leptin and 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

A high consumption of fructose leads not only to peripheral changes in insulin sensitivity and vascular function, but also to central changes in several brain regions. Given the role of the endogenous cannabinoid system in the control of energy intake, we undertook a pilot study to determine whether a high fructose diet produced changes in brain CB1 receptor functionality.. Male rats given access ad libitum to normal chow were given either water, glucose or fructose solutions to drink. CB1 receptor functionality was measured autoradiographically as the increase in [(35)S]GTPγS binding produced by the agonist CP55,940.. Seven regions were investigated: the prefrontal cortex, caudate-putamen, hippocampal CA1-CA3, dentate gyrus, amygdala, and dorsomedial and ventromedial hypothalami. Two-way robust Wilcoxon analyses for each brain region indicated that the dietary treatment did not produce significant main effects upon agonist-stimulated [(35)S]GTPγS binding in any of the regions, in contrast to a significant main effect upon both leptin and adiponectin levels in the blood. However, a MANCOVA of the data controlling for leptin and adiponectin as co-variables identified a significant effect of glucose and fructose treatment for five weeks upon the [(35)S]GTPγS response in the ventromedial hypothalamus, a region of importance for regulation of appetite.. It is concluded from this pilot study that palatable solutions do not produce overt changes in brain CB1 receptor functionality, although subtle changes in discrete brain regions may occur.

Topics: Adiponectin; Analysis of Variance; Animals; Autoradiography; Brain; Cyclohexanols; Dietary Carbohydrates; Fructose; Glucose; Guanosine 5'-O-(3-Thiotriphosphate); Leptin; Male; Pilot Projects; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Statistics, Nonparametric

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.

Topics: Adrenocorticotropic Hormone; Analgesics; Animals; Arousal; Attention; Behavior, Animal; Body Weight; Cannabinoids; Cyclohexanols; Exploratory Behavior; Female; Hypothalamo-Hypophyseal System; Inhibition, Psychological; Injections, Intraperitoneal; Leptin; Male; Maternal Deprivation; Maze Learning; Motor Activity; Organ Size; Pituitary-Adrenal System; Rats; Rats, Wistar; Risk-Taking; Sensory Gating; Sex Factors

Hemopressin is a short, nine amino acid peptide (H-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His-OH) isolated from rat brain that behaves as an inverse agonist at the cannabinoid receptor CB(1), and is shown here to inhibit agonist-induced receptor internalization in a heterologous cell model. Since this peptide occurs naturally in the rodent brain, we determined its effect on appetite, an established central target of cannabinoid signaling. Hemopressin dose-dependently decreases night-time food intake in normal male rats and mice, as well as in obese ob/ob male mice, when administered centrally or systemically, without causing any obvious adverse side effects. The normal, behavioral satiety sequence is maintained in male mice fasted overnight, though refeeding is attenuated. The anorectic effect is absent in CB(1) receptor null mutant male mice, and hemopressin can block CB(1) agonist-induced hyperphagia in male rats, providing strong evidence for antagonism of the CB(1) receptor in vivo. We speculate that hemopressin may act as an endogenous functional antagonist at CB(1) receptors and modulate the activity of appetite pathways in the brain.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzoxazines; Chlorocebus aethiops; Circadian Rhythm; COS Cells; Cyclohexanols; Dose-Response Relationship, Drug; Drinking Behavior; Dronabinol; Drug Administration Routes; Eating; Food Deprivation; Green Fluorescent Proteins; Hemoglobins; Hyperphagia; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Naphthalenes; Peptide Fragments; Piperidines; Protein Transport; Psychotropic Drugs; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors; Transfection

The cannabinoid CB1 receptor has been implicated in the regulation of appetite and the consumption of palatable foods. This experiment aimed to explore the involvement of the CB1 receptor in the early and late stages of high fat diet-induced obesity in C57BL/6 mice. The C57Bl/6 mice were placed on a high fat (HF) or low fat/high carbohydrate (LF) diet for 3 or 20 weeks. Quantitative autoradiography revealed that binding of [3H] CP-55,940 (CB1 receptor ligand) was elevated following 3 weeks of HF feeding in areas including the medial/ventral anterior olfactory nucleus (22.1%), agranular insular cortex (24.0%) and the hypothalamus (31.5%) compared to LF controls. This increased level of binding was correlated with an increase in plasma leptin in the hypothalamus, raising the possibility that this hormone may exert inhibitory control over endocannabinoid signalling at this stage of obesity. Mice fed a HF diet for 20 weeks were obese, hyperphagic and had decreased CB1 receptor binding levels in the substantia nigra (12.8%) and ventral tegmental area (17.1%) compared to LF controls. The low [3H] CP-55,940 binding density seen in these reward-related areas in the late stage of obesity may be indicative of increased endocannabinoid release due to the chronic HF diet consumption.

Topics: Animals; Body Weight; Brain; Cannabinoids; Cyclohexanols; Diet; Dietary Fats; Energy Intake; Humans; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Receptor, Cannabinoid, CB1