Adolescent intermittent ethanol exposure decreases perineuronal nets in the hippocampus in a sex dependent manner: Modulation through pharmacological inhibition of RPTPß/ζ.

Adolescence is a critical period for brain maturation in which this organ undergoes critical plasticity mechanisms that increase its vulnerability to the effects of alcohol. Significantly, ethanol-induced disruption of hippocampal neurogenesis has been related to cognitive decline in adulthood. During adolescence, the maturation of perineuronal nets (PNNs), extracellular matrix structures highly affected by ethanol consumption, plays a fundamental role in neurogenesis and plasticity in the hippocampus. Receptor Protein Tyrosine Phosphatase (RPTP) ß/ζ is a critical anchor point for PNNs on the cell surface. Using the adolescent intermittent access to ethanol (IAE) model, we previously showed that MY10, a small-molecule inhibitor of RPTPß/ζ, reduces chronic ethanol consumption in adolescent male mice but not in females and prevents IAE-induced neurogenic loss in the male hippocampus. We have now tested if these effects of MY10 are related to sex-dependent modulatory actions on ethanol-induced effects in PNNs. Our findings suggest a complex interplay between alcohol exposure, neural structures, and sex-related differences in the modulation of PNNs and parvalbumin (PV)-positive cells in the hippocampus. In general, IAE increased the number of PV + cells in the female hippocampus and reduced PNNs intensity in different hippocampal regions, particularly in male mice. Notably, we found that pharmacological inhibition of RPTPß/ζ with MY10 regulates ethanol-induced alterations of PNNs intensity, which correlates with the protection of hippocampal neurogenesis from ethanol neurotoxic effects and may be related to the capacity of MY10 to increase the gene expression of key components of PNNs.

Molecular Changes Associated with Suicide.

Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual's vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic-pituitary-adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual's ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies.

Cognitive Alterations in Addictive Disorders: A Translational Approach.

The cognitive decline in people with substance use disorders is well known and can be found during both the dependence and drug abstinence phases. At the clinical level, cognitive decline impairs the response to addiction treatment and increases dropout rates. It can be irreversible, even after the end of drug abuse consumption. Improving our understanding of the molecular and cellular alterations associated with cognitive decline could be essential to developing specific therapeutic strategies for its treatment. Developing animal models to simulate drug abuse-induced learning and memory alterations is critical to continue exploring this clinical situation. The main aim of this review is to summarize the most recent evidence on cognitive impairment and the associated biological markers in patients addicted to some of the most consumed drugs of abuse and in animal models simulating this clinical situation. The available information suggests the need to develop more studies to further explore the molecular alterations associated with cognitive impairment, with the ultimate goal of developing new potential therapeutic strategies.

Methods to Identify Cognitive Alterations from Animals to Humans: A Translational Approach.

The increasing prevalence of cognitive dysfunction and dementia in developed countries, associated with population aging, has generated great interest in characterizing and quantifying cognitive deficits in these patients. An essential tool for accurate diagnosis is cognitive assessment, a lengthy process that depends on the cognitive domains analyzed. Cognitive tests, functional capacity scales, and advanced neuroimaging studies explore the different mental functions in clinical practice. On the other hand, animal models of human diseases with cognitive impairment are essential for understanding disease pathophysiology. The study of cognitive function using animal models encompasses multiple dimensions, and deciding which ones to investigate is necessary to select the most appropriate and specific tests. Therefore, this review studies the main cognitive tests for assessing cognitive deficits in patients with neurodegenerative diseases. Cognitive tests, the most commonly used functional capacity scales, and those resulting from previous evidence are considered. In addition, the leading behavioral tests that assess cognitive functions in animal models of disorders with cognitive impairment are highlighted.

Cannabidiol regulates behavioral and brain alterations induced by spontaneous alcohol withdrawal.

The main goal of this study was to evaluate if the administration of cannabidiol (CBD) regulates behavioral and gene expression alterations induced by spontaneous alcohol withdrawal (SAW) in mice. Increasing doses of ethanol were administered to C57BL/6J male mice for 15 days (2.5, 3 and 3.5 g/kg/12 h, p. o.), and SAW was studied at 6, 12, 24, and 72 h after the last ethanol administration. The efficacy of acute CBD (10, 20, and 40 mg/kg, i. p.) to regulate behavioral changes induced by SAW was explored at 6 h. Gene expression analyses of cannabinoid receptors 1 (Cnr1) and 2 (Cnr2), mu-opioid receptor (Opmr1), and proopiomelanocortin (Pomc) in the nucleus accumbens (NAcc), and Pomc and tyrosine hydroxylase (Th) in the ventral tegmental area (VTA), were carried out by real time-PCR. Pearson correlation was used to identify potential associations between the gene expression data and the anxiety-like behaviors. Biostatistical studies suggest associations between gene expression data and the anxiogenic behaviors in mice exposed to the SAW model and treated with VEH and 40 mg/kg of CBD. Mice exposed to the SAW model showed significant somatic withdrawal signs, anxiety-like behaviors, and remarkable changes in the gene expression of all brain targets at 6 h. CBD dose-dependently normalized the behavioral, somatic withdrawal signs and anxiety-like behaviors and modulated gene expression changes in the NAcc, but not in the VTA. The results of this study suggest that CBD may regulate specific alcohol withdrawal-associated alterations. However, further studies are required to explore the possible mechanisms involved.

Cannabidiol repairs behavioral and brain disturbances in a model of fetal alcohol spectrum disorder.

Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3 g/kg/12 h, p.o.) was administered to C57BL/6 J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30 mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.

Pharmacological strategies for post-traumatic stress disorder (PTSD): From animal to clinical studies.

Post-traumatic stress disorder (PTSD) is a disabling psychiatric condition with a critical familiar, personal, and social impact. Patients diagnosed with PTSD show various symptoms, including anxiety, depression, psychotic episodes, and sleep disturbances, complicating their therapeutic management. Only sertraline and paroxetine, two selective serotonin reuptake inhibitors, are approved by different international agencies to treat PTSD. In addition, these drugs are generally combined with psychotherapy to achieve positive results. However, these pharmacological strategies present limited efficacy. Nearly half of the PTSD patients do not experience remission of symptoms, possibly due to the high prevalence of psychiatric comorbidities. Therefore, in clinical practice, other off-label medications are common, even though the effectiveness of these drugs needs to be further investigated. In this line, antipsychotics, antiepileptics, adrenergic blockers, benzodiazepines, and other emerging pharmacological agents have aroused interest as potential therapeutic tools to improve some specific symptoms of PTSD. Thus, this review is focused on the most widely used drugs for the pharmacological treatment of PTSD with a translational approach, including clinical and preclinical studies, to emphasize the need to develop safer and more effective medications.

Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies.

Cumulative evidence has pointed out cannabinoid CB2 receptors (CB2r) as a potential therapeutic key target for treating alcohol use disorder (AUD). This review provides the most relevant results obtained from rodent and human studies, including an integrative section focused on the involvement of CB2r in the neurobiology of alcohol addiction. A literature search was conducted using the electronic databases Medline and Scopus for articles. The search strategy was as follows: "Receptor, Cannabinoid, CB2" AND "Alcohol-Related Disorders" AND "human/or patients"; "Receptor, Cannabinoid, CB2" AND "Alcohol" OR "Ethanol" AND "rodents/or mice/or rats". Pharmacological approaches demonstrated that the activation or blockade of CB2r modulated different alcohol-addictive behaviors. Rodent models of alcoholism revealed significant alterations of CB2r in brain areas of the reward system. In addition, mice lacking CB2r (CB2KO) show increased alcohol consumption, motivation, and relapse alterations. It has been stressed that the potential neurobiological mechanisms underlying their behavioral effects involve critical elements of the alcohol reward system. Interestingly, recent postmortem studies showed CNR2 alterations in brain areas of alcoholic patients. Moreover, although the number of studies is limited, the results revealed an association between some genetic alterations of the CNR2 and an increased risk for developing AUD. This review provides evidence that CB2r may play a role in alcohol addiction. Clinical studies are necessary to figure out whether CB2r ligands may prove useful for the treatment of AUD in humans.

Molecular Alterations of the Endocannabinoid System in Psychiatric Disorders.

The therapeutic benefits of the current medications for patients with psychiatric disorders contrast with a great variety of adverse effects. The endocannabinoid system (ECS) components have gained high interest as potential new targets for treating psychiatry diseases because of their neuromodulator role, which is essential to understanding the regulation of many brain functions. This article reviewed the molecular alterations in ECS occurring in different psychiatric conditions. The methods used to identify alterations in the ECS were also described. We used a translational approach. The animal models reproducing some behavioral and/or neurochemical aspects of psychiatric disorders and the molecular alterations in clinical studies in post-mortem brain tissue or peripheral tissues were analyzed. This article reviewed the most relevant ECS changes in prevalent psychiatric diseases such as mood disorders, schizophrenia, autism, attentional deficit, eating disorders (ED), and addiction. The review concludes that clinical research studies are urgently needed for two different purposes: (1) To identify alterations of the ECS components potentially useful as new biomarkers relating to a specific disease or condition, and (2) to design new therapeutic targets based on the specific alterations found to improve the pharmacological treatment in psychiatry.

Cannabinoid CB1 Receptor Involvement in the Actions of CBD on Anxiety and Coping Behaviors in Mice.

The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD's ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD.

CBD-mediated regulation of heroin withdrawal-induced behavioural and molecular changes in mice.

Cannabidiol (CBD) may represent a promising therapeutic tool for treating opioid use disorder (OUD). This study was aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous heroin withdrawal. Thirty hours after cessation of 8-day heroin treatment (5, 10, 20 and 40 mg·kg-1 /12 h; s.c.), spontaneous heroin withdrawal was evaluated in CD1 male mice. The effects of CBD (5, 10 and 20 mg·kg-1 ; i.p.) on withdrawal-related behaviour were evaluated by measuring anxiety-like behaviour, motor activity and somatic signs. Furthermore, gene expression changes of mu-opioid receptor (Oprm1), proopiomelanocortin (Pomc), cannabinoid CB1 (Cnr1) and CB2 (Cnr2) receptors in the nucleus accumbens (NAcc) and tyrosine hydroxylase (TH) and Pomc in the ventral tegmental area (VTA) were also evaluated by real-time PCR. Anxiety-like behaviour, motor activity and withdrawal-related somatic signs were significantly increased in heroin-treated mice compared to the control group. Interestingly, CBD treatment significantly reduced these behavioural impairments and normalized gene expression of Cnr1 and Pomc in the NAcc and TH in the VTA of mice exposed to spontaneous heroin withdrawal. Also, CBD induced an up-regulation of Cnr2, whereas it did not change the increased gene expression of Oprm1 in the NAcc of abstinent animals. The results suggest that CBD alleviates spontaneous heroin withdrawal and normalizes the associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for the treatment of heroin withdrawal.

Biomarkers of the Endocannabinoid System in Substance Use Disorders.

Despite substance use disorders (SUD) being one of the leading causes of disability and mortality globally, available therapeutic approaches remain ineffective. The difficulty in accurately characterizing the neurobiological mechanisms involved with a purely qualitative diagnosis is an obstacle to improving the classification and treatment of SUD. In this regard, identifying central and peripheral biomarkers is essential to diagnosing the severity of drug dependence, monitoring therapeutic efficacy, predicting treatment response, and enhancing the development of safer and more effective pharmacological tools. In recent years, the crucial role that the endocannabinoid system (ECS) plays in regulating the reinforcing and motivational properties of drugs of abuse has been described. This has led to studies characterizing ECS alterations after exposure to various substances to identify biomarkers with potential diagnostic, prognostic, or therapeutic utility. This review aims to compile the primary evidence available from rodent and clinical studies on how the ECS components are modified in the context of different substance-related disorders, gathering data from genetic, molecular, functional, and neuroimaging experimental approaches. Finally, this report concludes that additional translational research is needed to further characterize the modifications of the ECS in the context of SUD, and their potential usefulness in the necessary search for biomarkers.

CB2 Receptor Involvement in the Treatment of Substance Use Disorders.

The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central nervous system (CNS) level by assessing evidence from preclinical and clinical studies. In rodents, several reports suggest the functional involvement of CB2r in the effects produced by drugs of abuse such as alcohol, cocaine, or nicotine. In addition, the discovery of CB2r in brain areas that are part of the reward system supports the relevance of CB2r in the field of addiction. Interestingly, animal studies support that the CB2r regulates anxiety and depression behavioral traits. Due to its frequent comorbidity with neuropsychiatric disorders, these pharmacological actions may be of great interest in managing SUD. Preliminary clinical trials are focused on exploring the therapeutic potential of modulating CB2r in treating addictive disorders. These promising results support the development of new pharmacological tools regulating the CB2r that may help to increase the therapeutic success in the management of SUD.

Cannabidiol and Sertraline Regulate Behavioral and Brain Gene Expression Alterations in an Animal Model of PTSD.

This study evaluated the effects of cannabidiol (CBD) and/or sertraline (STR) on behavioral and gene expression alterations induced by a new chronic animal model of post-traumatic stress disorder (PTSD). C57BL/6J male mice were repeatedly exposed to physical and psychogenic alternate stressful stimuli. Fear-related memory and anxiety-like behaviors were evaluated. The effects of the administration of CBD (20 mg/kg, i.p.) and/or STR (10 mg/kg, p.o.) were analyzed on behavioral and gene expression changes induced by the model of PTSD. Gene expression alterations of targets related with stress regulation, endocannabinoid and serotonergic systems were analyzed by real-time PCR. The results revealed an increased and long-lasting fear-related memory and anxiety-like behaviors in mice exposed to the animal model of PTSD. Treatment with CBD improved these behaviors in PTSD animals, effects that were significantly potentiated when combined with STR. Gene expression analyses revealed a long-term increase of corticotropin releasing factor (Crf) that was significantly normalized with the combination CBD plus STR. Cannabinoid receptors (Cnr1 and Cnr2) were up regulated in PTSD mice whereas the serotonin transporter (Slc6a4) was reduced. Interestingly, CBD and STR alone or combined induced a significant and marked increase of Slc6a4 gene expression. These results point out the cooperative action of the combination CBD plus STR to enhance fear extinction and reduce anxiety-like behaviors, normalizing gene expression alterations in this animal model of PTSD and suggesting that the combination of CBD with STR deserves to be further explored for the treatment of patients with PTSD.

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

Role of Cannabidiol in the Therapeutic Intervention for Substance Use Disorders.

Drug treatments available for the management of substance use disorders (SUD) present multiple limitations in efficacy, lack of approved treatments or alarming relapse rates. These facts hamper the clinical outcome and the quality of life of the patients supporting the importance to develop new pharmacological agents. Lately, several reports suggest that cannabidiol (CBD) presents beneficial effects relevant for the management of neurological disorders such as epilepsy, multiple sclerosis, Parkinson's, or Alzheimer's diseases. Furthermore, there is a large body of evidence pointing out that CBD improves cognition, neurogenesis and presents anxiolytic, antidepressant, antipsychotic, and neuroprotective effects suggesting potential usefulness for the treatment of neuropsychiatric diseases and SUD. Here we review preclinical and clinical reports regarding the effects of CBD on the regulation of the reinforcing, motivational and withdrawal-related effects of different drugs of abuse such as alcohol, opioids (morphine, heroin), cannabinoids, nicotine, and psychostimulants (cocaine, amphetamine). Furthermore, a special section of the review is focused on the neurobiological mechanisms that might be underlying the 'anti-addictive' action of CBD through the regulation of dopaminergic, opioidergic, serotonergic, and endocannabinoid systems as well as hippocampal neurogenesis. The multimodal pharmacological profile described for CBD and the specific regulation of addictive behavior-related targets explains, at least in part, its therapeutic effects on the regulation of the reinforcing and motivational properties of different drugs of abuse. Moreover, the remarkable safety profile of CBD, its lack of reinforcing properties and the existence of approved medications containing this compound (Sativex®, Epidiolex®) increased the number of studies suggesting the potential of CBD as a therapeutic intervention for SUD. The rising number of publications with substantial results on the valuable therapeutic innovation of CBD for treating SUD, the undeniable need of new therapeutic agents to improve the clinical outcome of patients with SUD, and the upcoming clinical trials involving CBD endorse the relevance of this review.

The administration of sertraline plus naltrexone reduces ethanol consumption and motivation in a long-lasting animal model of post-traumatic stress disorder.

This study was aimed to evaluate the effects of sertraline (STR) and/or naltrexone (NTX) on ethanol consumption and motivation in an animal model of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD). Male C57BL/6J mice were submitted to an intermittent and progressively increasing stressful stimuli simulating PTSD behavioural features. Behavioural alterations were explored by the fear conditioning (FC), novelty suppressed feeding test (NSFT) and acoustic startle response (ASR) paradigms. Afterwards, mice were evaluated in the voluntary ethanol consumption (VC) and the oral ethanol self-administration (OEA) paradigms. The effects of STR (10 mg/kg) and/or NTX (0.7 mg/kg) on ethanol consumption and motivation were analysed in the OEA. Furthermore, relative gene expression analyses of tyrosine hydroxylase (Th), mu-opioid receptor (Oprm1) and 5-hydroxitryptamine transporter (Slc6a4) were performed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) and dorsal raphe nucleus (DR), respectively. PTSD-like mice presented increased fear-related memory, anxiety-like behaviours, and startle response, as well as enhanced ethanol consumption and motivation in the VC and OEA paradigms. Interestingly, STR plus NTX combination significantly reduced ethanol intake and motivation in the OEA. Gene expression analyses revealed reduced Th and Oprm1 whereas Slc6a4 gene expression increased in PTSD-like mice. STR and/or NTX modulated Th and Slc6a4 gene expression changes in PTSD-like mice. Furthermore, NTX increased Oprm1 gene expression revealing a synergistic action when combined with STR. These results provide evidence about the efficacy of the STR plus NTX to attenuate ethanol reinforcement and motivation in an animal model of PTSD and AUD dual pathology.

Cannabidiol prevents priming- and stress-induced reinstatement of the conditioned place preference induced by cocaine in mice.

BACKGROUND: Cocaine dependence is an important problem without any effective pharmacological treatment. Some preclinical studies have suggested that cannabidiol (CBD), a component of the Cannabis sativa plant, could be useful for the treatment of cocaine use disorders. AIMS: This work aims to evaluate the ability of CBD to reduce priming- and stress-induced reinstatement of the conditioned place preference (CPP) induced by cocaine. METHODS: Young adult CD-1 male mice were allocated to 10 groups (n = 12/group), conditioned with cocaine (10 mg/kg) and exposed to extinction of CPP (two sessions per week). When extinction was achieved, each group received the corresponding treatment before the reinstatement test. In experiment 1, six groups were used: vehicle+saline (Veh+Sal), 5 mg/kg cocaine alone (Veh+Coc) or with CBD 30 or 60 mg/kg (CBD30+Coc, CBD60+Coc) and CBD alone (CBD30+Sal, CBD60+Sal). In experiment 2, four groups were used: exploration (Veh+Expl), social defeat (Veh+SD) and social defeat with CBD (CBD30+SD and CBD60+SD). Furthermore, the relative gene expression of the dopamine transporter (DAT) in the ventral tegmental area was measured. RESULTS: All mice acquired cocaine CPP and extinguished it after three or four weeks. Only the groups treated with cocaine priming (Veh+Coc) or exposed to social defeat (Veh+SD) showed reinstatement of CPP. Interestingly, CBD itself did not induce reinstatement and blocked the reinstating effects of cocaine priming and social defeat. Furthermore, cocaine priming increased DAT gene expression in the ventral tegmental area and CBD completely reversed this effect. CONCLUSION: These results suggest that CBD could reduce reinstatement to cocaine seeking after a period of abstinence.

Cannabidiol Modulates Behavioural and Gene Expression Alterations Induced by Spontaneous Cocaine Withdrawal.

The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12 days (15 to 60 mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6 h after the last cocaine administration. The effects of CBD (10, 20, and 40 mg/kg, i.p.) were evaluated on cocaine withdrawal-induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal.

Cannabis Use in Pregnant and Breastfeeding Women: Behavioral and Neurobiological Consequences.

Nowadays, cannabis is the most consumed illicit drug. The global prevalence of the use of cannabis in 2017 was estimated in 188 million of people, 3.8% of worldwide population. Importantly, the legalization of cannabis in different countries, together with the increase in the apparent safety perception, may result in a great variety of health problems. Indeed, an important concern is the increase in cannabis use among pregnant and breastfeeding women, especially since the content of delta9-tetrahidrocannabinol (THC) is currently around 2-fold higher than it was 15-20 years ago. The purpose of this study was to review cannabis use during pregnancy and breastfeeding including epidemiological aspects, therapeutic or preventive strategies, and experimental considerations and results from animal models of perinatal cannabis exposure to analyze the underlying neurobiological mechanisms and to identify new therapeutic approaches. A recent report revealed that among pregnant women aged 15-44, last month cannabis use prevalence was over 4.9%, raising to 8.5% in the 18-25-year-old age range. Pre- and post-natal exposure to cannabis may be associated with critical alterations in the newborn infants that are prolonged throughout childhood and adolescence. Briefly, several reports revealed that perinatal cannabis exposure was associated with low birth weight, reduction in the head circumference, cognitive deficits (attention, learning, and memory), disturbances in emotional response leading to aggressiveness, high impulsivity, or affective disorders, and higher risk to develop a substance use disorder. Furthermore, important neurobiological alterations in different neuromodulatory and neurotransmission systems have been associated with cannabis consumption during pregnancy and lactation. In spite of the evidences pointing out the negative behavioral and neurobiological consequences of cannabis use in pregnant and breastfeeding women, there are still limitations to identify biomarkers that could help to establish preventive or therapeutic approaches. It is difficult to define the direct association specifically with cannabis, avoiding other confusing factors, co-occurrence of other drugs consumption (mainly nicotine and alcohol), lifestyle, or socioeconomic factors. Therefore, it is necessary to progress in the characterization of short- and long-term cannabis exposure-related disturbances.