Effects of cannabis exposure in the prenatal and adolescent periods: Preclinical and clinical studies in both sexes.

Cannabis is the most commonly used illicit drug among adolescents and young adults, including pregnant women. There is substantial evidence for a significant association between prenatal cannabis exposure and lower birth weight in offspring, and mixed results regarding later behavioural outcomes in the offspring. Adolescent cannabis use, especially heavy use, has been associated with altered executive function, depression, psychosis and use of other drugs later in life. Human studies have limitations due to several confounding factors and have provided scarce information about sex differences. In general, animal studies support behavioural alterations reported in humans and have revealed diverse sex differences and potential underlying mechanisms (altered mesolimbic dopaminergic and hippocampal glutamatergic systems and interference with prefrontal cortex maturation). More studies are needed that analyse sex and gender influences on cannabis-induced effects with great clinical relevance such as psychosis, cannabis use disorder and associated comorbidities, to achieve more personalized and accurate treatments.

CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice.

Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists.

Histone Deacetylase Gene Expression Following Binge Alcohol Consumption in Rats and Humans.

BACKGROUND: Alcohol binge drinking is one of the most common patterns of excessive alcohol use and recent data would suggest that histone deacetylases (HDACs) gene expression profiling could be useful as a biomarker for psychiatric disorders. METHODS: This study aimed to characterize the gene expression patterns of Hdac 1-11 in samples of rat peripheral blood, liver, heart, prefrontal cortex, and amygdala following repeated binge alcohol consumption and to determine the parallelism of Hdac gene expression between rats and humans in peripheral blood. To accomplish this goal, we examined Hdac gene expression following 1, 4, or 8 alcohol binges (3 g/kg, orally) in the rat, in patients who were admitted to the hospital emergency department for acute alcohol intoxication, and in rats trained in daily operant alcohol self-administration. RESULTS: We primarily found that acute alcohol binging reduced gene expression (Hdac1-10) in the peripheral blood of alcohol-naïve rats and that this effect was attenuated following repeated alcohol binges. There was also a reduction of Hdac gene expression in the liver (Hdac2,4,5), whereas there was increased expression in the heart (Hdac1,7,8) and amygdala (Hdac1,2,5). Additionally, increased blood alcohol concentrations were measured in rat blood at 1 to 4 hours following repeated alcohol binging, and the only group that developed hepatic steotosis (fatty liver) were those animals exposed to 8 alcohol binge events. Finally, both binge consumption of alcohol in humans and daily operant alcohol self-administration in rats increased Hdac gene expression in peripheral blood. CONCLUSIONS: Our results suggest that increases in HDAC gene expression within the peripheral blood are associated with chronic alcohol consumption, whereas HDAC gene expression is reduced following initial exposure to alcohol.

Short-term fluoxetine treatment induces neuroendocrine and behavioral anxiogenic-like responses in adolescent male rats.

Fluoxetine (FLX) is prescribed to treat depression and anxiety in adolescent patients. However, FLX has anxiogenic effects during the acute phase of treatment, and caution has been raised due to increased suicidal thinking and behavior. Herein, we sought to study in adolescent (35-day-old) male rats, the effects of short-term FLX treatment (10 mg/kg/day, i.p. for 3-4 days) on hypothalamic-pituitary-adrenal axis activity, serotonin (5-hidroxytriptamine, 5-HT) transporter (SERT) mRNA expression in the dorsal raphe nucleus (DRN), energy balance-related variables and behavioral profiles in the holeboard. Our results revealed that daily FLX administration increased plasma corticosterone (B) concentrations without affecting basal gene expression of corticotrophin releasing hormone in the hypothalamic paraventricular nucleus (PVN) nor of pro-opiomelanocortin in the anterior pituitary. However, FLX had significant effects increasing the mRNA expression of PVN arginine vasopressin (AVP) and reducing SERT mRNA levels in the dorsolateral subdivision of the DRN. In the holeboard, FLX-induced anxiety/emotionality-like behaviors. As expected, FLX treatment was endowed with anorectic effects and reduced body weight gain. Altogether, our study shows that short-term FLX treatment results in physiological, neuroendocrine and behavioral stress-like effects in adolescent male rats. More importantly, considering that the AVP- and 5-HTergic systems: (1) are intimately involved in regulation of the stress response; (2) are regulated by sex hormones and (3) are related to regulation of aggressive behaviors, our results highlight the potential significance of these systems mediating the anxiogenic/emotionality/stress-like responses of adolescent male rats to short-term FLX treatment.

Early maternal deprivation enhances voluntary alcohol intake induced by exposure to stressful events later in life.

In the present study, we aimed to assess the impact of early life stress, in the form of early maternal deprivation (MD, 24 h on postnatal day, pnd, 9), on voluntary alcohol intake in adolescent male and female Wistar rats. During adolescence, from pnd 28 to pnd 50, voluntary ethanol intake (20%, v/v) was investigated using the two-bottle free choice paradigm. To better understand the relationship between stress and alcohol consumption, voluntary alcohol intake was also evaluated following additional stressful events later in life, that is, a week of alcohol cessation and a week of alcohol cessation combined with exposure to restraint stress. Female animals consumed more alcohol than males only after a second episode of alcohol cessation combined with restraint stress. MD did not affect baseline voluntary alcohol intake but increased voluntary alcohol intake after stress exposure, indicating that MD may render animals more vulnerable to the effects of stress on alcohol intake. During adolescence, when animals had free access to alcohol, MD animals showed lower body weight gain but a higher growth rate than control animals. Moreover, the higher growth rate was accompanied by a decrease in food intake, suggesting an altered metabolic regulation in MD animals that may interact with alcohol intake.

Cannabidiol attenuates sensorimotor gating disruption and molecular changes induced by chronic antagonism of NMDA receptors in mice.

BACKGROUND: Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801. METHODS: Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine. RESULTS: MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment. CONCLUSIONS: These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties.

Early maternal deprivation immunologically primes hippocampal synapses by redistributing interleukin-1 receptor type I in a sex dependent manner.

Challenges experienced in early life cause an enduring phenotypical shift of immune cells towards a sensitised state that may lead to an exacerbated reaction later in life and contribute to increased vulnerability to neurological diseases. Peripheral and central inflammation may affect neuronal function through cytokines such as IL-1. The extent to which an early life challenge induces long-term alteration of immune receptors organization in neurons has not been shown. We investigated whether a single episode of maternal deprivation (MD) on post-natal day (PND) 9 affects: (i) the synapse distribution of IL-1RI together with subunits of NMDA and AMPA receptors; and (ii) the interactions between IL-1RI and the GluN2B subunit of the NMDAR in the long-term, at PND 45. MD increased IL-1RI levels and IL-1RI interactions with GluN2B at the synapse of male hippocampal neurons, without affecting the total number of IL-1RI or NMDAR subunits. Although GluN2B and GluN2A were slightly but not significantly changed at the synapse, their ratio was significantly decreased in the hippocampus of the male rats who had experienced MD; the levels of the GluA1 and GluA2 subunits of the AMPAR were also decreased. These changes were not observed immediately after the MD episode. None of the observed alterations occurred in the hippocampus of the females or in the prefrontal cortex of either sex. These data reveal a long-term, sex-dependent modification in receptor organisation at the hippocampal post-synapses following MD. We suggest that this effect might contribute to priming hippocampal synapses to the action of IL-1ß.

Consequences of early life stress on the expression of endocannabinoid-related genes in the rat brain.

The endocannabinoid system is involved in several physiological and pathological states including anxiety, depression, addiction and other neuropsychiatric disorders. Evidence from human and rodent studies suggests that exposure to early life stress may increase the risk of psychopathology later in life. Indeed, maternal deprivation (MD) (24 h at postnatal day 9) in rats induces behavioural alterations associated with depressive-like and psychotic-like symptoms, as well as important changes in the endocannabinoid system. As most neuropsychiatric disorders first appear at adolescence, and show remarkable sexual dimorphisms in their prevalence and severity, in the present study, we analysed the gene expression of the main components of the brain cannabinoid system in adolescent (postnatal day 46) Wistar male and female rats reared under standard conditions or exposed to MD. For this, we analysed, by real-time quantitative PCR, the expression of genes encoding for CB1 and CB2 receptors, TRPV1 and GPR55 (Cnr1, Cnr2a, Cnr2b, Trpv1, and Gpr55), for the major enzymes of synthesis, N-acyl phosphatidyl-ethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL) (Nape-pld, Dagla and Daglb), and degradation, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) (Faah, Magl and Cox-2), in specific brain regions, that is, the frontal cortex, ventral and dorsal striatum, dorsal hippocampus and amygdala. In males, MD increased the genetic expression of all the genes studied within the frontal cortex, whereas in females such an increase was observed only in the hippocampus. In conclusion, the endocannabinoid system is sensitive to early life stress at the gene expression level in a sex-dependent and region-dependent manner, and these changes are already evident in the adolescent brain.

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

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.

The role of the endocannabinoid system in eating disorders: pharmacological implications.

The endocannabinoid (eCB) system is a widespread intercellular signalling mechanism that plays a critical role in body homoeostasis. It is located in key points involved in food intake and energy expenditure, coordinating all the players involved in energy balance. As such, it has come to be seen as an interesting target for the management of diseases characterized by an imbalanced energy homoeostasis, such as obesity and eating disorders. The aetiology of eating disorders and the molecular systems involved are still largely a mystery. Research has focused on brain circuits where the eCB system plays an important role, such as those related to feeding behaviour and the rewarding properties of food. Accordingly, recent findings have suggested a deregulation of the eCB system in eating disorders. At present, cannabinoid agonists are safe and effective tools in the management of diseases in which weight gain is needed, for example cachexia in AIDS patients. However, studies on the potential therapeutic validity of cannabinoids in eating disorders are scarce and inconclusive. Taken together, all these considerations warrant more preclinical and clinical investigations in the role of the eCB system in eating disorders. Eventually, they may provide novel pharmacological approaches for the treatment of these diseases.

Estradiol decreases cortical reactive astrogliosis after brain injury by a mechanism involving cannabinoid receptors.

The neuroactive steroid estradiol reduces reactive astroglia after brain injury by mechanisms similar to those involved in the regulation of reactive gliosis by endocannabinoids. In this study, we have explored whether cannabinoid receptors are involved in the effects of estradiol on reactive astroglia. To test this hypothesis, the effects of estradiol, the cannabinoid CB1 antagonist/inverse agonist AM251, and the cannabinoid CB2 antagonist/inverse agonist AM630 were assessed in the cerebral cortex of male rats after a stab wound brain injury. Estradiol reduced the number of vimentin immunoreactive astrocytes and the number of glial fibrillary acidic protein immunoreactive astrocytes in the proximity of the wound. The effect of estradiol was significantly inhibited by the administration of either CB1 or CB2 receptor antagonists. The effect of estradiol may be in part mediated by alterations in endocannabinoid signaling because the hormone increased in the injured cerebral cortex the messenger RNA levels of CB2 receptors and of some of the enzymes involved in the synthesis and metabolism of endocannabinoids. These findings suggest that estradiol may decrease reactive astroglia in the injured brain by regulating the activity of the endocannabinoid system.

Sex-dependent effects of maternal deprivation and adolescent cannabinoid treatment on adult rat behaviour.

Early life experiences such as maternal deprivation (MD) exert long-lasting changes in adult behaviour and reactivity to stressors. Adolescent exposure to cannabinoids is a predisposing factor in developing certain psychiatric disorders. Therefore, the combination of the two factors could exacerbate the negative consequences of each factor when evaluated at adulthood. The objective of this study was to investigate the long-term effects of early MD [24 hours at postnatal day (PND) 9] and/or an adolescent chronic treatment with the cannabinoid agonist CP-55,940 (0.4 mg/kg, PND 28-42) on diverse behavioural and physiological responses of adult male and female Wistar rats. We tested them in the prepulse inhibition (PPI) of the startle response and analysed their exploratory activity (holeboard) and anxiety (elevated plus maze, EPM). In addition, we evaluated their adrenocortical reactivity in response to stress and plasma leptin levels. Maternal behaviour was measured before and after deprivation. MD induced a transient increase of maternal behaviour on reuniting. In adulthood, maternally deprived males showed anxiolytic-like behaviour (or increased risk-taking behaviour) in the EPM. Adolescent exposure to the cannabinoid agonist induced an impairment of the PPI in females and increased adrenocortical responsiveness to the PPI test in males. Both, MD and adolescent cannabinoid exposure also induced sex-dependent changes in plasma leptin levels and body weights. The present results indicate that early MD and adolescent cannabinoid exposure exerted distinct sex-dependent long-term behavioural and physiological modifications that could predispose to the development of certain neuropsychiatric disorders, though no synergistic effects were found.

Converging action of alcohol consumption and cannabinoid receptor activation on adult hippocampal neurogenesis.

Alcoholism is characterized by successive periods of abstinence and relapse, resulting from long-lasting changes in various circuits of the central nervous system. Accumulating evidence points to the endocannabinoid system as one of the most relevant biochemical systems mediating alcohol addiction. The endocannabinoid system regulates adult neurogenesis, a form of long-lasting adult plasticity that occurs in a few areas of the brain, including the dentate gyrus. Because exposure to psychotropic drugs regulates adult neurogenesis, it is possible that neurogenesis might be implicated in the pathophysiology, and hence treatment, of neurobiological illnesses related to drugs of abuse. Here, we investigated the sensitivity of adult hippocampal neurogenesis to alcohol and the cannabinoid receptor agonist WIN 55,212-2 (WIN). Specifically, we analysed the potential link between alcohol relapse, cannabinoid receptor activation, and adult neurogenesis. Adult rats were exposed to subchronic alcohol binge intoxication and received the cannabinoid receptor agonist WIN. Another group of rats were subjected to an alcohol operant self-administration task. Half of these latter animals had continuous access to alcohol, while the other half were subjected to alcohol deprivation, with or without WIN administration. WIN treatment, when administered during alcohol deprivation, resulted in the greatest increase in alcohol consumption during relapse. Together, forced alcohol binge intoxication and WIN administration dramatically reduced hippocampal neurogenesis. Furthermore, adult neurogenesis inversely correlated with voluntary consumption of alcohol. These findings suggest that adult hippocampal neurogenesis is a key factor involved in drug abuse and that it may provide a new strategy for the treatment of alcohol addiction and dependence.

Maternal deprivation induces a rapid decline in circulating leptin levels and sexually dimorphic modifications in hypothalamic trophic factors and cell turnover.

Pathological outcomes, including metabolic and endocrine disturbances, of maternal deprivation (MD) in Wistar rats depend on gender and the timing of deprivation during development. We analyzed the effect of MD between postnatal days 9 and 10, a critical period in hypothalamic development, on circulating hormones and local production of trophic factors involved in this process, as well as on markers of cell turnover and maturation. Males and females were studied 12 and 24 h after MD and 12 h (MD36) after returning the dam to her pups. Circulating corticosterone levels were increased and glucose and leptin levels decreased throughout the study in both sexes. Hypothalamic mRNA levels of leptin receptor increased significantly at MD24 in both sexes, normalizing in females at MD36, but not in males. In male rats insulin-like growth factor mRNA levels were significantly decreased at MD24 and brain derived neurotrophic factor mRNA levels decreased at MD12 and MD24, with both trophic factors unaffected in females. In males cell proliferation was significantly decreased at MD36, as were the glial structural proteins, glial fibrillary acidic protein and vimentin. In females, nestin levels decreased significantly at MD24. These results indicate that MD differently affects trophic factors and cell-turnover in the hypothalamus of males and females, which may underlie the sex differences seen in the endocrine and metabolic outcome.

Maternal deprivation has sexually dimorphic long-term effects on hypothalamic cell-turnover, body weight and circulating hormone levels.

Maternal deprivation (MD) has numerous outcomes, including modulation of neuroendocrine functions. We previously reported that circulating leptin levels are reduced and hypothalamic cell-turnover is affected during MD, with some of these effects being sexually dimorphic. As leptin modulates the development of hypothalamic circuits involved in metabolic control, we asked whether MD has long-term consequences on body weight, leptin levels and the expression of neuropeptides involved in metabolism. Rats were separated from their mother for 24h starting on postnatal day (PND) 9 and sacrificed at PNDs 13, 35 and 75. In both sexes MD reduced body weight, but only until puberty, while leptin levels were unchanged at PND 35 and significantly reduced at PND 75. Adiponectin levels were also reduced at PND 75 in females, while testosterone levels were reduced in males. At PND 13, MD modulated cell-turnover markers in the hypothalamus of males, but not females and increased nestin, a marker of immature neurons, in both sexes, with males having higher levels than females and a significantly greater rise in response to MD. There was no effect of MD on hypothalamic mRNA levels of the leptin receptor or metabolic neuropeptides or the mRNA levels of leptin and adiponectin in adipose tissue. Thus, MD has long-term effects on the levels of circulating hormones that are not correlated with changes in body weight. Furthermore, these endocrine outcomes are different between males and females, which could be due to the fact that MD may have sexually dimorphic effects on hypothalamic development.

Detrimental psychophysiological effects of early maternal deprivation in adolescent and adult rodents: altered responses to cannabinoid exposure.

Environmental rearing conditions during the neonatal period are critical for the establishment of neurobiological factors controlling behavior and stress responsiveness. Early maternal deprivation (MD), consisting of a single 24-h maternal deprivation episode during early neonatal life, has been proposed as an animal model for certain psychopathologies including anxiety, depression and schizophrenic-related disorders. Despite first onset of mental disorders usually occur during adolescence, characterization of MD has been mostly developed in adult animals. We review here a series of experiments that were conducted on rats and mice, in which we analyzed the psychoimmunoendocrine outcomes of MD at both adolescence and adulthood. As a whole our results indicate that MD might promote a depressive-like trait that may be present from adolescence to maturity. Maternally deprived adolescent animals also displayed altered locomotor responses, a reduced interest for social investigation and seemed prone for impulsive behavior. Therefore, MD in rodents is further confirmed as a suitable animal model for the study of neuropsychiatric disorders that might become evident during adolescence. Given the increasing consumption of cannabis derivatives among the juvenile population and the reported comorbidity of neuropsychiatric symptoms with cannabis abuse, we also discuss our results indicating altered responses of maternally deprived adolescent animals to cannabinoid compounds.

Early maternal deprivation induces gender-dependent changes on the expression of hippocampal CB(1) and CB(2) cannabinoid receptors of neonatal rats.

Early maternal deprivation (MD) in rats (24 h, postnatal day 9-10) is a model for neurodevelopmental stress. There are some data proving that MD affects the endocannabinoid system (ECS) in a gender-dependent manner, and that these changes may account for the proposed schizophrenia-like phenotype of MD rats. The impact of MD on cannabinoid receptor distribution in the hippocampus is unknown. The aim of this study is to evaluate the expression of CB(1) and CB(2) receptors in diverse relevant subregions (DG, CA1, and CA3) of the hippocampus in 13-day-old rats by immunohistochemistry and densitometry. MD induced a significant decrease in CB(1) immunoreactivity (more marked in males than in females), which was mainly associated with fibers in the strata pyramidale and radiatum of CA1 and in the strata oriens, pyramidale, and radiatum of CA3. In contrast, MD males and females showed a significant increase in CB(2) immunoreactivity in the three hippocampal areas analyzed that was detected in neuropil and puncta in the stratum oriens of CA1 and CA3, and in the polymorphic cell layer of the dentate gyrus. A marked sex dimorphism was observed in CA3, with females exhibiting higher CB(1) immunoreactivity than males, and in dentate gyrus, with females exhibiting lower CB(2) immunoreactivity than males. These results point to a clear association between developmental stress and dysregulation of the ECS. The present MD procedure may provide an interesting experimental model to further address the role of the ECS in neurodevelopmental mental illnesses such as schizophrenia.

Bath salts and polyconsumption: in search of drug-drug interactions.

BACKGROUND AND RATIONALE: Polydrug use is a widespread phenomenon, especially among adolescents and young adults. Synthetic cathinones are frequently consumed in combination with other drugs of abuse. However, there is very little information regarding the consequences of this specific consumption pattern. OBJECTIVES: The aim of this review is to introduce this topic and highlight the gaps in the existing literature. In three different sections, we focus on specific interactions of synthetic cathinones with alcohol, cannabinoids, and the stimulants nicotine and cocaine. We then dedicate a section to the existence of sex and gender differences in the effects of synthetic cathinones and the long-term psychophysiological consequences of adolescent and prenatal exposure to these drugs. MAJOR FINDINGS: Epidemiological studies, case reports, and results obtained in animal models point to the existence of pharmacological and pharmacokinetic interactions between synthetic cathinones and other drugs of abuse. This pattern of polyconsumption can cause the potentiation of negative effects, and the dissociation between objective and subjective effects can increase the combined use of the drugs and the risk of toxicity leading to serious health problems. Certain animal studies indicate a higher vulnerability and effect of cathinones in females. In humans, most of the users are men and case reports show long-term psychotic symptoms after repeated use. CONCLUSIONS: The co-use of synthetic cathinones and the other drugs of abuse analyzed indicates potentiation of diverse effects including dependence and addiction, neurotoxicity, and impaired cognition and emotional responses. The motivations for and effects of synthetic cathinone use appear to be influenced by sex/gender. The long-term consequences of their use by adolescents and pregnant women deserve further investigation.

Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55,940 on morphine self-administration behaviour and the endogenous opioid system.

Early cannabinoid consumption may predispose individuals to the misuse of addictive drugs later in life. However, there is a lack of experimental evidence as to whether cannabinoid exposure during adolescence might differently affect opiate reinforcing efficacy and the opioid system in adults of both sexes. Our aim was to examine whether periadolescent chronic exposure to the cannabinoid agonist CP-55,940 could exert sex-dependent effects on morphine reinforcing and the opioid system in adulthood. Morphine reinforcing was studied under a progressive ratio (PR) reinforcement schedule in adult male and female rats that previously acquired morphine self-administration under a fixed ratio 1 (FR1) schedule. Binding levels and functionality of mu-opioid receptors were also evaluated. Periadolescent cannabinoid exposure altered morphine self-administration and the opioid system in adult rats in a sex-dependent manner. CP-55,940-exposed males exhibited higher self-administration rates under a FR1, but not under a PR schedule. In females, CP-55,940 did not modify morphine self-administration under either schedule. Moreover, CP-55,940 also increased mu-opioid receptor levels in the subcallosal streak of pre-treated animals and decreased mu-opioid receptor functionality in the nucleus accumbens shell but again, only in males. Our data indicate that adult male rats exposed to the cannabinoid in adolescence self-administer more morphine than females, but only when the demands required by the schedule of reinforcement are low, which might be related to the decrease in mu-opioid receptor functionality in the NAcc-shell observed in these animals.

Effects of adolescent nicotine and SR 147778 (Surinabant) administration on food intake, somatic growth and metabolic parameters in rats.

Tobacco smoking and obesity are worldwide important health problems with a growing impact in adolescent and young adults. One of the consequences of nicotine withdrawal is an increase in body weight that can act as a risk factor to relapse. Experimental therapies with a cannabinoid receptor antagonist have been recently proposed for both cigarette smoking and complicated overweight. In the present study, we aimed to investigate metabolic and hormonal effects of chronic nicotine treatment (during treatment and in abstinence) in an animal model of adolescence as well as to address the pharmacological effects of the novel selective CB1 cannabinoid receptor antagonist, SR 147778 (Surinabant). Adolescence (postnatal days 37-44) and/or post-adolescence (postnatal days 45-59) administration of Surinabant reduced body weight gain, as well as plasma glucose levels and triglycerides. The drug also reduced insulin and leptin secretion, and increased adiponectin and corticosterone levels. The effects showed sexual dimorphisms and, in general, were more pronounced in females. Chronic exposure to nicotine (0.8 mg/kg), from postnatal days 30-44 did not result in overt effects on food intake or body weight gain. However, it altered certain responses to the administration of Surinabant, both when the two drugs were given simultaneously and when Surinabant was administered during the post-adolescence period, along nicotine withdrawal. The present results indicate that the endogenous cannabinoid system is active as a metabolic modulator during adolescence and that nicotine exposure can induce long-lasting effects on metabolic regulation, altering cannabinoid modulation of energy expenditure and metabolism.