this occurs at vulnerable ages such as adolescence. In fact literature from animal models support adolescence as a highly vulnerable age for the consequences of cannabis exposure on different domains (such as cognition and social behaviour) that are altered in psychotic disorders.
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http://dx.doi.org/10.2174/138161212802884744DOI Listing
March 2013

SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance.

Nat Neurosci 2012 Jan 8;15(2):284-93. Epub 2012 Jan 8.

Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.

Endocannabinoids (eCBs) regulate neuronal activity in the dorso-lateral striatum (DLS), a brain region that is involved in habitual behaviors. How synaptic eCB signaling contributes to habitual behaviors under physiological and pathological conditions remains unclear. Using a mouse model of cannabinoid tolerance, we found that persistent activation of the eCB pathway impaired eCB-mediated long-term depression (LTD) and synaptic depotentiation in the DLS. The loss of eCB LTD, occurring preferentially at cortical connections to striatopallidal neurons, was associated with a shift in behavioral control from goal-directed action to habitual responding. eCB LTD and behavioral alterations were rescued by in vivo modulation of small-conductance calcium activated potassium channel (SK channel) activity in the DLS, which potentiates eCB signaling. Our results reveal a direct relationship between drug tolerance and changes in control of instrumental performance by establishing a central role for eCB LTD in habit expression. In addition, SK channels emerge as molecular targets to fine tune the eCB pathway under pathological conditions.
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http://dx.doi.org/10.1038/nn.3022DOI Listing
January 2012

Sexually dimorphic effects of cannabinoid compounds on emotion and cognition.

Front Behav Neurosci 2011 28;5:64. Epub 2011 Sep 28.

Department of Structural and Functional Biology and Neuroscience Center, University of Insubria Busto Arsizio, Italy.

This review addresses the issue of sex differences in the response to cannabinoid compounds focusing mainly on behaviors belonging to the cognitive and emotional sphere. Sexual dimorphism exists in the different components of the endocannabinoid system. Males seem to have higher CB1 receptor binding sites than females, but females seem to possess more efficient CB1 receptors. Differences between sexes have been also observed in the metabolic processing of THC, the main psychoactive ingredient of marijuana. The consistent dimorphism in the endocannabinoid system and THC metabolism may justify at least in part the different sensitivity observed between male and female animals in different behavioral paradigms concerning emotion and cognition after treatment with cannabinoid compounds. On the basis of these observations, we would like to emphasize the need of including females in basic research and to analyze results for sex differences in epidemiological studies.
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http://dx.doi.org/10.3389/fnbeh.2011.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181427PMC
November 2011

Adolescent exposure to cannabis as a risk factor for psychiatric disorders.

J Psychopharmacol 2012 Jan 18;26(1):177-88. Epub 2011 Jul 18.

DBSF and Neuroscience Center, University of Insubria, Busto Arsizio, Italy.

Adolescence represents a critical period for brain development and the endocannabinoid system plays a crucial role in the regulation of neuronal refinement during this period. Cannabis is the most consumed drug among adolescent people and its heavy use may affect maturational refinement by disrupting the regulatory role of the endocannabinoid system. In animals, adolescent cannabinoid exposure has been reported to cause long-term impairment in specific components of learning and memory and to differentially affect emotional reactivity with milder effects on anxiety behaviour and more pronounced effects on depression-like behaviour. Moreover, adolescent exposure to cannabinoids might represent a risk factor for developing psychotic-like symptoms at adulthood. Also epidemiological studies suggest that heavy adolescent cannabis use may increase the risk of cognitive abnormalities, psychotic illness, mood disorders and other illicit substance use later in life. In conclusion, the available data point to the hypothesis that heavy cannabis use in adolescence could increase the risk of developing psychiatric disorders, especially in people who already have a vulnerability to develop a psychiatric syndrome. Only few papers have investigated the neurobiological substrates of this vulnerability, thus further studies are needed to clarify the molecular mechanisms underlying the effect of cannabis on the adolescent brain.
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http://dx.doi.org/10.1177/0269881111405362DOI Listing
January 2012
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