Reduced sensitivity to reward in CB1 knockout mice

Sanchis‐Segura, Carles; Cline, Brandon H.; Marsicano, Giovanni; Lutz, Beat; Spanagel, Rainer

doi:10.1007/s00213-004-1877-8

Cited by 149 publications

(91 citation statements)

References 37 publications

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“…During the maintenance phase of Experiment 1, CB1 KO mice responded significantly less for Ensure s under an FR1 schedule of reinforcement. The effect of CB1 KO on Ensure s -maintained responding was robust and persistent, observed for active nose-poke hole responding and food entries, and complements other reports that CB1 KO mice responded significantly less than WT controls for sucrose under an FR1 schedule (Sanchis-Segura et al, 2004) and for sucrose and Ensure s under PR schedules of reinforcement (Sanchis-Segura et al, 2004;Ward and Dykstra, 2005). Conversely, this is the first report in the literature on the effect of CB1 KO on responding for a fat reinforcer under a fixed-ratio schedule.…”

Section: Discussionsupporting

confidence: 85%

“…Other data from CB1 KO mice support the hypothesis that the CB1 receptor system can modulate intake of sweet palatable foods. It has been demonstrated, for example, that sucrose intake (Poncelet et al, 2003) and sucrose self-administration (Sanchis-Segura et al, 2004) are reduced in CB1 KO mice. Our laboratory recently reported that motivation for Ensure s is attenuated in CB1 KO mice, whereas motivation to consume corn oil is not attenuated in these mice (Ward and Dykstra, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

Ward

Walker

Dykstra

2007

Neuropsychopharmacol

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The cannabinoid CB1 receptor antagonist SR141716A decreases cue-induced reinstatement of sucrose and drug seeking in rats. Reinstatement behavior is not well characterized in C57Bl/6 mice, including CB1 receptor knockout mice generated on a C57Bl/6 background. In the present study, male C57Bl/6, CB1 knockout (CB1 KO), and wild-type littermate (WT) mice were trained to respond for the sweet reinforcer Ensure s or corn oil. Responding was maintained on a fixed ratio 1 (FR1) schedule of reinforcement for 10 days, and then extinguished by the removal of the reinforcer and associated cues. Subsequently, the effect of either pretreatment with SR141716A or CB1 receptor knockout on cue-induced reinstatement of Ensure s or corn-oil seeking was assessed. Both 1.0 and 3.0 mg/ kg SR141716A decreased reinstatement of Ensure s seeking in C57Bl/6 mice. A tenfold higher dose of SR141716A (10.0 mg/kg) was required to attenuate reinstatement behavior in C57Bl/6 mice responding for corn oil, suggesting that CB1 receptors may be selectively involved in the neurobiology underlying reinstatement of responding for some food reinforcers but not others. Whereas CB1 receptor antagonism selectively attenuated reinstatement of responding for Ensure s , genetic deletion of the CB1 receptor produced only a trend in decreasing reinstatement of Ensure s seeking, and did not attenuate reinstatement of corn-oil seeking. Baseline differences in levels of operant responding were also observed in WT vs CB1 KO mice maintained by Ensure s and corn oil. This and other possible reasons for the observed discrepancy between pharmacological blockade vs genetic invalidation of the CB1 receptor on reinstatement of Ensure s seeking are discussed.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

Ward

Walker

Dykstra

2007

Neuropsychopharmacol

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“…19 Given the high comorbidity between anxiety and major depression, 20 recent research has also focused on a potential role of the endocannabinoid system in the pathology of major depression 13,21 particularly of the melancholic subtype. 13 CB1 receptor-deficient mice share several symptoms with patients suffering from melancholic depression such as, for example, altered responsiveness to reward stimuli, 22 altered neurovegetative functions, 23 a predominance and persistence of aversive memories, 8,9 and possibly neurodegeneration. 24 Furthermore, it was shown by us and others that impaired endocannabinoid signaling can lead to sustained hyperreactivity of the hypothalamic-pituitaryadrenocortical (HPA) axis 23,25 and might also interfere with the proliferation of neural progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

et al. 2007

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Dysregulation of the endocannabinoid system is known to interfere with emotional processing of stressful events. Here, we studied the role of cannabinoid receptor type 1 (CB1) signaling in stress-coping behaviors using the forced swim test (FST) with repeated exposures. We compared effects of genetic inactivation with pharmacological blockade of CB1 receptors both in male and female mice. In addition, we investigated potential interactions of the endocannabinoid system with monoaminergic and neurotrophin systems of the brain. Naive CB1 receptor-deficient mice (CB1 À/À ) showed increased passive stress-coping behaviors as compared to wild-type littermates (CB1 þ / þ ) in the FST, independent of sex. These findings were partially reproduced in C57BL/6N animals and fully reproduced in female CB1 þ / þ mice by pharmacological blockade of CB1 receptors with the CB1 receptor antagonist SR141716. The specificity of SR141716 was confirmed in female CB1 À/À mice, where it failed to affect behavioral performance. Sensitivity to the antidepressants desipramine and paroxetine was preserved, but slightly altered in female CB1 À/À mice. There were no genotype differences between CB1 þ / þ and CB1 À/À mice in monoamine oxidase A and B activities under basal conditions, nor in monoamine content of hippocampal tissue after FST exposure. mRNA expression of vesicular glutamate transporter type 1 was unaffected in CB1 À/À mice, but mRNA expression of brain-derived neurotrophic factor (BDNF) was reduced in the hippocampus. Our results suggest that impaired CB1 receptor function promotes passive stress-coping behavior, which, at least in part, might relate to alterations in BDNF function.

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“…CB 1 receptor activation increases extracellular dopamine overflow in terminal regions of the reward circuit, an effect reversed by CB 1 receptor blockade (Cheer et al, 2004;Tanda et al, 1997). In addition, genetic deletion of the CB 1 receptor results in a reduction in the sensitivity to the rewarding effects of sucrose (Sanchis-Segura et al, 2004). CB 1 receptor activation accentuates whereas CB 1 receptor blockade attenuates the rewarding effects of sweet and palatable foods (Ward and Dykstra, 2005).…”

Section: Introductionmentioning

confidence: 99%

Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward

Rademacher

Hillard

2007

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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

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Reduced sensitivity to reward in CB1 knockout mice

Abstract: These results demonstrate a modulatory role of CB1 in the determination of the rewarding properties of sucrose and probably, as suggested by previous studies, other reinforcers.

Cited by 149 publications

References 37 publications

Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice

Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward

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