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

Endogenous cannabinoid signaling, mediated predominately by CB1 receptor activation, is involved in food intake control and body weight regulation. Despite advances in determining the role of the CB1 receptor in obesity, its involvement in the driven nature of eating pathologies has received little attention. The present study examined CB1 receptor alterations as a consequence of dietary-induced binge eating in female Sprague Dawley rats. Four control groups were used to control for calorie restriction and highly palatable food variables characterizing this behavioral model. All groups were kept on their respective feeding schedules for 6-weeks and were given a uniform 33% calorie restriction (~22 h food deprivation) prior to sacrifice. Our findings indicate that regional CB1 mRNA and density were influenced by dietary conditions, but were not specific to the dietary-induced binge eating paradigm used. An increase of approximately 50% (compared with naive controls) in CB1 receptor mRNA levels in the nucleus of the solitary tract as measured by in situ hybridization was found in animals receiving continuous access to a highly palatable food (i.e., vegetable shortening with 10% sucrose). This group also had a significant increase in body weight and adiposity. An approximate 20% reduction in CB1 mRNA was observed in the cingulate cortex (areas 1 and 2) in animals exposed to an intermittent schedule of feeding, compared with groups that had ad libitum feeding schedules (i.e., continuous access and naive controls). Receptor density as measured by [(3)H]CP55,940 autoradiography, was reduced by approximately 30% in the nucleus accumbens shell region in groups receiving repeated access to the highly palatable food. Taken together, these findings indicate that dietary conditions can differentially influence CB1 receptors in forebrain and hindbrain regions.

Topics: Analysis of Variance; Animals; Autoradiography; Body Weight; Brain; Bulimia; Cannabinoids; Cyclohexanols; Diet; Disease Models, Animal; Eating; Female; Food Deprivation; Food Preferences; Gene Expression Regulation; Genes; Nodose Ganglion; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; RNA, Messenger; Tritium

We have analysed the long-term effects of adolescent (postnatal day 28-43) exposure of male and female rats to nicotine (NIC, 1.4 mg/kg/day) and/or the cannabinoid agonist CP 55,940 (CP, 0.4 mg/kg/day) on the following parameters measured in the adulthood: (1) the memory ability evaluated in the object location task (OL) and in the novel object test (NOT); (2) the anxiety-like behaviour in the elevated plus maze; and (3) nicotinic and CB(1) cannabinoid receptors in cingulated cortex and hippocampus. In the OL, all pharmacological treatments induced significant decreases in the DI of females, whereas no significant effects were found among males. In the NOT, NIC-treated females showed a significantly reduced DI, whereas the effect of the cannabinoid agonist (a decrease in the DI) was only significant in males. The anxiety-related behaviour was not changed by any drug. Both, nicotine and cannabinoid treatments induced a long-lasting increase in CB(1) receptor activity (CP-stimulated GTPγS binding) in male rats, and the nicotine treatment also induced a decrease in nicotinic receptor density in the prefrontal cortex of females. The results show gender-dependent harmful effects of both drugs and long-lasting changes in CB(1) and nicotinic receptors.

Topics: Animals; Autoradiography; Body Weight; Brain; Cyclohexanols; Female; Male; Maze Learning; Memory Disorders; Nicotine; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Nicotinic; Sex Characteristics

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

In this study, we report that α,β-amyrin, a plant-derived pentacyclic triterpene, reduced persistent inflammatory and neuropathic hyperalgesia in mice by a direct activation of the CB(1) and CB(2) cannabinoid receptors (CB(1)R and CB(2)R). The oral treatment with α,β-amyrin (30 mg/kg) significantly reduced mechanical and thermal hyperalgesia and inflammation induced by complete Freund's adjuvant (CFA) and by partial sciatic nerve ligation (PSNL). The pretreatment with either CB(1)R or CB(2)R antagonists and the knockdown gene of the receptors significantly reverted the antinociceptive effect of α,β-amyrin. Of note, binding studies showed that α,β-amyrin directly bound with very high affinity to CB(1)R (K(i)=0.133 nM) and with a lower affinity to CB(2)R (K(i)=1989 nM). Interestingly, α,β-amyrin, ACEA (CB(1)R agonist), or JWH-133 (CB(2)R agonist), at doses that caused antinociception, failed to provoke any behavioral disturbance, as measured in the tetrad assay. In addition, α,β-amyrin largely decreased interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), keratinocyte-derived chemokine (KC) and interleukin 6 (IL-6) levels, and myeloperoxidase activity. Likewise, α,β-amyrin prevented the activation of the transcriptional factors: nuclear factor κB (NF-κB) and cyclic adenosine monophosphate response element binding (CREB) and the expression of cyclooxygenase 2 in mice footpads and spinal cords. The present results demonstrated that α,β-amyrin exhibits long-lasting antinociceptive and anti-inflammatory properties in 2 models of persistent nociception via activation of cannabinoid receptors and by inhibiting the production of cytokines and expression of NF-κB, CREB and cyclooxygenase 2.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Area Under Curve; Body Weight; Cyclohexanols; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Edema; Enzyme-Linked Immunosorbent Assay; Freezing Reaction, Cataleptic; Hyperalgesia; Inflammation; Locomotion; Male; Mice; Neuralgia; Oleanolic Acid; Oligodeoxyribonucleotides, Antisense; Pain Threshold; Pentacyclic Triterpenes; Peroxidase; Protein Binding; Rats; Rats, Wistar; Receptors, Cannabinoid; Tritium

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.

Topics: Amides; Analysis of Variance; Animals; Autoradiography; Benzoxazines; Body Weight; Brain; Cyclohexanols; Diet Fads; Disease Models, Animal; Eating; Female; Guanosine 5'-O-(3-Thiotriphosphate); International Cooperation; Morpholines; Naphthalenes; Obesity; Piperidines; Protein Binding; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Sulfur Isotopes; Time Factors; Tomography Scanners, X-Ray Computed; Tritium; Whole Body Imaging

The short- and long-term behavioral effects of cannabinoids differ in adolescent and adult rodents. Few studies though have examined the underlying neurochemical changes that occur in the brain following adolescent cannabinoid exposure. In this study, we examined the effect of treatment with the synthetic cannabinoid, HU210, on CB1 receptor density in the brain and on body weight in adolescent male rats. Rats were treated daily with 25, 50, or 100 μg/kg HU210 for 4 or 14 days, or received a single dose of 100 μg/kg HU210 and sacrificed 24 h later. Receptor density was investigated using in vitro autoradiography with the CB1 receptor ligand [(3)H] CP55,940. In contrast to adult animals treated under the same paradigm in a previous study, adolescents continued on average, to gain weight over the course of the study. Weight gain was slowest in the 100 μg/kg group and improved dose dependently with controls gaining the most weight. Following the acute dose of HU210, a trend for a reduction in [(3)H] CP55,940 binding and a significant effect of treatment was observed. Statistically significant, dose-dependent, region-specific decreases in binding were observed in all brain regions examined following 4 and 14 days treatment. The pattern of CB1 receptor downregulation was similar to that observed in adults treated with cannabinoids in previous studies; however, its magnitude was smaller in adolescents. This reduced compensatory response may contribute to some acute behavioral effects, the pharmacological cross-tolerance and the long-lasting, adverse psychological consequences of cannabinoid exposure during adolescence.

Topics: Age Factors; Analgesics; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Brain; Brain Mapping; Cannabinoids; Cyclohexanols; Dose-Response Relationship, Drug; Dronabinol; Male; Protein Binding; Radioligand Assay; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Tissue Distribution; Tritium

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

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.

Topics: Animals; Anti-Obesity Agents; Benzodioxoles; Body Weight; Crystallography, X-Ray; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Humans; Hypothermia; Ligands; Male; Mice; Microsomes; Models, Molecular; Molecular Structure; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Structure-Activity Relationship

Since endocannabinoids modulate reward processing and the stress response, we tested the hypothesis that endocannabinoids regulate stress-induced decreased sensitivity to natural reward. Restraint was used to produce stress-induced reductions in sucrose consumption and preference in male mice. Central cannabinoid receptor (CB(1)) signaling was modulated pharmacologically prior to the application of stress. The preference for sucrose over water was significantly decreased in mice exposed to restraint. Treatment of mice with a cannabinoid receptor agonist (CP55940) or fatty acid amide hydrolase inhibitor (URB597) attenuated, while the CB(1) receptor antagonist/inverse agonist, rimonabant (SR141716), enhanced, stress-induced decreases in sucrose preference. These data are consistent with a tonically active, stress-inhibitory role for the CB(1) receptor. Mice treated with 10 daily episodes of restraint showed reduced sucrose preference that was unaffected by CP55940 and URB597. However, rimonabant produced a greater reduction in sucrose preference on day 10 compared to day 1. These data suggest that on day 10, endocannabinoid signaling is maximally activated and essential for reward sensitivity. The findings of the present study indicate that the CB(1)/endocannabinoid signaling system is an important allostatic mediator that both modulates the responses of mice to stress and is itself modulated by stress.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzamides; Body Weight; Cannabinoid Receptor Modulators; Carbamates; Cyclohexanes; Cyclohexanols; Dose-Response Relationship, Drug; Drinking Behavior; Drug Interactions; Endocannabinoids; Food Deprivation; Food Preferences; Male; Mice; Mice, Inbred ICR; Phenols; Piperidines; Pyrazoles; Restraint, Physical; Reward; Rimonabant; Stress, Psychological; Sucrose; Time Factors; Water Deprivation

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.

Topics: Amides; Animals; Anti-Obesity Agents; Binding, Competitive; Body Temperature; Body Weight; CHO Cells; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; Cyclohexanols; Dose-Response Relationship, Drug; Eating; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Obesity; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Transfection

Despite the increasing use of cannabis among adolescents, there is scarce information about the long-term effects of cannabinoid receptor agonists in appropriate animal models.. We aimed to investigate the behavioural features of adult male and female Wistar rats that had been exposed to a chronic treatment with the cannabinoid receptor agonist CP 55,940 (CP) during the juvenile period.. CP (0.4 mg/kg i.p.) or its corresponding vehicle was administered once daily, from day 35 to day 45. In adulthood, the animals were tested in the holeboard, the open field and the elevated plus-maze, under different stress (illumination) conditions. After a resting period, the serum corticosterone levels (radioimmunoassay) of the animals were measured. The effects of CP on food intake and somatic growth were monitored throughout the experimental period.. The CP treatment induced significant sex-dependent effects on holeboard activity, as well as a decrease in the level of emotionality/anxiety in the open field and in the plus-maze. The animals receiving CP also showed diminished food intake and body weights during the treatment period, but both parameters recovered normal values during the period after treatment. No significant effect of the CP treatment on corticosterone levels was found.. The results demonstrate that chronic administration of CP during the peri-adolescent period resulted in marked behavioural effects in adulthood. The nature of these effects depended on the sex of the animals and on the specific behavioural test. The possible neurobiological substrates underlying the effects of CP are discussed.

Topics: Analgesics; Analysis of Variance; Animals; Body Weight; Corticosterone; Cyclohexanols; Eating; Female; Growth; Male; Maze Learning; Motor Activity; Rats; Rats, Wistar; Sex Factors; Time Factors