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.

We hypothesized that the six-monthly application of silver diamine fluoride (SDF) can arrest the development of caries in the deciduous dentition of six-year-old schoolchildren and prevent caries in their first permanent molars. A prospective controlled clinical trial was conducted on the efficacy of a 38% SDF solution for caries reduction. Four hundred and twenty-five six-year-old children were divided into two groups: One group received SDF solution in primary canines and molars and first permanent molars every 6 mos for 36 mos. The second group served as controls. The 36-month follow-up was completed by 373 children. The mean number of new decayed surfaces appearing in primary teeth during the study was 0.29 in the SDF group vs. 1.43 in controls. The mean of new decayed surfaces in first permanent molars was 0.37 in the SDF group vs. 1.06 in controls. The SDF solution was found to be effective for caries reduction in primary teeth and first permanent molars in schoolchildren.

The majority of Parkinson's disease patients undergoing levodopa therapy develop disabling motor complications (dyskinesias) within 10 years of treatment. Stimulation of cannabinoid receptors, the pharmacological target of D 9 -tetrahydrocannabinol, is emerging as a promising therapy to alleviate levodopa-associated dyskinesias. However, the mechanisms underlying this bene®cial action remain elusive, as do the effects exerted by levodopa therapy on the endocannabinoid system. Although levodopa is known to cause changes in CB 1 receptor expression in animal models of Parkinson's disease, we have no information on whether this drug alters the brain concentrations of the endocannabinoids anandamide and 2-arachidonylglycerol. To address this question, we used an isotope dilution assay to measure endocannabinoid levels in the caudate±putamen, globus pallidus and substantia nigra of intact and unilaterally 6-OHDA-lesioned rats undergoing acute or chronic treatment with levodopa (50 mg/kg). In intact animals, systemic administration of levodopa increased anandamide concentrations throughout the basal ganglia via activation of dopamine D 1 /D 2 receptors. In 6-OHDAlesioned rats, anandamide levels were signi®cantly reduced in the caudate±putamen ipsilateral to the lesion; however, neither acute nor chronic levodopa treatment affected endocannabinoid levels in these animals. In lesioned rats, chronic levodopa produced increasingly severe oro-lingual involuntary movements which were attenuated by the cannabinoid agonist R()-WIN55,212-2 (1 mg/kg). This effect was reversed by the CB 1 receptor antagonist rimonabant (SR141716A). These results indicate that a de®ciency in endocannabinoid transmission may contribute to levodopa-induced dyskinesias and that these complications may be alleviated by activation of CB 1 receptors.

Cannabinoid CB 1 receptors are densely expressed on striatal projection neurons expressing dopamine D 1 or D 2 receptors. However, the specific neuronal distribution of CB 1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D 2 receptors, but it is not clear if endocannabinoids also modulate D 1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB 1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D 1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D 2 receptors. We explored the functional relevance of the interaction between dopamine D 1 and D 2 receptors and cannabinoid CB 1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D 1 receptor-mediated grooming and D 2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D 1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D 1 receptor-mediated behaviors in addition to its previously described effect on dopamine D 2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D 1 receptor knockout mice, demonstrating its dependence on D 1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D 1 and D 2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.