Valentina Satta

Adolescent Δ 9 -Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats

Cannabis is the most commonly used illicit drug worldwide, and use is typically initiated during adolescence. The endocannabinoid system has an important role in formation of the nervous system, from very early development through adolescence. Cannabis exposure during this vulnerable period might lead to neurobiological changes that affect adult brain functions and increase the risk of cannabis use disorder. The aim of this study was to investigate whether exposure to Δ9-tetrahydrocannabinol (THC) in adolescent rats might enhance reinforcing effects of cannabinoids in adulthood. Male adolescent rats were treated with increasing doses of THC (or its vehicle) twice/day for 11 consecutive days (PND 45–55). When the animals reached adulthood, they were tested by allowing them to intravenously self-administer the cannabinoid CB1-receptor agonist WIN55,212-2. In a separate set of animals given the same THC (or vehicle) treatment regimen, electrophysiological and neurochemical experiments were performed to assess possible modifications of the mesolimbic dopaminergic system, which is critically involved in cannabinoid-induced reward. Behavioral data showed that acquisition of WIN55,212-2 self-administration was enhanced in THC-exposed rats relative to vehicle-exposed controls. Neurophysiological data showed that THC-exposed rats displayed a reduced capacity for WIN55,212-2 to stimulate firing of dopamine neurons in the ventral tegmental area and to increase dopamine levels in the nucleus accumbens shell. These findings—that early, passive exposure to THC can produce lasting alterations of the reward system of the brain and subsequently increase cannabinoid self-administration in adulthood—suggest a mechanism by which adolescent cannabis exposure could increase the risk of subsequent cannabis dependence in humans.

Emotional profile of female rats showing binge eating behavior

Abstract Binge eating disorder (BED) is characterized by uncontrolled consumption of a large amount of food in a brief period of time. A large body of evidence has shown that BED can be a chronic condition associated with elevated psychiatric comorbidity, including depression and anxiety, and compulsive behavior. In this study we used an animal model of BED in which binge eating behavior was induced in female rats by providing limited access to high fat diet (margarine) to investigate the emotional traits of bingeing animals before and after the binge-like consumption of margarine. Using the plus maze test to disclose a potential anxious phenotype, we found that bingeing rats are much more anxious before the access to margarine, and that this condition is significantly reduced after its consumption. Conversely, no difference was detected between bingeing rats in the marble burying test before and after access to margarine. Yet, the number of marbles buried by bingeing rats before margarine consumption was significantly higher than control groups thus suggesting a compulsive-like trait. In the forced swimming test, bingeing rats showed a decrease in depression-like behavior after the consumption of margarine. Altogether, our findings demonstrate the occurrence of an altered emotional state in female rats showing binge eating behavior.

Limited Access to a High Fat Diet Alters Endocannabinoid Tone in Female Rats

Emerging evidence suggest an impaired endocannabinoid activity in the pathophysiology of binge eating disorder (BED). Herein, we investigated whether endocannabinoid tone could be modified as a consequence of dietary-induced binge eating in female rats. For this purpose, brain levels of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), as well as two endocannabinoid-like lipids, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), were assessed in different brain areas involved in the hedonic feeding (i.e., prefrontal cortex, nucleus accumbens, amygdala, hippocampus, and hypothalamus). The brain density of cannabinoid type-1 receptors (CB1) was also evaluated. Furthermore, we determined plasma levels of leptin, ghrelin, and corticosterone hormones, which are well-known to control the levels of endocannabioids and/or CB1 receptors in the brain. To induce binge eating behavior, rats were subject to an intermittent and limited access to a high fat diet (HFD) (margarine). Three experimental groups were used, all with ad libitum access to chow: control (CTRL), with no access to margarine; low restriction (LR), with 2 h margarine access 7 days/week; high restriction (HR), with 2 h margarine access 3 days/week. Bingeing was established when margarine intake in the HR group exceeded that of the LR group. Our results show that, compared to CTRL, AEA significantly decreased in the caudate putamen, amygdala, and hippocampus of HR group. In contrast, 2-AG significantly increased in the hippocampus while OEA decreased in the hypothalamus. Similar to the HR group, AEA and OEA decreased respectively in the amygdala and hypothalamus and 2-AG increased in the hippocampus of LR group. Moreover, LR group also had AEA decreased in the prefrontal cortex and increased in the nucleus accumbens. In both groups we found the same reduction of CB1 receptor density in the prefrontal cortex compared to CTRL. Also, LR and HR groups showed alterations in both ghrelin and corticosterone levels, while leptin remained unaltered. In conclusion, our findings show a modified endocannabinoid tone due to margarine exposure, in several brain areas that are known to influence the hedonic aspect of food. Even if not uniquely specific to binge eating, margarine-induced changes in endocannabinoid tone could contributes to the development and maintenance of this behavior.

Cannabinoid CB1/CB2 receptor agonists attenuate hyperactivity and body weight loss in a rat model of activity‐based anorexia

Anorexia nervosa (AN) is a serious psychiatric condition characterized by excessive body weight loss and disturbed perceptions of body shape and size, often associated with excessive physical activity. There is currently no effective drug‐related therapy of this disease and this leads to high relapse rate. Clinical data suggest that a promising therapy to treat and reduce reoccurrence of AN may be based on the use of drugs that target the endocannabinoid (EC) system, which appears dysregulated in AN patients.

The endocannabinoid system: Anorexia nervosa and binge eating disorder

Eating disorders (EDs) include a range of chronic and disabling related psychiatric pathologies characterized by aberrant eating patterns or weight-control behavior and distorted body image. The etiology of EDs is complex and not yet completely understood. The endocannabinoid system has been widely reported to be involved in the regulation of feeding and energy balance, and cannabinoid type-1 receptors (CB1Rs) are expressed in many brain regions that control food intake. Animal and human studies indicate that CB1R agonists possess orexigenic effects enhancing appetite and increasing the perceived reward value of food. Conversely, CB1R antagonists have been shown to inhibit food intake. Previous clinical and preclinical evidence has led us to hypothesize a link between defects in the endocannabinoid system and EDs and supports the development of drugs that modulate this system in ED-related pathologies.

Cannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders

Graphical abstract Figure. No Caption available. ABSTRACT The endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases. In the context of brain genetic or acquired encephalopathies administration of cannabinoid‐based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds. This review article summarizes the main evidences indicating the beneficial action of cannabinoid‐derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long‐term neural cell plasticity.

Brain activity of anandamide: a rewarding bliss?

Anandamide is a lipid mediator that acts as an endogenous ligand of CB1 receptors. These receptors are also the primary molecular target responsible for the pharmacological effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient in Cannabis sativa. Several studies demonstrate that anandamide exerts an overall modulatory effect on the brain reward circuitry. Several reports suggest its involvement in the addiction-producing actions of other abused drugs, and it can also act as a behavioral reinforcer in animal models of drug abuse. Importantly, all these effects of anandamide appear to be potentiated by pharmacological inhibition of its metabolic degradation. Enhanced brain levels of anandamide after treatment with inhibitors of fatty acid amide hydrolase, the main enzyme responsible for its degradation, seem to affect the rewarding and reinforcing actions of many drugs of abuse. In this review, we will provide an overview from a preclinical perspective of the current state of knowledge regarding the behavioral pharmacology of anandamide, with a particular emphasis on its motivational/reinforcing properties. We will also discuss how modulation of anandamide levels through inhibition of enzymatic metabolic pathways could provide a basis for developing new pharmaco-therapeutic tools for the treatment of substance use disorders.