BACKGROUND AND PURPOSE Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing ...PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3‐cyclopentyloxy‐4‐methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR‐7b, on memory performance, nausea, hippocampal cAMP and amyloid‐β (Aβ) levels.
EXPERIMENTAL APPROACH To measure memory performance, we performed object recognition tests on rats and mice treated with GEBR‐7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Aβ peptides were measured in hippocampal tissues and cultured N2a cells by elisa.
KEY RESULTS GEBR‐7b increased hippocampal cAMP, did not influence Aβ levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR‐7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents.
CONCLUSION AND IMPLICATIONS Our results demonstrate that GEBR‐7b enhances memory functions at doses that do not cause emesis‐like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment.
Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a ...conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.
Rolipram, a phosphodiesterase-4 (PDE4) inhibitor, is of current interest as a cognitive enhancer and as a treatment for inflammatory diseases. Originally developed as an anti-depressant, rolipram's ...efficacy was limited due to its side effects of nausea and vomiting. The experiments reported here evaluated the potential of rolipram to produce conditioned gaping (a selective measure of nausea in rats) to a flavor in the taste reactivity test (Experiment 1) and to a context (Experiment 2). In Experiment 1, rats were intra-orally infused with 17% sucrose solution prior to being injected with rolipram (Vehicle, 0.03, 0.1 or 0.3 mg/kg). Following 3 conditioning trials, rats conditioned with 0.3 mg/kg rolipram displayed conditioned gaping reactions during the infusion of sucrose. In Experiment 2, rats received 4 conditioning trials in which they were injected with 0.3 mg/kg rolipram and placed into a distinctive chamber. At test, when returned to the chamber rats displayed conditioned gaping. These results demonstrate the ability of the conditioned gaping model to detect the nauseating properties of a rolipram-paired flavor (Experiment 1) and rolipram-paired context (Experiment 2), further validating the potential use of the conditioned gaping model as a pre-clinical screening tool to evaluate the side effect of nausea produced by newly developed drugs.
BACKGROUND AND PURPOSE To evaluate the hypothesis that activation of somatodendritic 5‐HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti‐emetic/anti‐nausea effects of cannabidiol ...(CBD), a primary non‐psychoactive cannabinoid found in cannabis.
EXPERIMENTAL APPROACH The potential of systemic and intra‐DRN administration of 5‐HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti‐emetic effect of CBD in shrews (Suncus murinus) and the anti‐nausea‐like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra‐DRN administration of CBD to produce anti‐nausea‐like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5‐HT1A receptors and to modify the ability of the 5‐HT1A agonist, 8‐OH‐DPAT, to stimulate 35SGTPγS binding in rat brainstem membranes.
KEY RESULTS CBD suppressed nicotine‐, lithium chloride (LiCl)‐ and cisplatin (20 mg·kg−1, but not 40 mg·kg−1)‐induced vomiting in the S. murinus and LiCl‐induced conditioned gaping in rats. Anti‐emetic and anti‐nausea‐like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti‐nausea‐like effects of systemic CBD, and (ii) CBD suppressed nausea‐like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell‐shaped dose–response curve) at enhancing the ability of 8‐OH‐DPAT to stimulate 35SGTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8‐OH‐DPAT synergistically suppressed LiCl‐induced conditioned gaping.
CONCLUSIONS AND IMPLICATIONS These results suggest that CBD produced its anti‐emetic/anti‐nausea effects by indirect activation of the somatodendritic 5‐HT1A autoreceptors in the DRN.
LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid ...antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.
EXPERIMENTAL APPROACH Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated.
KEY RESULTS AM6545 binds to CB1 receptors with a Ki of 1.7 nM and CB2 receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 receptor antagonist. AM6545 reversed the effects of WIN55212‐2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose‐dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 receptor gene‐deficient mice, but not in CB1/CB2 receptor double knockout mice.
CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
Background and Purpose
To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5‐HT1A receptor activation in animal models.
Experimental Approach
We ...investigated the effect of CBDA on (i) lithium chloride (LiCl)‐induced conditioned gaping to a flavour (nausea‐induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion‐, LiCl‐ or cisplatin‐induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5‐HT1A receptor activation by 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) and mouse whole brain CB1 receptor activation by CP55940, using 35SGTPγS‐binding assays.
Key Results
In shrews, CBDA (0.1 and/or 0.5 mg·kg−1 i.p.) reduced toxin‐ and motion‐induced vomiting, and increased the onset latency of the first motion‐induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg−1 i.p.) suppressed LiCl‐ and context‐induced conditioned gaping, effects that were blocked by the 5‐HT1A receptor antagonist, WAY100635 (0.1 mg·kg−1 i.p.), and, at 0.01 mg·kg−1 i.p., enhanced saccharin palatability. CBDA‐induced suppression of LiCl‐induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg−1 i.p.). In vitro, CBDA (0.1–100 nM) increased the Emax of 8‐OH‐DPAT.
Conclusions and Implications
Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5‐HT1A receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.
Highlights • Intra-VIC administration of 2-AG suppressed nausea-induced conditioned gaping in rats. • Intra-VIC administration of anandamide did not suppress conditioned gaping. • The anti-nausea ...effects of 2-AG were not reversed by CB1 antagonism. • None of these manipulations affected LiCl-induced taste avoidance.
BACKGROUND AND PURPOSE Conditioned gaping reactions reflect nausea‐induced behaviour in rats. Cannabinoid 1 receptor (CB1) agonists interfere with the establishment of nausea‐induced conditioned ...gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB1 receptors.
EXPERIMENTAL APPROACH We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB1 agonist, CB13, on the establishment of LiCl‐induced gaping in rats. We further evaluated the ability of HU‐210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl‐induced conditioned gaping and determined if this effect was mediated by CB1 receptors.
KEY RESULTS Central, but not peripheral, CB13 suppressed LiCl‐induced conditioned gaping. Central administration of the potent CB1 agonist, HU‐210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl‐induced gaping reactions, but not LiCl‐induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU‐210 delivered to the VIC prevented LiCl‐induced nausea, but not learning per se. The suppression of LiCl‐induced conditioned gaping by HU‐210 was mediated by CB1 receptors because it was prevented by co‐administration of CB1 antagonist/inverse agonist, AM‐251, into the VIC. A high dose of AM‐251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions.
CONCLUSIONS AND IMPLICATIONS The nausea‐relieving effects of CB1 agonists, but not the nausea‐inducing effects of CB1 inverse agonists, are mediated, at least in part, by their action at the VIC in rats.
Abstract Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through ...the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus . In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB1 antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB + AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.
BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists/inverse agonists, potentiate toxin‐induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea ...was mediated by inverse agonism or neutral antagonism of the CB1 receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist.
EXPERIMENTAL APPROACH The conditioned gaping model of nausea in rats was used to compare the CB1 receptor antagonist/inverse agonist, AM251, and the CB1 receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl‐induced gaping in this model was also evaluated.
KEY RESULTS At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg·kg−1) potentiated LiCl‐induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg·kg−1 of AM6545 and AM6527 neither potentiated LiCl‐induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 µg) or the 4th ventricle (2.5, 12.5 and 125 µg) did not potentiate LiCl‐induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test.
CONCLUSIONS AND IMPLICATIONS Inverse agonism, but not neutral antagonism, of CB1 receptors potentiated toxin‐induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB1 receptors, located distal to the cerebral ventricles.
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