The dual face of the endocannabinoid system in schizofrenia: experimental evidence.

Investigating the association between Cannabis, the endogenous cannabinoid system and schizophrenia must take into account two aspects of major relevance. On the one hand, Cannabis is the most widely used illegal drug and there is substantial evidence that its consumption has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. On the other hand, there are several lines of evidence that clearly indicate the presence of a dysregulation in the endocannabinoid system in animal models of psychosis and at least in a subgroup of schizophrenic patients. Concerning the first point, our recent studies in female rats demonstrated that chronic THC treatment during adolescence induced a complex phenotype in adulthood characterized by the presence of anhedonia, behavioral despair in the forced swim test, reduced sociability as well as significant deficits in spatial working and object recognition memory. Moreover, adolescent THC administration also sensitizes to the locomotor activating effect induced by acute psychostimulant administration in adulthood. This response is consistent with the presence of a psychotic-like phenotype. Thus, the simultaneous presence of pronounced depressive-like behaviors, cognitive deficits as well as psychotic-like signs suggests that adolescent THC exposure had led to a behavioral phenotype in adulthood that reflects the presence of complex schizoaffective-like disorder. Interestingly, when the same protocol of THC exposure was performed in adult animals, no behavioral alterations were observed, thus highlighting the specific vulnerability of the adolescent brain to the long-lasting adverse effects of THC. The neurobiology of cannabis-induced schizophrenia is still unknown. However, we recently demonstrated that adolescent exposure to THC produces-long lasting alterations in the endocannabinoid system, that ultimately could result in imbalances of excitatory and inhibitory neurotransmission within specific brain regions. Accordingly, our data demonstrate that the schizoaffective-like disorder induced by adolescent THC exposure in female rats is strictly associated with alterations in the inhibitory neurotransmission which are particularly prominent within the prefrontal cortex, a brain region that has been found to be severely affected in schizophrenia. With regard to the second aspect, there are several lines of evidence that clearly indicate the presence of a dysregulation in the endocannabinoid system in different animal models of psychosis and based on these observations, the pharmacological modulation of the endocannabinoid system has been taken into account as a new therapeutic possibility for psychotic disorders. In line with this, we demonstrated that chronic treatment with the cannabinoid CB1 receptor antagonist, AM251, counteracts the psychotic-like phenotype in a neurodevelopmental model of schizophrenia in rats. This recovery at behavioral level was paralleled by the normalization of the endocannabinoid system functionality both in terms of endocannabinoid levels and CB1 receptor/G protein coupling in all the brain areas analyzed, possibly suggesting that the ability of AM251 to restore normal endocannabinoid system may account for its antipsychotic action. As a whole, data reported in this thesis, strongly suggest an association between an altered endocannabinoid tone and the development of psychotic symptoms, thus supporting the exploitation of compounds acting on the endocannabinoid system as new therapeutic agents in the treatment of schizophrenia and related disorders

The dual face of the endocannabinoid system in schizofrenia: experimental evidence.

Investigating the association between Cannabis, the endogenous cannabinoid system and schizophrenia must take into account two aspects of major relevance. On the one hand, Cannabis is the most widely used illegal drug and there is substantial evidence that its consumption has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. On the other hand, there are several lines of evidence that clearly indicate the presence of a dysregulation in the endocannabinoid system in animal models of psychosis and at least in a subgroup of schizophrenic patients. Concerning the first point, our recent studies in female rats demonstrated that chronic THC treatment during adolescence induced a complex phenotype in adulthood characterized by the presence of anhedonia, behavioral despair in the forced swim test, reduced sociability as well as significant deficits in spatial working and object recognition memory. Moreover, adolescent THC administration also sensitizes to the locomotor activating effect induced by acute psychostimulant administration in adulthood. This response is consistent with the presence of a psychotic-like phenotype. Thus, the simultaneous presence of pronounced depressive-like behaviors, cognitive deficits as well as psychotic-like signs suggests that adolescent THC exposure had led to a behavioral phenotype in adulthood that reflects the presence of complex schizoaffective-like disorder. Interestingly, when the same protocol of THC exposure was performed in adult animals, no behavioral alterations were observed, thus highlighting the specific vulnerability of the adolescent brain to the long-lasting adverse effects of THC. The neurobiology of cannabis-induced schizophrenia is still unknown. However, we recently demonstrated that adolescent exposure to THC produces-long lasting alterations in the endocannabinoid system, that ultimately could result in imbalances of excitatory and inhibitory neurotransmission within specific brain regions. Accordingly, our data demonstrate that the schizoaffective-like disorder induced by adolescent THC exposure in female rats is strictly associated with alterations in the inhibitory neurotransmission which are particularly prominent within the prefrontal cortex, a brain region that has been found to be severely affected in schizophrenia. With regard to the second aspect, there are several lines of evidence that clearly indicate the presence of a dysregulation in the endocannabinoid system in different animal models of psychosis and based on these observations, the pharmacological modulation of the endocannabinoid system has been taken into account as a new therapeutic possibility for psychotic disorders. In line with this, we demonstrated that chronic treatment with the cannabinoid CB1 receptor antagonist, AM251, counteracts the psychotic-like phenotype in a neurodevelopmental model of schizophrenia in rats. This recovery at behavioral level was paralleled by the normalization of the endocannabinoid system functionality both in terms of endocannabinoid levels and CB1 receptor/G protein coupling in all the brain areas analyzed, possibly suggesting that the ability of AM251 to restore normal endocannabinoid system may account for its antipsychotic action. As a whole, data reported in this thesis, strongly suggest an association between an altered endocannabinoid tone and the development of psychotic symptoms, thus supporting the exploitation of compounds acting on the endocannabinoid system as new therapeutic agents in the treatment of schizophrenia and related disorders

The dual face of the endocannabinoid system in schizofrenia: experimental evidence.

Investigating the association between Cannabis, the endogenous cannabinoid system and schizophrenia must take into account two aspects of major relevance. On the one hand, Cannabis is the most widely used illegal drug and there is substantial evidence that its consumption has to be classified as an independent risk factor for psychosis that may lead to a worse outcome of the disease. On the other hand, there are several lines of evidence that clearly indicate the presence of a dysregulation in the endocannabinoid system in animal models of psychosis and at least in a subgroup of schizophrenic patients. Concerning the first point, our recent studies in female rats demonstrated that chronic THC treatment during adolescence induced a complex phenotype in adulthood characterized by the presence of anhedonia, behavioral despair in the forced swim test, reduced sociability as well as significant deficits in spatial working and object recognition memory. Moreover, adolescent THC administration also sensitizes to the locomotor activating effect induced by acute psychostimulant administration in adulthood. This response is consistent with the presence of a psychotic-like phenotype. Thus, the simultaneous presence of pronounced depressive-like behaviors, cognitive deficits as well as psychotic-like signs suggests that adolescent THC exposure had led to a behavioral phenotype in adulthood that reflects the presence of complex schizoaffective-like disorder. Interestingly, when the same protocol of THC exposure was performed in adult animals, no behavioral alterations were observed, thus highlighting the specific vulnerability of the adolescent brain to the long-lasting adverse effects of THC. The neurobiology of cannabis-induced schizophrenia is still unknown. However, we recently demonstrated that adolescent exposure to THC produces-long lasting alterations in the endocannabinoid system, that ultimately could result in imbalances of excitatory and inhibitory neurotransmission within specific brain regions. Accordingly, our data demonstrate that the schizoaffective-like disorder induced by adolescent THC exposure in female rats is strictly associated with alterations in the inhibitory neurotransmission which are particularly prominent within the prefrontal cortex, a brain region that has been found to be severely affected in schizophrenia. With regard to the second aspect, there are several lines of evidence that clearly indicate the presence of a dysregulation in the endocannabinoid system in different animal models of psychosis and based on these observations, the pharmacological modulation of the endocannabinoid system has been taken into account as a new therapeutic possibility for psychotic disorders. In line with this, we demonstrated that chronic treatment with the cannabinoid CB1 receptor antagonist, AM251, counteracts the psychotic-like phenotype in a neurodevelopmental model of schizophrenia in rats. This recovery at behavioral level was paralleled by the normalization of the endocannabinoid system functionality both in terms of endocannabinoid levels and CB1 receptor/G protein coupling in all the brain areas analyzed, possibly suggesting that the ability of AM251 to restore normal endocannabinoid system may account for its antipsychotic action. As a whole, data reported in this thesis, strongly suggest an association between an altered endocannabinoid tone and the development of psychotic symptoms, thus supporting the exploitation of compounds acting on the endocannabinoid system as new therapeutic agents in the treatment of schizophrenia and related disorders

The phytocannabinoid, Δ(9) -tetrahydrocannabivarin, can act through 5-HT1 A receptors to produce antipsychotic effects

Funded by: •GW Pharmaceuticals Acknowledgements: The authors wish to thank Mrs Lesley Stevenson for technical support and Dr John Raymond, Dr Keith Parker and Dr Ethan Russo for providing human 5-HT1A CHO cells. This research was supported by a grant from GW Pharmaceuticals to M. G. C. and R. G. P.Peer reviewedPostprin

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

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

Maternal immune activation impairs endocannabinoid signaling in the mesolimbic system of adolescent male offspring

Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers. We revealed that MIA offspring displayed an altered locomotor activity in response to THC, a higher bursting activity of VTA dopamine neurons and a lack of response to cumulative doses of THC. Consistently, MIA adolescence offspring showed an enhanced 2-arachidonoylglycerol-mediated synaptic plasticity and decreased monoacylglycerol lipase activity in mesolimbic structures. Moreover, they displayed a higher expression of cyclooxygenase 2 (COX-2) and ionized calcium-binding adaptor molecule 1 (IBA-1), associated with latent inflammation and persistent microglia activity. In conclusion, we unveiled neurobiological mechanisms whereby inflammation caused by MIA influences the proper development of endocannabinoid signaling that negatively impacts the dopamine system, eventually leading to psychotic-like symptoms in adulthood

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

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

Dos(e)Age: Role of Dose and Age in the Long-Term Effect of Cannabinoids on Cognition

Cannabis is still the most widely used illicit drug around the world. While its use has always been prevalent among adolescents, recent evidence suggests that its consumption is also increasing among other population groups, such as pregnant women and aged people. Given the known impact of cannabis on brain development and behavior, it is important to dissect the possible long-term impact of its use across different age groups, especially on measures of cognitive performance. Animal models of cannabinoid exposure have represented a fundamental tool to characterize the long-lasting consequences of cannabinoids on cognitive performance and helped to identify possible factors that could modulate cannabinoids effects in the long term, such as the age of exposure and doses administered. This scoping review was systematically conducted using PubMed and includes papers published from 2015 to December 2021 that examined the effects of cannabinoids, either natural or synthetic, on cognitive performance in animal models where exposure occurred in the prenatal period, during adolescence, or in older animals. Overall, available data clearly point to a crucial role of age in determining the long-term effect of cannabinoid on cognition, highlighting possible detrimental consequences during brain development (prenatal and adolescent exposure) and beneficial outcomes in old age. In contrast, despite the recent advances in the field, it appears difficult to clearly establish a possible role of dosage in the effects of cannabinoids on cognition, especially when the adolescent period is taken into account

The endocannabinoid system and autism spectrum disorders: Insights from animal models

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