Neuropharmacology. 2008 Jun 7. [Epub ahead of print]
Contextual renewal of nicotine seeking in rats and its suppression by the cannabinoid-1 receptor antagonist Rimonabant (SR141716A).
Diergaarde L, de Vries W, Raasø H, Schoffelmeer AN, De Vries TJ.
Center for Neurogenomics and Cognitive Research, Department of Anatomy and Neurosciences, VU Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Nicotine-associated paraphernalia such as cigarettes and ashtrays are potent smoking relapse triggers. In addition to these discrete cues, environmental contexts previously associated with smoking elicit strong cigarette craving, indicating that contextual stimuli also contribute to high smoking relapse rates. Nonetheless, little is known about the precise role of these stimuli in smoking relapse and the neuropharmacological mechanisms implicated herein. To address this issue, we determined whether re-exposure to the nicotine self-administration context after long-term extinction reinstates nicotine seeking behavior in rats. Further, we examined the effects of SR141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist which has been shown to attenuate cue-induced relapse to nicotine seeking, on context-induced reinstatement of nicotine seeking. Rats were trained to self-administer nicotine intravenously (30mug/kg/infusion). Nicotine infusions were paired with an audiovisual compound stimulus. Subsequently, nose poking behavior was extinguished in the presence of this discrete cue in a context different from the self-administration context. Hereafter, rats were injected with 0, 1, or 3mg/kg Rimonabant (i.p.) prior to re-exposure to either the self-administration or the extinction context. Re-exposure to the self-administration context, but not to the extinction context robustly reinstated responding for the discrete nicotine cues, an effect that was dose-dependently attenuated by Rimonabant. This is the first demonstration of contextual renewal of nicotine seeking in rodents after prolonged withdrawal. Further, our results indicate that the endocannabinoid system is involved in context-induced relapse to nicotine seeking, and as such these data provide further evidence for the use of CB1 antagonists in smoking cessation.
nothing new here, just a competitive effort....
Chem Rec. 2008;8(3):156-68.
Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives.
Lange JH, Kruse CG.
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. jos.lange@solvay.com
The observed antiobesity effect of rimonabant (1) in a pharmacological rodent model 10 years ago has led to a surge in the search for novel cannabinoid CB1 antagonists as a new therapeutic target for the treatment of obesity. Rimonabant showed clinical efficacy in the treatment of obesity and also improved cardiovascular and metabolic risk factors. Cannabinoid CB1 receptor antagonists have also good prospects in other therapeutic areas, including smoking and alcohol addiction as well as cognitive impairment. Solvay's research achievements in this fast-moving field are reported in relation with the current state of the art. Several medicinal chemistry strategies have been pursued. The application of the concept of conformational constraint led to the discovery of more rigid analogs of the prototypic CB1 receptor antagonist rimonabant. Replacement of the central heterocyclic pyrazole ring in rimonabant yielded imidazoles, triazoles, and thiazoles as selective CB1 receptor antagonists. Dedicated medium-throughput screening efforts delivered one 3,4-diarylpyrazoline hit. Its poor pharmacokinetic properties were successfully optimized which led to the discovery of orally active and highly CB1/CB2 receptor selective analogs in this series. Regioisomeric 1,5-diarylpyrazolines, 1,2-diarylimidazolines, and water-soluble imidazoles have been designed as novel CB1 receptor antagonist structure classes. |
