Publications by authors named "Erica Zamberletti"

24 Publications

  • Page 1 of 1

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

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

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

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

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

Int J Mol Sci 2017 Sep 7;18(9). Epub 2017 Sep 7.

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

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.
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http://dx.doi.org/10.3390/ijms18091916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618565PMC
September 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 phytocannabinoid, Δ⁹-tetrahydrocannabivarin, can act through 5-HT₁A receptors to produce antipsychotic effects.

Br J Pharmacol 2015 Mar;172(5):1305-18

School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.

Background And Purpose: This study aimed to address the questions of whether Δ(9)-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1 A receptors in vitro and (ii) induce any apparent 5-HT₁A receptor-mediated antipsychotic effects in vivo.

Experimental Approach: In vitro studies investigated the effect of THCV on targeting by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) of 5-HT₁A receptors in membranes obtained from rat brainstem or human 5-HT₁A CHO cells, using [(35)S]-GTPγS and 8-[(3)H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT₁A receptor-mediated antipsychotic effects in rats.

Key Results: THCV (i) potently, albeit partially, displaced 8-[(3) H]-OH-DPAT from specific binding sites in rat brainstem membranes; (ii) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of receptors in these membranes; (iii) produced concentration-related increases in 8-[(3)H]-OH-DPAT binding to specific sites in membranes of human 5-HT₁A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT₁A receptors. In phencyclidine-treated rats, THCV, like clozapine (i) reduced stereotyped behaviour; (ii) decreased time spent immobile in the forced swim test; and (iii) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5-HT₁A receptor antagonist, WAY100635, or could be reproduced by the CB₁ antagonist, AM251.

Conclusions And Implications: Our findings suggest that THCV can enhance 5-HT₁A receptor activation, and that some of its apparent antipsychotic effects may depend on this enhancement. We conclude that THCV has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia.
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http://dx.doi.org/10.1111/bph.13000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337703PMC
March 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

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

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

Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251.

Int J Neuropsychopharmacol 2012 Mar 6;15(2):267-80. Epub 2010 Oct 6.

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

In this work we investigated the ability of AM251 to reverse schizophrenia-like symptoms produced by a neurodevelopmental animal model based on a social isolation procedure. First, we assessed the validity of our isolation-rearing protocol and, as expected, isolation-reared rats showed hyperlocomotion in a novel environment, cognitive impairment in the novel object recognition (NOR) test and a significant increase in the number of aggressive behaviours in the social interaction test compared to group-housed controls. This behavioural picture was associated with a reduction in CB₁ receptor/G protein coupling in specific brain areas as well as reduced c-Fos immunoreactivity in the prefrontal cortex and caudate putamen. In this model, chronic but not acute treatment with the CB₁ receptor antagonist AM251 counteracted isolation-induced cognitive impairment in the NOR test and aggressive behaviours in the social interaction test. This behavioural recovery was accompanied by the rescue of CB₁ receptor functionality and c-Fos levels in all brain regions altered in isolation-reared rats. Moreover, chronic AM251 also increased c-Fos immunoreactivity in the nucleus accumbens, as previously demonstrated for antipsychotic drugs. Interestingly, the behavioural recovery due to chronic AM251 administration persisted until 10 d after discontinuing the treatment, indicating a long-lasting effect of the cannabinoid antagonist on psychotic-like symptoms.
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http://dx.doi.org/10.1017/S1461145710001185DOI Listing
March 2012

Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine.

Int J Neuropsychopharmacol 2011 Feb 3;14(1):17-28. Epub 2010 Mar 3.

DBSF and Neuroscience Center, University of Insubria, Varese, Italy.

Clinical and laboratory studies suggest that the endocannabinoid system is involved in schizophrenia disorders. Recent evidence indicates that cannabinoid receptor (CB1) antagonists have a pharmacological profile similar to antipsychotic drugs. We investigated the behavioural and biochemical effects of the CB1 antagonist AM251 in a phencyclidine (PCP) animal paradigm modelling the cognitive deficit and some negative symptoms of schizophrenia. Chronic AM251 (0.5 mg/kg for 3 wk) improved the PCP-altered recognition memory, as indicated by a significant amelioration of the discrimination index compared to chronic PCP alone (2.58 mg/kg for 1 month). AM251 also reversed the PCP-induced increase in immobility in the forced swim test resembling avolition, a negative sign of schizophrenia. In order to analyse the mechanisms underlying these behaviours, we studied the effects of AM251 on the endocannabinoid system (in terms of CB1 receptor density and functional activity and endocannabinoid levels) and c-Fos protein expression. The antagonist counteracted the alterations in CB1 receptor function induced by PCP in selected cerebral regions involved in schizophrenia. In addition, in the prefrontal cortex, the key region in the integration of cognitive and negative functions, AM251 markedly raised anandamide levels and reversed the PCP-induced increase of 2-arachidonoylglycerol concentrations. Finally, chronic AM251 fully reversed the PCP-elicited expression of c-Fos protein in the prefrontal cortical region. These findings suggest an antipsychotic-like profile of the CB1 cannabinoid receptor antagonist which, by restoring the function of the endocannabinoid system, might directly or indirectly normalize some of the neurochemical maladaptations present in this schizophrenia-like animal model.
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http://dx.doi.org/10.1017/S1461145710000209DOI Listing
February 2011
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