piperidines and Hyperphagia

Cannabidiol, a cannabinoid and serotonin receptor antagonist, may alleviate hyperphagia without the side effects of rimonabant (for example depression and reduced insulin sensitivity). Similar to the peroxisome proliferator-activated receptor-gamma agonists, it may also help the differentation of adipocytes. Cannabidiol has an immunomodulating effect, as well, that helps lessen the progression of atherosclerosis induced by high glucose level. It may also be effective in fighting ischaemic diseases, the most harmful complications of metabolic syndrome. However, it can only be administered as an adjuvant therapy because of its low binding potency, and its inhibiting effect of cytochrome P450 enzymes should also be considered. Nevertheless, it may be beneficially used in adjuvant therapy because of its few side effects.

Topics: Adipocytes; Appetite Depressants; Atherosclerosis; Cannabidiol; Cannabinoid Receptor Antagonists; Disease Progression; Humans; Hyperphagia; Ischemia; Metabolic Syndrome; Obesity; Piperidines; PPAR gamma; Pyrazoles; Rimonabant

Dysregulation of the endocannabinoid system can lead to the development of obesity and metabolic disorders. Endogenous endocannabinoids act on two cannabinoid receptor subtypes, type 1 (CB1) and type 2 (CB2), to exert their biological actions. The aim of this study was to determine whether CB1 and CB2 receptors modulate feeding behavior.. We investigated the different roles of CB1 and CB2 receptors in spontaneous and centrally administered splice variants of ghrelin, O-n-octanoylated ghrelin and des-Gln(14)-ghrelin, stimulation of food intake in conscious rats.. Intraperitoneal (IP) injection of different doses of selective CB2 receptor antagonist AM-630 (0.3, 1, and 3 mg/kg) enhanced cumulative food intake during the first 12 h with a dome-shaped dose-response relationship in freely fed rats, with the most effective dose being 1 mg/kg. In comparison, the selective CB1 receptor antagonist AM-251 (0.3, 1, and 3 mg/kg, IP) dose-dependently suppressed the cumulative food intake in 16-h food-deprived rats. Centrally administered O-n-octanoylated ghrelin and des-Gln(14)-ghrelin-induced hyperphagic effects were counteracted dose-dependently by IP AM-251, but not AM-630.. We demonstrated that the endogenous CB2 receptor plays a role in inhibiting food intake in the satiated state, whereas the CB1 receptor promotes food intake in the fasted condition. The induction of feeding by central acyl ghrelin is a CB1 receptor-dependent mechanism. Differentially nibbling CB1 and CB2 receptor subtypes may provide a new avenue to treating eating and metabolic disorders.

Topics: Animals; Eating; Endocannabinoids; Fasting; Ghrelin; Hyperphagia; Indoles; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Over the past decade, pharmacological manipulation of cannabinoid 1 receptor (CB1R) has become an interesting approach for the management of food ingestion disorders, among other physiological functions. Searching for new substances with similar desirable effects, but fewer side-effects we have synthesized a SR141716A (a cannabinoid receptor inverse agonist also called Rimonabant) analog, 1-(2,4-Difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, ENP11, that so far, as we have previously shown, has induced changes in glucose availability, i.e. hypoglycemia, in rats. In this study we tested the effects, if any, of ENP11 (0.5, 1.0, and 3.0mg/kg) in food ingestion, core temperature, pain perception and motor control in adult Wistar rats. Results showed that ENP11 reduced food ingestion during the first hour immediately after administration. Likewise, ENP11 (1.0mg/kg) blocked anandamide (AEA)-induced hyperphagia during the first 4h of the dark phase of the light-dark cycle, and it also blocked AEA-induced hypothermia. However, none of the ENP11 doses used affected pain perception or motor control. We believe that ENP11 is a potential useful CB1R antagonist that reduces food ingestion and regulates core temperature.

Topics: Animals; Appetite Depressants; Arachidonic Acids; Body Temperature; Body Weight; Cannabinoid Receptor Antagonists; Eating; Endocannabinoids; Feeding Behavior; Hyperphagia; Male; Pain; Pain Perception; Piperidines; Polyunsaturated Alkamides; Postural Balance; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Cannabinoid receptor type 1 (CB1)-dependent signaling in the brain is known to modulate food intake. Recent evidence has actually shown that CB1 can both inhibit and stimulate food intake in fasting/refeeding conditions, depending on the specific neuronal circuits involved. However, the exact brain sites where this bimodal control is exerted and the underlying neurobiological mechanisms are not fully understood yet. Using pharmacological and electrophysiological approaches, we show that local CB1 blockade in the paraventricular nucleus of the hypothalamus (PVN) increases fasting-induced hyperphagia in rats. Furthermore, local CB1 blockade in the PVN also increases the orexigenic effect of the gut hormone ghrelin in animals fed ad libitum. At the electrophysiological level, CB1 blockade in slices containing the PVN potentiates the decrease of the activity of PVN neurons induced by long-term application of ghrelin. Hence, the PVN is (one of) the site(s) where signals associated with the body's energy status determine the direction of the effects of endocannabinoid signaling on food intake.

Topics: Animals; Cannabinoid Receptor Antagonists; Ghrelin; Hyperphagia; Male; Membrane Potentials; Neurons; Paraventricular Hypothalamic Nucleus; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for their acute and chronic responses to anorexic substances related to the ghrelin pathway. In comparison with their wild-type littermates, the food intake rate of Snord116del mice was 14% higher when fed ad libitum, and 32% to 49% higher within 12 hours after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive antagonist [d-Lys(3)]-GHRP6, YIL-781, and reverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P (SPA) of ghrelin receptor GHS-R. All 3 GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-type mice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acute anorexic effect of glucagon-like peptide 1 receptor agonist exenatide, those fed ad libitum required a higher dose and more frequent delivery to achieve ∼15% suppression of long-term food intake in comparison with wild-type mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fed mice, as shown by the fact that exenatide did not reduce ghrelin levels in fed mice and food intake of ghrelin(-/-) mice fed ad libitum could be suppressed by exenatide. In conclusion, this study suggests that GHS-R may not be an effective therapeutic target, and in contrast, exenatide may produce anorexic effect in PWS individuals.

Topics: Analysis of Variance; Animals; Anorexia; Disease Models, Animal; Eating; Exenatide; Fasting; Ghrelin; Humans; Hyperphagia; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Peptides; Piperidines; Prader-Willi Syndrome; Quinazolinones; Receptors, Ghrelin; RNA, Small Nucleolar; Substance P; Venoms

BACKGROUND AND PURPOSE Endocannabinoid systems are strongly implicated in the physiological control of appetite and eating behaviour, with cannabinoid CB(1) receptor agonists and antagonists, respectively, increasing or decreasing food intake. This study examined the acute actions of the putative endocannabinoid noladin ether on food intake and eating motivation, assessing how it affects the amount of work expended by animals to obtain food. EXPERIMENTAL APPROACH Non-deprived male rats were injected systemically with noladin ether to assess its acute effects on ad libitum feeding of a standard laboratory diet. Additionally, the effects of noladin on lever pressing for palatable food were determined using a progressive ratio (PR) operant paradigm. KEY RESULTS Noladin dose dependently increased 2 h food intake, with a significant effect over 1 h after a dose of 0.5 mg·kg(-1). In the PR test, this hyperphagic dose of noladin ether promoted sustained high rates of responding and significantly increased the total number of lever presses and break-point. These latter effects were prevented by pretreatment with 1.0 mg·kg(-1) of the selective CB(1) antagonist surinabant (SR147778), that alone had no effect on responding. CONCLUSIONS AND IMPLICATIONS This is the first report of hyperphagia induced by acute noladin administration, and the first description of behavioural actions in rats. Consistent with prevailing notions about the role of endocannabinoids in appetite, a hyperphagic dose of noladin markedly increased efforts expended by animals to obtain food. Thus, noladin exerts a specific action on eating motivation; possibly promoting eating by increasing the incentive value of food.

Topics: Animals; Behavior, Animal; Cannabinoid Receptor Modulators; Eating; Endocannabinoids; Glycerides; Hyperphagia; Male; Motivation; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1

Stimulation of cannabinoid CB(1) receptors in nucleus accumbens shell has been shown to stimulate feeding and enhance positive 'liking' reactions to intraoral sucrose. This study examined the behavioural effects of noladin ether and 2-arachidonoylglycerol following infusion into accumbens shell, on chow intake and food preference in high-carbohydrate and high-fat preferring rats. Noladin ether, potently and dose-dependently stimulated chow intake as compared with 2-arachidonoylglycerol in free-feeding rats. In the diet preference paradigm, in which rats were given free access to both, high-carbohydrate (HC) and high-fat (HF) diets simultaneously, an intra-accumbens administration of noladin ether as well as 2-arachidonoylglycerol, preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. These effects were significantly attenuated by the CB(1) receptor antagonist, AM 251. These results suggesting that, the endocannabinoids through CB(1) receptors, affects appetite for specific dietary components. Both these agents exert a specific action on eating motivation and possibly promoting eating by enhancing the incentive value of food. Altogether these findings reinforce the idea that the endogenous cannabinoid system in the accumbens shell may be important to augment reward-driven feeding via modulation of CB(1) receptor signalling pathways.

Topics: Animals; Appetite; Arachidonic Acids; Cannabinoid Receptor Modulators; Diet; Diet, High-Fat; Dietary Carbohydrates; Eating; Endocannabinoids; Food Preferences; Glycerides; Hyperphagia; Male; Nucleus Accumbens; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sucrose

G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.

Topics: Adiposity; AMP-Activated Protein Kinases; Animals; Diet; Dyslipidemias; Energy Metabolism; Enzyme Activation; Gene Silencing; Gene Targeting; Glucose Intolerance; Hyperinsulinism; Hyperphagia; Hypothalamus; Mice; Mice, Inbred C57BL; Obesity; Phosphorylation; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Rimonabant; Weight Loss

The cannabinoid receptor 1 (CB(1)R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB(1)R that regulate these physiological functions are unknown. CB(1)R is widely expressed, including in neurons of the parasympathetic branches of the autonomic nervous system. The vagus nerve has been implicated in the regulation of several aspects of metabolism and energy balance (e.g., food intake and glucose balance), and gastrointestinal functions including motility. To directly test the relevance of CB(1)R in neurons of the vagus nerve on metabolic homeostasis and gastrointestinal motility, we generated and characterized mice lacking CB(1)R in afferent and efferent branches of the vagus nerve (Cnr1(flox/flox); Phox2b-Cre mice). On a chow or on a high-fat diet, Cnr1(flox/flox); Phox2b-Cre mice have similar body weight, food intake, energy expenditure, and glycemia compared with Cnr1(flox/flox) control mice. Also, fasting-induced hyperphagia and after acute or chronic pharmacological treatment with SR141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] (CB(1)R inverse agonist) paradigms, mutants display normal body weight and food intake. Interestingly, Cnr1(flox/flox); Phox2b-Cre mice have increased gastrointestinal motility compared with controls. These results unveil CB(1)R in the vagus nerve as a key component underlying normal gastrointestinal motility.

Topics: Animals; Body Weight; Diet, High-Fat; Eating; Food Deprivation; Gastrointestinal Motility; Homeostasis; Hyperphagia; Mice; Mice, Transgenic; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Vagus Nerve

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 central nervous system control of food intake has been extensively studied, hence, several neurotransmitter systems regulating this function are now clearly identified, for example, the endocannabinoid and serotoninergic systems. The former stimulates feeding while the latter inhibits it. Oleamide (Ole) is a cannabimimetic molecule affecting both systems. In this work, we tested the orexigenic and anorectic potential of Ole when administered into the nucleus accumbens shell (NAcS), a brain region that has been related to the orexigenic effects of cannabinoids. Additionally, we tested if Ole administered into this nucleus affects the activity of the hypothalamic nuclei involved in feeding behaviour, just as other cannabinoids do. We found a hyperphagic effect of Ole that is mediated through CB1 activation. The combination of Ole and the CB1 antagonist, AM251, produced a hypophagia that was fully blocked by SB212084, a 5-HT2C receptor antagonist. We also show that blockade of 5-HT2C and 5-HT2A receptors in the NAcS stimulates food intake. Finally, the combination of Ole and AM251 activates hypothalamic nuclei, an effect also blocked by SB242084. In conclusion, we show, for the first time, that Ole administered into the NAcS has a dual effect on feeding behaviour, acting through cannabinoid and serotonin receptors. These effects probably result from a downstream interaction with the hypothalamus.

Topics: Aminopyridines; Animals; Eating; Feeding Behavior; Hyperphagia; Hypothalamus; Indoles; Ketanserin; Male; Motor Activity; Nucleus Accumbens; Oleic Acids; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin 5-HT2 Receptor Antagonists

Endocannabinoids have a variety of effects by acting through cannabinoid 1 (CB1) receptors located throughout the brain. However, since CB1 receptors are located presynaptically, and because the strength of downstream coupling varies with brain region, expression studies alone do not provide a firm basis for interpreting sites of action. Likewise, to date most functional studies have used high doses of drugs, which can bias results toward non-relevant adverse effects, and which mask more behaviourally-relevant actions. Here we use a low, orexigenic dose of the full CB1 agonist, CP55940, to map responsive brain regions using the complementary techniques of pharmacological-challenge functional magnetic resonance imaging (phMRI) and immediate-early gene activity. Areas of interest demonstrate a drug interaction when the CB1 receptor inverse agonist, rimonabant, is co-administered. This analysis highlights the corticostriatal-hypothalamic pathway, which is central to the motivational drive to eat.

Topics: Animals; Brain; Brain Mapping; Cannabinoids; Central Nervous System Agents; Cyclohexanols; Drug Interactions; Eating; Genes, Immediate-Early; Hyperphagia; Immunohistochemistry; Magnetic Resonance Imaging; Male; Oxygen; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant

Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.

Topics: Age Factors; Animals; Appetite Depressants; Body Composition; Dietary Fats; Energy Intake; Hyperphagia; Ion Channels; Leptin; Male; Mitochondrial Proteins; Obesity; Piperidines; Pyrazoles; Rats; Rats, Inbred F344; Receptor, Cannabinoid, CB1; STAT3 Transcription Factor; Uncoupling Protein 1; Weight Gain

Leptin receptor dysfunction results in overeating and obesity. Leptin regulates hypothalamic signaling that underlies the motivation to hyperphagia, but the interaction between leptin and cannabinoid signaling is poorly understood. We evaluated the role of cannabinoid 1 receptors (CB(1)R) in overeating and the effects of food deprivation on CB(1)R in the brain. One-month-old Zucker rats were divided into unrestricted and restricted (fed 70% of unrestricted rats) diet groups and maintained until adulthood (4 months). Levels of relative binding sites of CB(1)R (CB(1)R binding levels) were assessed using [(3)H] SR141716A in vitro autoradiography. These levels were higher (except cerebellum and hypothalamus) at 4 months than at 1 month of age. One month CB(1)R binding levels for most brain regions did not differ between Ob and Lean (Le) rats (except in frontal and cingulate cortices in Le and in the hypothalamus in Ob). Four month Ob rats had higher CB(1)R binding levels than Le in most brain regions and food restriction was associated with higher CB(1)R levels in all brain regions in Ob, but not in Le rats. CB(1)R binding levels increased between adolescence and young adulthood which we believe was influenced by leptin and food availability. The high levels of CB(1)R in Ob rats suggest that leptin's inhibition of food-intake is in part mediated by downregulation of CB(1)R and that leptin interferes with CB(1)R upregulation under food-deprivation conditions. These results are consistent with prior findings showing increased levels of endogenous cannabinoids in the Ob rats corroborating the regulation of cannabinoid signaling by leptin.

Topics: Age Factors; Animals; Autoradiography; Body Weight; Cannabinoid Receptor Modulators; Eating; Food Deprivation; Hyperphagia; Leptin; Limbic System; Male; Obesity; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Receptors, Leptin; Rimonabant; Tritium; Up-Regulation

Despite the well-established role of histamine as an anorexigenic neurotransmitter, the role of histamine H(3) receptors in feeding behavior is controversial. Herein we investigated the role of histamine H(3) receptor on several orexigenic agents in mice. Thioperamide (histamine H(3) receptor inverse agonist) inhibited neuropeptide Y- and nociceptin-induced hyperphagia but had no effect on U-50488 (opioid kappa-receptor agonist)-induced hyperphagia. In contrast, imetit (histamine H(3) receptor agonist) inhibited U-50488-induced hyperphagia but augmented neuropeptide Y-induced hyperphagia while it did not alter nociceptin-induced hyperphagia. These results indicate distinctive roles of histamine H(3) receptors in various orexigenic pathways.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Appetite; Histamine Agonists; Histamine H3 Antagonists; Hyperphagia; Imidazoles; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Nociceptin; Opioid Peptides; Piperidines; Receptors, Histamine H3; Thiourea

We tested the hypothesis that cannabinoids modulate feeding in male guinea pigs, and correlated cannabinoid-induced changes in feeding behavior with alterations in glutamatergic synaptic currents impinging upon proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus. Feeding experiments were performed as follows: after a three-day acclimation period, animals were weighed and injected with either the CB1 receptor agonist WIN 55,212-2 (1 mg/kg, s.c.), antagonist AM251 (3 mg/kg, s.c.) or their cremophore/ethanol/saline vehicle (1:1:18; 1 ml/kg, s.c.) each day for seven days. WIN 55,212-2 increased, whereas AM251 decreased, the rate of cumulative food intake. The agonist effect was manifest primarily by increases in meal frequency and the amount of food eaten per meal. By contrast, the antagonist effect was associated with decreases in meal frequency, duration and weight loss. For the electrophysiological experiments, we performed whole-cell patch-clamp recordings from POMC neurons in hypothalamic slices. WIN 55,212-2 decreased the amplitude of evoked, glutamatergic excitatory postsynaptic currents (eEPSCs) and increased the S2:S1 ratio. Conversely, AM251 increased eEPSC amplitude per se, and blocked the inhibitory effects of the agonist. WIN 55,212-2 also decreased miniature EPSC (mEPSC) frequency; whereas AM251 increased mEPSC frequency per se, and again blocked the inhibitory effect of the agonist. A subpopulation of cells exhibited an agonist-induced outward current, which was blocked by AM251, associated with increased conductance and reversed polarity near the Nernst equilibrium potential for K(+). These data demonstrate that cannabinoids regulate appetite in the guinea pig in part through both presynaptic and postsynaptic actions on anorexigenic POMC neurons.

Topics: Analgesics; Analysis of Variance; Animals; Behavior, Animal; Benzoxazines; Body Weight; Cannabinoids; Dose-Response Relationship, Drug; Drug Interactions; Eating; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Agents; Guinea Pigs; Hyperphagia; Hypothalamus; In Vitro Techniques; Male; Morpholines; Naphthalenes; Neural Inhibition; Neurons; Piperidines; Pro-Opiomelanocortin; Pyrazoles; Statistics as Topic

This study examined effects of the CB1 receptor antagonist/inverse agonist SR-141716 and the CB1 receptor agonist delta9-tetrahydrocannabinol (delta9-THC) on feeding behavior in male Sprague-Dawley rats. Rats were housed individually with free access to regular pelletized laboratory chow [after a 2 weeks handling phase, animals had access to regular chow for 21 h (Study 1) or 22 h (Study 2); high-fat powder food for 3 h in Study 1 and 2 h in Study 2, respectively], and free access to water. Animals were maintained on a reversed 12-h light/dark cycle (dark beginning at noon). Rats were habituated to this type of feeding and light/dark schedule for 3 weeks until a stable baseline for food intake was achieved. In Study 1, animals were examined after administration of delta9-THC alone (dose range 0.1-1.8 mg/kg), SR-141716 alone (dose range 0.03-0.3 mg/kg), and the two drugs combined; injections were given i.p. at the beginning of the second hour after presenting the high-fat diet and drugs were given twice weekly. There was a dose-related increase in high-fat diet intake, peaking at 0.56-1 mg/kg delta9-THC. SR-141716 alone suppressed the high-fat diet intake below control levels. A combination of 0.3 mg/kg SR-141716 and 0.56 mg/kg delta9-THC counteracted the effects on consumption of either drug alone. In Study 2, experimental rats were treated initially with 0.56 mg/kg delta9-THC for six consecutive days; controls received vehicle. Attenuation of the hyperphagia (high-fat diet) was evident after the second injection. Increasing doses of delta9-THC (1 and 1.8 mg/kg, for two and three consecutive days, respectively) did not reinstate the initial hyperphagia. In conclusion, low-to-moderate doses of delta9-THC produced hyperphagia (to a high-fat food source), which was antagonized by SR-141716. SR-141716 singly suppressed intake of the high-fat diet. Delta9-THC-induced hyperphagia dissipated rapidly upon chronic treatment; however, it is unclear whether this reflects pharmacological tolerance or the emergence of a conditioned taste aversion in Study 2.

Topics: Analysis of Variance; Animals; Body Weight; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Drug Tolerance; Eating; Feeding Behavior; Hyperphagia; Male; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Time Factors

Considerable interplay exists between the brain's opioid and cannabinoid systems. These systems are both involved in the control of appetite and research supports the notion that the opioid system modulates the role of the cannabinoid system on appetite. However, the ability of the cannabinoid system to modulate the opioid system's control over appetite has not been well studied.. The present study examined the role of cannabinoid CB(1) receptors in the control of opioid-induced feeding, and sought to identify specific brain regions underlying this role.. After being habituated to the test environment and injection procedure, sated rats were injected with the cannabinoid CB(1) receptor antagonist SR 141716 (0.03-3.0 mg/kg, IP). Thirty minutes later, morphine or its vehicle were administered systemically (2.5 mg/kg SC, experiments 1 and 2) or intracranially into the nucleus accumbens (nAcc, experiment 3) or paraventricular nucleus of the hypothalamus (PVN, experiment 4). Food intake and locomotor activity was then recorded for 120 min.. A significant increase in food intake was observed following systemic and intracranial (10 nmol) application of morphine in all experiments. SR 141716 suppressed systemic and intra-PVN morphine induced feeding (experiments 2 and 4), but did not attenuate food intake induced by intra-nAcc application of morphine (experiment 3).. Because SR 141716 had no effect on intra-nAcc morphine-stimulated feeding, it would appear that cannabinoid receptors do not modify opioid-mediated hedonic responses to food. Rather, we conclude that cannabinoid CB(1) receptor blockade may suppress opioid-induced feeding by stimulating the release of satiety-related peptides within the hypothalamus. Further, because SR 141716 did not block morphine induced locomotor activity, the observed effects on feeding do not appear to be due to a non-specific reduction in motivated behaviour.

Topics: Animals; Appetite Depressants; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Feeding Behavior; Hyperphagia; Injections; Male; Morphine; Motor Activity; Narcotics; Paraventricular Hypothalamic Nucleus; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Opioid; Rimonabant; Stereotaxic Techniques

Recent studies suggest that the endocannabinoid system modulates feeding. Despite the existence of central mechanisms for the regulation of food intake by endocannabinoids, evidence indicates that peripheral mechanisms may also exist. To test this hypothesis, we investigated (1) the effects of feeding on intestinal anandamide accumulation; (2) the effects of central (intracerebroventricular) and peripheral (intraperitoneal) administration of the endocannabinoid agonist anandamide, the synthetic cannabinoid agonist R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone monomethanesulfonate (WIN55,212-2), and the CB1-selective antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716A) on food intake in rats; and (3) the effects of sensory deafferentation on the modulation of feeding by cannabinoids. Food deprivation produced a sevenfold increase in anandamide content in the small intestine but not in the brain or stomach. Refeeding normalized intestinal anandamide levels. Peripheral but not central administration of anandamide or WIN55,212-2 promoted hyperphagia in partially satiated rats. Similarly, peripheral but not central administration of SR141716A reduced food intake. Capsaicin deafferentation abolished the peripheral effects of both cannabinoid agonists and antagonists, suggesting that these agents modulate food intake by acting on CB1 receptors located on capsaicin-sensitive sensory terminals. Oleoylethanolamide, a noncannabinoid fatty ethanolamide that acts peripherally, prevented hyperphagia induced by the endogenous cannabinoid anandamide. Pretreatment with SR141716A enhanced the inhibition of feeding induced by intraperitoneal administration of oleoylethanolamide. The results reveal an unexpected role for peripheral CB1 receptors in the regulation of feeding.

Topics: Animals; Appetite Regulation; Arachidonic Acids; Behavior, Animal; Benzoxazines; Brain; Cannabinoid Receptor Modulators; Capsaicin; Denervation; Dose-Response Relationship, Drug; Drug Synergism; Eating; Endocannabinoids; Feeding Behavior; Gastric Mucosa; Hyperphagia; Injections, Intraperitoneal; Injections, Intraventricular; Intestine, Small; Male; Morpholines; Naphthalenes; Oleic Acid; Oleic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Satiety Response

Feeding induced in rats by cerebroventricular (i.c.v.) injection of orphanin FQ was potently and dose-dependently reversed by peripheral injection of either the opioid antagonist naloxone or the cannabinoid CB(1) receptor antagonist SR 141716[N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophelyl)-4-methyl-3-pyrazole-carboxamine]. The combination of these two agents inhibited food intake in a manner suggestive of additivity or supra-additivity.

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Eating; Female; Hyperphagia; Male; Naloxone; Narcotic Antagonists; Nociceptin; Opioid Peptides; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The acute administration of the neurosteroid precursor, progesterone (10 mg/kg, s.c.) produced significant hyperphagia in female mice as observed at 0.5-, 1-, 2- and 3-h time intervals. At this dose progesterone also produced significant increase in immobility period duration in Porsolt's forced swim test and nociceptive response in hot-plate and tail-flick tests. Treatment with direct (quipazine, 5 mg/kg, i.p.) and indirect (fluoxetine, 10 mg/kg, i.p.) acting serotonergic agents per se produced significant hypophagia, decrease in immobility period and induced analgesic effect in hot-plate and tail-flick test. Further, treatment with both fluoxetine (10 mg/kg, i.p.) and quipazine (5 mg/kg, i.p.) significantly reversed progesterone-induced hyperphagia, depression and algesia in the female mice. Pretreatment with seganserin, a 5-HT(2) receptor antagonist (2 mg/kg, i.p.) significantly reversed fluoxetine and quipazine-induced antidepressant and analgesic effects. Seganserin reversed quipazine-induced hypophagia but in a replicate study it failed to reverse fluoxetine-induced hypophagia. Further, seganserin, 2 mg/kg, i.p., significantly reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced hyperphagia, depression and algesia in hot-plate test. Seganserin also reversed the suppressive effect of fluoxetine and quipazine on progesterone-induced algesia in hot-plate test. These data suggest that the modulation of progesterone-induced effects by these serotonergic agents possibly involve 5-HT(2) receptor mechanisms. Further, the study underscores the use of serotonergic agents for the treatment of eating and affective disorders caused by the regular changes or disturbances of ovarian steroid levels in females.

Topics: Analgesics; Animals; Antidepressive Agents, Second-Generation; Brain; Depression; Disease Models, Animal; Drug Interactions; Female; Fluoxetine; Hyperphagia; Menstrual Cycle; Mice; Mice, Inbred Strains; Motor Activity; Pain; Pain Measurement; Piperidines; Progesterone; Quipazine; Receptors, Serotonin; Serotonin; Serotonin Antagonists

Whether or not peptide YY (PYY)-induced hyperphagia is modified by the histaminergic system in the brain is not yet known.. We investigated the effect on feeding of intracerebroventricular (ICV) administration of a specific histamine H3 receptor antagonist prior to ICV administration of PYY in rats.. PYY (1, 3, and 10 micrograms/10 microL) strongly induced feeding behavior in a dose-dependent manner in sated rats. The 4-hour food intake induced by 3 micrograms/10 microL of PYY was equal to that induced by a 16-hour fast. The ICV administration of thioperamide (40.8, 122.4, and 408.5 micrograms/10 microL) did not suppress the 4-hour food intake induced by 16-hour fasting; however, thioperamide produced dose-dependent and strong inhibition of hyperphagia induced by a 3-microgram dose of PYY.. These results suggest that the effect of PYY on appetite is different than that induced by fasting and may involve a histaminergic mechanism.

Topics: Analysis of Variance; Animals; Appetite Regulation; Bulimia; Disease Models, Animal; Dose-Response Relationship, Drug; Drinking; Eating; Fasting; Histamine Antagonists; Hyperphagia; Injections, Intraventricular; Male; Peptide YY; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Satiation; Time Factors

Central cannabinoid systems have been implicated in appetite regulation by the respective hyperphagic actions of exogenous cannabinoids, such as delta9-THC, and hypophagic effects of selective cannabinoid receptor antagonists.. This study examined whether an endogenous cannabinoid, anandamide, could induce overeating, via a specific action at central (CB1) cannabinoid receptors.. Pre-satiated male rats (n=18), received subcutaneous injections of anandamide (0.5, 1.0, 5.0, 10.0 mg/kg) before 3-h, nocturnal food intake tests. In a second series of intake tests (n=8), anandamide injection (1.0 mg/kg) was preceded by injection of the specific CB1 receptor antagonist, SR141716 (0.1, 0.5, 1.0 mg/kg SC).. All doses of anandamide induced significant overeating, with 1.0 mg/kg being most potent. Additionally, hyperphagia induced by 1.0 mg/kg anandamide was dose-dependently attenuated by SR141716 pretreatment.. This first demonstration of anandamide-induced, CB -mediated, overeating provides important evidence for the involvement of a central cannabinoid system in the normal control of eating.

Topics: Animals; Arachidonic Acids; Cannabinoids; Endocannabinoids; Hyperphagia; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Antagonism of the histamine (H2) receptor reduces antinociception induced by naloxone-resistant foot-shock, naloxone-sensitive foot-shock, and morphine with a rank-order potency similar to their H2 antagonism. The antimetabolic glucose analog 2-deoxy-D-glucose (2DG) produces antinociceptive and hyperphagic responses that dissociate from each other and are in part mediated by opioid systems. The present study determined the effects of the brain-penetrating H2 receptor antagonist zolantidine (ZOL) on 2DG antinociception on the tail-flick and jump tests, as well as on 2DG hyperphagia, in rats. ZOL (0.01-1 mg/kg) potentiated the antinociceptive responses induced by a moderate (450 mg/kg) dose of 2DG, but had lesser effects upon antinociception induced by a lower (100 mg/kg) 2DG dose. ZOL itself slightly increased jump thresholds, but not tail-flick latencies. Combinations of ZOL and 2DG produced supraadditive antinociception, even though ZOL failed to significantly shift the 2DG dose-response curve to the left. In contrast, ZOL failed to alter basal intake or 2DG hyperphagia, supporting previous evidence implicating the H1 but not the H2 receptor in these effects. These results further dissociate the antinociceptive and hyperphagic effects of 2DG, and also support previous results indicating both pro- and antinociceptive roles for H2 receptors.

Topics: Animals; Benzothiazoles; Deoxyglucose; Histamine H2 Antagonists; Hot Temperature; Hyperphagia; Male; Nociceptors; Phenoxypropanolamines; Piperidines; Rats; Rats, Inbred Strains; Thiazoles

The anorectic effect of CM 57373 in dogs and in rats food-deprived or with experimentally induced hyperphagia (cafeteria-diet hyperphagia and insulin hyperphagia) was compared to the effect of serotoninergic anorectic drug dl-fenfluramine. CM 57373 and dl-fenfluramine administered orally caused a dose-related reduction of food consumption by food-deprived rats (ID50 = 7.4 mg/kg and 2.5 mg/kg respectively). The oral ID50 in dogs was 2.4 mg/kg for CM 57373 and 1.1 mg/kg for dl-fenfluramine. This animal species tolerated CM 57373 better than dl-fenfluramine. The latter induced mydriasis, dyskinesia and reduced spontaneous activity. The anorectic effects of CM 57373 and dl-fenfluramine in cafeteria-diet hyperphagic rats were comparable. Tolerance to the anorectic effect developed in rats treated with both CM 57373 and dl-fenfluramine although tolerance was initially less pronounced with CM 57373 than dl-fenfluramine. The brain serotonin levels of cafeteria-fed rats were unchanged by CM 57373 throughout treatment whereas dl-fenfluramine decreased the monoamine levels starting from the 8th day. Both drugs reduced 5-hydroxyindolacetic acid levels. CM 57373 (7.4 mg/kg p.o.) and dl-fenfluramine (2.5 mg/kg p.o.) markedly reduced the overeating caused by insulin injection. These results indicate that CM 57373 shows several characteristics of drugs that act via serotonin to depress food intake in various animal species.

Topics: Animals; Appetite Depressants; Body Weight; Diet; Dogs; Eating; Feeding and Eating Disorders; Female; Fenfluramine; Hydroxyindoleacetic Acid; Hyperphagia; Insulin; Male; Piperidines; Rats; Rats, Inbred Strains; Serotonin