Cannabinoid CB1 Receptor Antagonist Rimonabant Research Articles

Receptor mechanism of infarct-limiting effect of adaptation to normobaric hypoxia

The aim of the study was to investigate the involvement of bradykinin, cannabinoid and vanilloid (TRPV1 channel) receptors in the implementation of the infarct-limiting effect of chronic normobaric hypoxia (CNH). Materials and methods . The study was performed on male Wistar rats ( n = 117) weighing 250–300 g. Adaptation to CNH was modeled for 21 days at 12% pO 2 , 0.3% pCO 2 and normal atmospheric pressure. A day after adaptation of rats to CNH coronary artery occlusion (45 min) and reperfusion (2 h) was performed. In the study the following compounds were used: selective cannabinoid CB1 receptor antagonist rimonabant (1 mg/kg), selective cannabinoid CB2 receptor antagonist AM630 (2.5 mg/kg), selective bradykinin B2 receptor antagonist HOE140 (50 μg/kg), and vanilloid receptor (TRPV1 channel) antagonist capsazepine (3 mg/kg). All antagonists were administered 15 min before coronary artery occlusion. Results. Adaptation to normobaric hypoxia promoted the formation of the pronounced infarct-limiting effect. The blockade of B2 receptor eliminated the infarct-limiting effect of CNH. Blockade of cannabinoid or vanilloid receptors did not affect the infarct-limiting effect of CNH. Conclusion . The infarct-limiting effect of CNH depends on the activation of B2 receptor, and the adaptive increase in cardiac tolerance to ischemia/reperfusion does not depend on cannabinoid or vanilloid receptors.

Novel object recognition memory in REM sleep-deprived rats: Role of the cannabinoid CB1 receptor

A survey of the literature indicates that both rapid eye movement sleep deprivation (RSD) and activation of cannabinoid CB1 receptor (CB1R) may impair novel object recognition (NOR) memory in rodents. To our knowledge, so far, no previous study has investigated the probable effects of RSD on the different phases of NOR memory. Moreover, far too little attention has been paid to the potential role of the CB1R in the effects of RSD on object memory. Therefore, the major objective of this study was to investigate the probable role of the CB1R in the acquisition, consolidation, retrieval, and reconsolidation of NOR memory in the RSD rats. A 12-h paradigm of RSD using the multiple platform method did not affect acquisition, but it impaired the consolidation, retrieval, and reconsolidation of NOR memory. Administration of the CB1R antagonist rimonabant (1 or 3 mg/kg, i.p.) did not have significant effects on the acquisition and reconsolidation, but it improved RSD-induced impairment of the consolidation and retrieval of object memory, especially at the dose of 3 mg/kg. In addition, the RSD paradigm did not affect the levels of plasma corticosterone as an important marker of stress in rat. The results revealed that RSD may have different effects on the different phases of NOR memory which may not be attributable to the effects of stress. Our findings would seem to suggest that the CB1R can be targeted to, at least partially, modulate the adverse effects of RSD on the process of NOR memory.

A medium throughput rodent model of relapse from addiction with behavioral and pharmacological specificity

One of most formidable problems in the treatment of addiction is the high rate of relapse. The discovery of medicines to help mitigate relapse are aided by animal models that currently involve weeks of training and require surgical preparations and drug delivery devices. The present set of experiments was initiated to investigate a rapid 8-day screening method that utilizes food instead of intravenous drug administration. Male Sprague-Dawley rats were trained in a reinstatement paradigm in which every lever press produced a 45 mg food pellet concurrently paired with a light and tone. Behavior was subsequently extinguished with lever responses producing neither food nor food-associated stimuli. Reinstatement of responding was evaluated under conditions in which the first three responses of every 5 min time bin produced a food pellet along with food-associated stimuli. The mGlu5 receptor antagonists MPEP and MTEP produced a significant reduction in reinstatement while failing to alter responding where every response produced food. The cannabinoid CB1 receptor antagonist rimonabant and the mGlu2/3 receptor agonist LY379268 also selectively reduced reinstatement. Other compounds including clozapine, d-amphetamine, chlordiazepoxide, ABT-431, naltrexone and citalopram were without effect. The results suggest that relapse-like behavioral effects can be extended to non-pharmacological reinforcers. Drug effects demonstrated both behavioral and pharmacological specificity. The present experimental design thus allows for efficient and rapid assessment of the effects of drugs that might be useful in the treatment of addiction-associated relapse.

Role of Cannabinoid CB1, Receptor in Object Recognition Memory Impairment in Chronically Rapid Eye Movement Sleep-deprived Rats

ObjectiveWe aimed to investigate whether antagonism of the cannabinoid CB1 receptor (CB1R) could affect novel object recognition (NOR) memory in chronically rapid eye movement sleep-deprived (RSD) rats. MethodsThe animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique. The CB1R antagonist rimonabant (1 or 3 mg/kg, i.p.) was administered either at one hour prior to the sample phase for acquisition, or immediately after the sample phase for consolidation, or at one hour before the test phase for retrieval of NOR memory. For the reconsolidation task, rimonabant was administered immediately after the second sample phase. ResultsThe RSD episode impaired acquisition, consolidation, and retrieval, but it did not affect the reconsolidation of NOR memory. Rimonabant administration did not affect acquisition, consolidation, and reconsolidation; however, it attenuated impairment of the retrieval of NOR memory induced by chronic RSD. ConclusionsThese findings, along with our previous report, would seem to suggest that RSD may affect different phases of recognition memory based on its duration. Importantly, it seems that the CB1R may, at least in part, be involved in the adverse effects of chronic RSD on the retrieval, but not in the acquisition, consolidation, and reconsolidation, of NOR memory.

Cannabinoid CB1 Receptor Antagonist Rimonabant Decreases Levels of Markers of Organ Dysfunction and Alters Vascular Reactivity in Aortic Vessels in Late Sepsis in Rats.

Sepsis is a life-threatening condition with high mortality rates that is caused by dysregulation of the host response to infection. We previously showed that treatment with the cannabinoid CB1 receptor antagonist rimonabant reduced mortality rates in animals with sepsis that was induced by cecal ligation and puncture (CLP). This improvement in the survival rate appeared to be related to an increase in arginine vasopressin (AVP) levels 12h after CLP. The present study investigated the effects of rimonabant on organ dysfunction, hematologic parameters, and vascular reactivity in male Wistar rats with sepsis induced by CLP. Intraperitoneal treatment with rimonabant (10mg/kg, 4h after CLP) abolished the increase in the plasma levels of lactate, lactate dehydrogenase, glucose, and creatinine kinase MB without altering hematological parameters (i.e., leukopenia and a reduction of platelet counts). CLP increased plasma levels of nitrate/nitrite (NOx) and induced vasoconstriction in the tail artery. The treatment of CLP rats with rimonabant did not alter NOx production but reduced the vasoconstriction. Rimonabant also attenuated the hyperreactivity to AVP induced by CLP without affecting hyporesponsiveness to phenylephrine in aortic rings. These results suggest that rimonabant reduces organ dysfunction during sepsis, and this effect may be related to AVP signaling in blood vessels. This effect may have contributed to the higher survival rate in rimonabant-treated septic animals.

Anti-nociceptive and desensitizing effects of olvanil on capsaicin-induced thermal hyperalgesia in the rat.

BackgroundOlvanil (NE 19550) is a non-pungent synthetic analogue of capsaicin, the natural pungent ingredient of capsicum which activates the transient receptor potential vanilloid type-1 (TRPV1) channel and was developed as a potential analgesic compound. Olvanil has potent anti-hyperalgesic effects in several experimental models of chronic pain. Here we report the inhibitory effects of olvanil on nociceptive processing using cultured dorsal root ganglion (DRG) neurons and compare the effects of capsaicin and olvanil on thermal nociceptive processing in vivo; potential contributions of the cannabinoid CB1 receptor to olvanil’s anti-hyperalgesic effects were also investigated.MethodsA hot plate analgesia meter was used to evaluate the anti-nociceptive effects of olvanil on capsaicin-induced thermal hyperalgesia and the role played by CB1 receptors in mediating these effects. Single cell calcium imaging studies of DRG neurons were employed to determine the desensitizing effects of olvanil on capsaicin-evoked calcium responses. Statistical analysis used Student’s t test or one way ANOVA followed by Dunnett’s post-hoc test as appropriate.ResultsBoth olvanil (100 nM) and capsaicin (100 nM) produced significant increases in intracellular calcium concentrations [Ca2+]i in cultured DRG neurons. Olvanil was able to desensitise TRPV1 responses to further capsaicin exposure more effectively than capsaicin. Intraplantar injection of capsaicin (0.1, 0.3 and 1 μg) produced a robust TRPV1-dependant thermal hyperalgesia in rats, whilst olvanil (0.1, 0.3 and 1 μg) produced no hyperalgesia, emphasizing its lack of pungency. The highest dose of olvanil significantly reduced the hyperalgesic effects of capsaicin in vivo. Intraplantar injection of the selective cannabinoid CB1 receptor antagonist rimonabant (1 μg) altered neither capsaicin-induced thermal hyperalgesia nor the desensitizing properties of olvanil, indicating a lack of involvement of CB1 receptors.ConclusionsOlvanil is effective in reducing capsaicin-induced thermal hyperalgesia, probably via directly desensitizing TRPV1 channels in a CB1 receptor-independent fashion. The results presented clearly support the potential for olvanil in the development of new topical analgesic preparations for treating chronic pain conditions while avoiding the unwanted side effects of capsaicin treatments.

Abstract P189: Angiotensin II - Endocannabinoid Interactions in the Nucleus of the Solitary Tract are Important for Regulation of Baroreflex Control of Heart Rate

Hypertension resulting from elevated brain angiotensin (Ang) II is associated with impaired functioning of neural reflexes regulating sympathetic and parasympathetic outflow. Restoration of normal baroreflex sensitivity (BRS) for control of heart rate (HR) is achieved in a rat model of Ang II - dependent hypertension [ (mRen2)27 transgenic rats ] by local injection of the cannabinoid CB 1 receptor antagonist rimonabant (SR141716A), a CB 1 receptor antagonist, into the solitary tract nucleus (NTS) of anesthetized rats or by chronic oral rimonabant treatment, which has central and peripheral sites of action. Together with elevated brain dorsal medullary tissue concentrations of 2-arachidonylglycerol present in the (mRen2)27 rats, these findings are consistent with an activated endocannabinoid system contributing to the impaired BRS in these animals. To further explore acute interactions between Ang II - mediated suppression of BRS and the endocannabinoids, Ang II was injected into NTS of anesthetized Sprague-Dawley rats 10 minutes following NTS injection of rimonabant or aCSF (120 nL, bilaterally). In the presence of aCSF, Ang II reduced BRS by ~50% (In msec/mm Hg: 1.14 ± 0.14 before versus 0.53 ± 0.16; n = 7, p < 0.008); this effect was abolished in the presence of rimonabant (In msec/mm Hg: 0.92 ± 0.16 before versus 0.86 ± 0.21; n = 4, p = 0.8). There was no difference in mean arterial pressure or heart rate before or after Ang II treatment in either aCSF or rimonabant groups. Thus, the data support the interpretation that Ang II - mediated attenuation of BRS for control of HR involves release of endocannabinoids. Others report that the pressor actions following acute local injections of Ang II into the hypothalamic paraventricular nucleus are prevented by blockade of CB 1 receptors. We conclude that functional interactions between these two systems occur at multiple brain sites relevant to blood pressure control mechanisms and together the findings support a role for elevated brain endocannabinoids as contributors to the altered reflexes characteristic of Ang II - dependent hypertension. Support: HL-51952, DA-024863 and DA-03690, the Hypertension & Vascular Research Center, Farley[[Unable to Display Character: ‐]]Hudson Foundation

Modulation of Fear Memory by Dietary Polyunsaturated Fatty Acids via Cannabinoid Receptors

Although the underlying mechanism remains unknown, several studies have suggested benefits of n-3 long-chain polyunsaturated fatty acid (PUFA) for patients with anxiety disorders. Elevated fear is thought to contribute to the pathogenesis of particular anxiety disorders. The aim of the present study was to evaluate whether the dietary n-3 to n-6 PUFA (3:6) ratio influences fear memory. For this purpose, the effects of various dietary 3:6 ratios on fear memory were examined in mice using contextual fear conditioning, and the effects of these diets on central synaptic transmission were examined to elucidate the mechanism of action of PUFA. We found that fear memory correlated negatively with dietary, serum, and brain 3:6 ratios in mice. The low fear memory in mice fed a high 3:6 ratio diet was increased by the cannabinoid CB1 receptor antagonist rimonabant, reaching a level seen in mice fed a low 3:6 ratio diet. The agonist sensitivity of CB1 receptor was enhanced in the basolateral nucleus of the amygdala (BLA) of mice fed a high 3:6 ratio diet, compared with that of mice fed a low 3:6 ratio diet. Similar enhancement was induced by pharmacological expulsion of cholesterol in the neuronal membrane of brain slices from mice fed a low 3:6 ratio diet. CB1 receptor-mediated short-term synaptic plasticity was facilitated in pyramidal neurons of the BLA in mice fed a high 3:6 ratio diet. These results suggest that the ratio of n-3 to n-6 PUFA is a factor regulating fear memory via cannabinoid CB1 receptors.

Endocannabinoids underlie reconsolidation of hedonic memories in Wistar rats

Drug addicts constantly relapse to drug seeking after recall of memories linked to the drug experience. It is believed that a successful application of therapies that block memory reconsolidation may end the continuous cycle of drug relapse. The purpose of this study is to investigate whether modulation of the endocannabinoid system would impact the reconsolidation of opioid-related hedonic memories in rats previously paired to morphine context. Male Wistar rats were trained to acquire a morphine-conditioned place preference (CPP). One week later, morphine-CPP memory was reactivated by a brief exposure to a drug-paired context. Immediately after the memory reactivation session, independent groups of morphine-trained rats received a single subcutaneous injection of different doses of cannabinoid CB1 receptor antagonist rimonabant, CB2-selective antagonist AM630, potent CB1/CB2 agonist WIN 55,212-2, inhibitor of enzyme fatty acid amide hydrolase URB597, or vehicle. Morphine-CPP was retested 1 and 2 weeks after reactivation. Blockade of CB1 (but not CB2) cannabinoid receptors impaired CPP reconsolidation of morphine-CPP at both tests 1 and 2 weeks post-reactivation, whereas direct activation of cannabinoid receptors did not produce significant effects on morphine-induced CPP. However, boosting endocannabinoid signaling by inhibition of anandamide metabolism promoted a transient CB1-dependent enhancement of the CPP.

Additive effect of rimonabant and citalopram on extracellular serotonin levels monitored with in vivo microdialysis in rat brain

Current pharmacological therapies for depression, including selective serotonin reuptake inhibitors (SSRI), are far from ideal. The cannabinoid system has been implicated in control of mood and neural processing of emotional information, and the modulation of serotonin (5-HT) release in the synaptic clefts. The aim of the present study was to evaluate whether the combination of a selective SSRI (citalopram) with a selective cannabinoid CB1 receptor antagonist (rimonabant) represents a more effective strategy than the antidepressant alone to enhance serotonergic transmission. For this purpose extracellular 5-HT levels were monitored with microdialysis in forebrain (prefrontal cortex, PFC) and mesencephalic (locus coeruleus, LC) serotonergic terminal areas in freely awake rats. Rimonabant at 10mg/kg, i.p., but not at 3mg/kg i.p. increased 5-HT in both areas. Citalopram at 3, 5 and 10mg/kg i.p. increased 5-HT both in PFC and LC in a dose-dependent manner. The effect of citalopram (5mg/kg, i.p.) on 5-HT levels was significantly enhanced by rimonabant at 10mg/kg, i.p. but not at 3mg/kg i.p. in both areas. The present results demonstrate that the cannabinoid CB1 receptor antagonist rimonabant is able to enhance in an additive manner the citalopram-induced increase of 5-HT concentrations in serotonergic terminal areas. The combination of a cannabinoid antagonist and a SSRI may provide a novel strategy to increase 5-HT availability, reducing the dose of SSRIs, and potentially decreasing the time lag for the clinical onset of the antidepressant effect.

Antidepressant-like effects of Δ9-tetrahydrocannabinol and rimonabant in the olfactory bulbectomised rat model of depression

The endocannabinoid signalling system is widely accepted to play a role in controlling the affective state. Plant cannabinoids are well known to have behavioural effects in animals and humans and the cannabinoid CB1 receptor antagonist rimonabant has recently been shown to precipitate depression-like symptoms in clinical trial subjects. The aim of the present study was to investigate the behavioural and neurochemical effects of chronic administration of Δ9-tetrahydrocannabinol (THC) and rimonabant on intact and olfactory bulbectomised (OB) rats used as a model of depression.As expected, OB rats were hyperactive in the open field. Repeated THC (2mg/kg, i.p. once every 48h for 21days) and rimonabant (5mg/kg, i.p. once every 48h for 21days) reduced this hyperactivity, which is typical of clinically effective antidepressant drugs. In intact animals, chronic THC increased brain derived neurotrophic factor (BDNF) expression levels in the hippocampus and frontal cortex but rimonabant had no effect. Rimonabant increased the levels of phosphorylated extracellular signal regulated kinases (p-ERKs1/2) in the hippocampus and prefrontal cortex and THC also increased expression in frontal cortex. OB did not affect BDNF or p-ERK1/2 expression in the hippocampus or frontal cortex and in, contrast to the intact animals, neither THC nor rimonabant altered expression in the OB rats.These findings indicate antidepressant-like behavioural properties of both THC and rimonabant in OB rats although additional studies are required to clarify the relationship between the chronic effects of cannabinoids in other pre-clinical models and in human depression.

The CB1 receptor antagonist rimonabant controls cell viability and ascitic tumour growth in mice

Emerging findings suggested the efficacy of the cannabinoid CB1 receptor antagonist rimonabant (SR141716) in several pathological conditions included tumours. In this study we investigated in vitro the effects of SR141716 on viability and the molecular pathways of methylcholanthrene-induced fibrosarcoma (Meth-A) cells and in vivo its anti-tumour properties in Meth-A-bearing mice. We evaluated in vitro the effect of SR141716 on Meth-A cell viability by trypan blue staining assay. Cell cycle progression and apoptosis were assessed by flow cytometry. Protein expression was investigated by Western blot. The anti-tumour efficacy of SR141716 was evaluated in vivo monitoring weight increase and survival of Meth-A injected mice. SR141716 affects Meth-A cell viability inducing apoptosis and controls cell cycle progression by modulation of the levels of the cell cycle inhibitor p21waf, cyclins E, D1 and NF-kB molecules. Importantly, SR141716 affects AKT/pFoxO1 pathway which promotes cell survival and regulates the cell cycle. The molecular effects observed are accompanied by reduced COX2 expression and induction of the CB1 receptor expression. Finally, SR141716 was able to reduce the tumour size and prolong animal survival, when administered in vivo during tumour growth. Our findings shed light on a novel molecular pathway associated with control of tumour growth by SR141716 and confirm the anti-cancer and anti-inflammatory properties of this drug suggesting its potential applications in the treatment of cancer.

Acute myocardial ischemia enhances the vanilloid TRPV1 and serotonin 5-HT3 receptor-mediated Bezold-Jarisch reflex in rats

AbstractThe Bezold-Jarisch reflex is characterized by a sudden bradycardia associated with hypotension induced by the activation of the vanilloid TRPV1 and serotonin 5-HT3 receptors. This reflex is associated with several health conditions, including myocardial infarction. The aim of the present study was to elucidate the influence of acute experimental myocardial ischemia on the reflex bradycardia induced by anandamide and phenylbiguanide, agonists of the TRPV1 and 5-HT3 receptors, respectively.In urethane-anesthetized rats, the rapid iv injection of anandamide (0.6µmol/kg) or phenylbiguanide (0.03µmol/kg) decreased heart rate (HR) by about 7–10% of the basal values. Myocardial ischemia (MI) was induced by ligation of the left anterior coronary artery. The agonists were injected 5min before MI (S1) and 10, 20 and 30min thereafter (S2–S4).MI potentiated the anandamide-induced reflex bradycardia by approximately 105% at S2 and 70% at S3 but had no effect at S4. This amplificatory effect of MI was virtually abolished by the TRPV1 receptor antagonist capsazepine (1µmol/kg) and was not modified by the cannabinoid CB1 receptor antagonist rimonabant (0.1µmol/kg). MI also amplified the reflex bradycardia elicited by phenylbiguanide by approximately 110, 60 and 90% (S2, S3 and S4, respectively), and this effect was sensitive to the 5-HT3 receptor antagonist ondansetron (3µmol/kg).In conclusion, our results suggest that acute myocardial ischemia augments the Bezold-Jarisch reflex induced via activation of TRPV1 and 5-HT3 receptors located on sensory vagal nerves in the heart.

Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats

Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB1 receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB1 receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0mg/kg) and saline. Rimonabant at a dose of 3.0mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB1 receptors play a role in nicotine reward memory, suggesting that CB1 receptor antagonists may be a potential target for managing nicotine addiction.

Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats

Dysregulation in signaling of the endocannabinoid 2-arachidonoylglycerol (2-AG) is implicated in hyperresponsiveness to stress. We hypothesized that blockade of monoacylglycerol lipase (MGL), the primary enzyme responsible for 2-AG deactivation in vivo, would produce context-dependent anxiolytic effects in rats. Environmental aversiveness was manipulated by varying illumination of an elevated plus maze. Percentage open arm time and numbers of open and closed arm entries were measured in rats receiving a single intraperitoneal (i.p.) injection of either vehicle, the MGL inhibitor JZL184 (1–8mg/kg), the benzodiazepine diazepam (1mg/kg), the cannabinoid CB1 receptor antagonist rimonabant (1mg/kg), or JZL184 (8mg/kg) coadministered with rimonabant (1mg/kg). JZL184 (8mg/kg) produced anxiolytic-like effects (i.e., increased percentage open arm time and number of open arm entries) under high, but not low, levels of environmental aversiveness. Diazepam produced anxiolytic effects in either context. Rimonabant blocked the anxiolytic-like effects of JZL184, consistent with mediation by CB1. Anxiolytic effects of JZL184 were preserved following chronic (8mg/kg per day×6 days) administration. Chronic and acute JZL184 treatment similarly enhanced behavioral sensitivity to an exogenous cannabinoid (WIN55,212-2; 2.5mg/kg i.p.) 24 or 72h following the terminal injection, suggesting a pervasive effect of MGL inhibition on the endocannabinoid system. We attribute our results to alterations in emotion rather than locomotor activity as JZL184 did not alter the number of closed arm entries in the plus maze or produce motor ataxia in the bar test. Our results demonstrate that JZL184 has beneficial, context-dependent effects on anxiety in rats, presumably via inhibition of MGL-mediated hydrolysis of 2-AG. These data warrant further testing of MGL inhibitors to elucidate the functional role of 2-AG in controlling anxiety and stress responsiveness. Our data further implicate a role for 2-AG in the regulation of emotion and validate MGL as a therapeutic target.

Central mediation and differential blockade by cannabinergics of the discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Discovery of an endocannabinoid signaling system launched the development of the blocker rimonabant, a cannabinoid CB1 receptor (CB(1)R) antagonist/inverse agonist. Due to untoward effects, this medication was withdrawn and efforts have been directed towards discovering chemicals with more benign profiles. This study aims to comparatively evaluate new ligands using a rimonabant discriminated drinking aversion procedure. Rats discriminated between rimonabant (5.6mg/kg) and vehicle. The 30min saccharin (0.1%) drinking after rimonabant pretreatment was followed by injection of lithium chloride (120mg/kg) in the experimental animals. After vehicle pretreatment, experimental animals were given i.p. NaCl (10ml/kg). Postdrinking treatment for controls was NaCl, irrespective of pretreatment condition (rimonabant or vehicle). The centrally acting neutral CB(1)R antagonist AM4113, but not the limited brain penetrating CB(1)R neutral antagonist AM6545, substituted for rimonabant. The CB(1)R agonists THC (1-10mg/kg), AM1346 (1-10mg/kg) did not substitute. The rimonabant-induced conditioned suppression of saccharin drinking was attenuated when CB(1)R agonists AM5983 (0.01-1mg/kg) and THC (10mg/kg), but not the CB(1)R agonist AM1346 (0.1-18mg/kg), were combined with rimonabant (5.6mg/kg). By varying the injection-to-test interval, we gauged the relative duration of the cueing effects of rimonabant, and the in vivo functional half-life was estimated to be approximately 1.5h. A neutral CB(1)R antagonist (AM4113) produced cueing effects similar to those of rimonabant and generalization likely was centrally mediated. The functional cueing effects of rimonabant are relatively short-acting, pharmacologically selective, and differentially blocked by cannabinergics.

Synergistic inhibition of human colon cancer cell growth by the cannabinoid CB1 receptor antagonist rimonabant and oxaliplatin

Rimonabant (SR141716), a highly selective cannabinoid receptor antagonist, exerts along with its anti-obesity action, pleiotropic functions affecting a broad range of diseases, from obesity-related co-morbidities to drug dependence and cancer. Several studies suggested an anti-tumour activity of rimonabant in several in vitro and in vivo models. In this study, we compared the anti-proliferative effect of SR141716 in the human colon cancer cell line DLD-1 with oxaliplatin, one of the cytotoxic drugs currently used in the treatment of colorectal cancer. We show that SR141716 inhibits DLD-1 cell proliferation similarly to oxaliplatin and if administered in combination SR141716 potentiated the inhibitory effect caused by oxaliplatin. Assessment of drug interaction was performed calculating combination index that showed a strong synergistic effect between the two drugs added to cells in combination. Our findings suggest that the combined synergic effect of SR141716 and oxaliplatin improves the blocking of colon cancer cell proliferation. Therefore, this combination merits further explorations in preclinical and clinical settings.

The Effects of Rimonabant on Brown Adipose Tissue in Rat: Implications for Energy Expenditure

The cannabinoid CB1 receptor antagonist rimonabant (SR 141716) produces a sustained decrease in body weight on a background of a transient reduction in food intake. An increase in energy expenditure has been implicated, possibly mediated via peripheral endocannabinoid system; however, the role of the central endocannabinoid system is unclear. The present study investigates this role. Rimonabant (10 mg/kg IP) was administered for 21 days to rats surgically implanted with biotelemetry devices to measure temperature in the interscapular brown adipose tissue (BAT). BAT temperature as a putative measure of thermogenesis in the BAT, physical activity, body weight, food intake, as well as changes in UCP1 messenger RNA (mRNA) and protein were measured. In addition, role of the CNS in mediating these actions of rimonabant was determined in rats where the BAT was sympathetically denervated. As expected, chronic administration of rimonabant significantly reduced body weight for the entire treatment period despite only a transient decrease in food intake. There was a profound increase in BAT temperature, particularly during the dark phase of each circadian cycle throughout the treatment period. A corresponding increase in uncoupling protein (UCP1) was also observed following chronic rimonabant treatment. The rimonabant-induced elevation in BAT temperature and decrease in body weight were significantly attenuated following denervation, indicating an involvement of the CNS. These findings suggest that the long-term weight loss associated with rimonabant treatment is due at least in part to an elevation in energy expenditure, represented here by elevated temperature recorded in the BAT, which is mediated primarily by the central endocannabinoid system.

Effects of cannabinoid CB1 receptor antagonist rimonabant in consolidation and reconsolidation of methamphetamine reward memory in mice

Previous studies have shown that cannabinoid CB1 receptors play an important role in specific aspects of learning and memory, yet there has been no systematic study focusing on the involvement of cannabinoid CB1 receptors in methamphetamine-related reward memory. The purpose of this study was to examine whether rimonabant, a cannabinoid CB1 receptor antagonist, would disrupt the consolidation and reconsolidation of methamphetamine-related reward memory, using conditioned place preference paradigm (CPP). Separate groups of male Kunming mice were trained to acquire methamphetamine CPP. Vehicle or rimonabant (1 mg/kg or 3 mg/kg, i.p.) was given at different time points: immediately after each CPP training session (consolidation), 30 min before the reactivation of CPP (retrieval), or immediately after the reactivation of CPP (reconsolidation). Methamphetamine CPP was retested 24 h and 1 and 2 weeks after rimonabant administration. Rimonabant at doses of 1 and 3 mg/kg significantly inhibited the consolidation of methamphetamine CPP. Only high-dose rimonabant (3 mg/kg) disrupted the retrieval and reconsolidation of methamphetamine CPP. Rimonabant had no effect on methamphetamine CPP in the absence of methamphetamine CPP reactivation. Our findings suggest that cannabinoid CB1 receptors play a major role in methamphetamine reward memory, and cannabinoid CB1 receptor antagonists may be a potential pharmacotherapy to manage relapse associated with drug-reward-related memory.

The Cannabinoid CB1 Receptor Antagonist Rimonabant Stimulates 2-Deoxyglucose Uptake in Skeletal Muscle Cells by Regulating the Expression of Phosphatidylinositol-3-kinase

The endocannabinoid system regulates food intake, energy, and glucose metabolism at both central and peripheral levels. We have investigated the mechanism by which it may control glucose uptake in skeletal muscle cells. Detectable levels of the cannabinoid receptor type 1 (CB1) were revealed in L6 cells. Exposure of differentiated L6 myotubes to the CB1 antagonist rimonabant (SR141716) selectively increased 2-deoxyglucose uptake (2-DG) in a time- and dose-dependent manner. A similar effect was induced by genetic silencing of CB1 by small interfering RNA. Protein expression profiling revealed that both the regulatory p85 and the catalytic p110 subunits of the phosphatidylinositol-3-kinase (PI3K) were increased by SR141716. No significant change in the cellular content of other known molecules regulating PI3K was observed. However, phosphoinositide-dependent kinase-1, Akt/protein kinase B, and protein kinase Czeta activities were rapidly induced after SR141716 treatment of L6 cells in a PI3K-dependent manner. The stimulatory effect of SR141716 on PI3K expression and activity was largely prevented by N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H-89), an inhibitor of the cAMP-dependent protein kinase. Moreover, SR141716-stimulated 2-DG uptake was blunted by the coincubation either with H-89 or with the PI3K inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), both in L6 cells and in mouse primary myocytes. Thus, modulation of CB1 regulates glucose uptake at the level of the PI3K signaling system in skeletal muscle cells. Interfering with CB1 signaling may therefore ameliorate glucoregulatory functions in peripheral tissues.