Cortical astrocytes regulate ethanol consumption and intoxication in mice.

Astrocytes are fundamental building blocks of the central nervous system. Their dysfunction has been implicated in many psychiatric disorders, including alcohol use disorder, yet our understanding of their functional role in ethanol intoxication and consumption is very limited. Astrocytes regulate behavior through multiple intracellular signaling pathways, including G-protein coupled-receptor (GPCR)-mediated calcium signals. To test the hypothesis that GPCR-induced calcium signaling is also involved in the behavioral effects of ethanol, we expressed astrocyte-specific excitatory DREADDs in the prefrontal cortex (PFC) of mice. Activating Gq-GPCR signaling in PFC astrocytes increased drinking in ethanol-naïve mice, but not in mice with a history of ethanol drinking. In contrast, reducing calcium signaling with an astrocyte-specific calcium extruder reduced ethanol intake. Cortical astrocyte calcium signaling also altered the acute stimulatory and sedative-hypnotic effects of ethanol. Astrocyte-specific Gq-DREADD activation increased both the locomotor-activating effects of low dose ethanol and the sedative-hypnotic effects of a high dose, while reduced astrocyte calcium signaling diminished sensitivity to the hypnotic effects. In addition, we found that adenosine A1 receptors were required for astrocyte calcium activation to increase ethanol sedation. These results support integral roles for PFC astrocytes in the behavioral actions of ethanol that are due, at least in part, to adenosine receptor activation.

Influence of fluoride availability of dentifrices on eroded enamel remineralization in situ.

Remineralization of eroded enamel by dentifrices containing similar sources/concentrations of fluoride was investigated in situ. Fifty-three subjects completed a double-blind crossover study with 3 randomly assigned dentifrice treatments: placebo (0 ppm F, PD); reference (1,450 ppm NaF, RD) and test (1,450 ppm NaF + 5% KNO(3), TD). Fluoride availability for each dentifrice was analyzed in vitro by standard tests (1-min fluoride release rate and enamel fluoride uptake). The subjects wore palatal appliances holding bovine enamel specimens previously eroded in vitro. Surface microhardness was determined before and after the in vitro erosive challenge, after in situ remineralization and after a second in vitro erosive challenge. ANOVA and pairwise comparisons were performed (alpha=0.05). TD was superior to RD in the fluoride release tests, but similar to RD in the enamel fluoride uptake test. The mean percent surface microhardness recovery was 21.9 (standard deviation 8.0) for PD, 28.6 (8.0) for RD and 36.0 (8.0) for TD. The mean percent relative erosion resistance change was -58.8 (12.7) for PD, -31.3 (12.7) for RD and -27.3 (12.6) for TD. Both fluoride-containing dentifrices provided superior remineralization (p<0.001) and erosion resistance (p<0.001) compared to PD. The percent surface microhardness recovery demonstrated by the TD was significantly greater than for the RD (p<0.001). There was no significant difference (p=0.073) between TD and RD in relative resistance to further erosive challenge. The results suggest that fluoride availability may be different in dentifrices with similar sources/concentrations of fluoride, providing different levels of remineralization of eroded enamel.

Evaluation of different fluoridated dentifrice formulations using an in situ erosion remineralization model.

OBJECTIVE: The objective of these three clinical in situ studies was to investigate the relative performance of commercially available and experimental dentifrice formulations, having different fluoride sources and excipient ingredients, at remineralizing a bovine enamel surface previously softened by a dietary acid challenge. METHODS: Each study utilized the same randomized, placebo-controlled, single-blind, crossover design. Subjects undertook single brushings of their natural teeth, with an in situ appliance in place, using different dentifrices in a randomly assigned order. Study A involved 58 subjects with the following dentifrices: Sensodyne Pronamel (1450 ppm F as NaF/5% KNO3); Blend-a-Med Classic (1450 ppm F as NaF); and a matched (Pronamel) placebo control (0 ppm F). Study B involved 56 subjects with the following dentifrices: Sensodyne Pronamel (1150 ppm F as NaF/5% KNO3); Crest Cavity Protection (1100 ppm F as NaF); Crest Pro-Health (0.454% SnF2 [1100 ppm F]/sodium hexametaphosphate); and a matched (Pronamel) placebo control (0 ppm F). Study C involved 56 subjects with the following dentifrices: Sensodyne Pronamel (1150 ppm F as NaF/5% KNO3); Sensodyne Pronamel Gentle Whitening (1150 ppm F as NaF/5% KNO3); Colgate Sensitive Multi Protection (1000 ppm F as NaMFP/5.53% potassium citrate/2% zinc citrate); and a matched (Pronamel) placebo control (0 ppm F). Subjects wore their palatal appliances holding eight bovine enamel blocks, previously exposed for 25 minutes to an in vitro erosive challenge with grapefruit juice, for the duration of the experiment. Five minutes after appliance insertion, subjects undertook a supervised, 90-second brush/rinse regimen with their assigned dentifrice. Surface microhardness (SMH) of the specimens was determined prior to the erosive challenge (baseline), after the in vitro erosive challenge, and were remeasured after four hours in situ remineralization following the tooth brushing event. Finally, SMH values were determined after a second in vitro erosive challenge at the end of the in situ remineralization period. Statistical analyses included ANOVA and pair-wise comparisons between treatments, testing at a 5% significance level. RESULTS: All three studies demonstrated significantly greater percent surface microhardness recovery (% SMHr) and percent relative erosion resistance (% RER) for dentifrices containing sodium fluoride compared to placebo controls. Overall, significantly greater % SMHr (p < 0.0001) was observed for Sensodyne Pronamel compared to Blend-a-Med Classic, Crest Pro-Health, and Colgate Sensitive Multi Protection dentifrices. Similarly, Sensodyne Pronamel delivered directionally better % RER vs. Blend-a-Med Classic (p = 0.0731), and significantly higher % RER vs. Crest Pro-Health (p = 0.0074) and Colgate Sensitive Multi Protection (p <0.0001). Crest Cavity Protection demonstrated significantly better % RER (p = 0.031) than Crest Pro-Health, which in turn demonstrated significantly better % RER than the placebo control (p < 0.0001). No other statistically significant between-product comparisons were observed. CONCLUSION: The results of these in situ studies support the effectiveness of dentifrices containing sodium fluoride to reharden enamel previously softened with an erosive challenge. Furthermore, these studies demonstrate the protective effects conferred to enamel, from erosion following the remineralization process in the presence of "ionic" fluoride. Under clinically relevant conditions, Sensodyne Pronamel and Sensodyne Pronamel Gentle Whitening offered superior anti-erosion performance compared to currently marketed dentifrice controls. These studies reinforce previous research indicating the importance of formulation effects on the relative remineralization performance of dentifrices under erosive conditions.

Dentinal hypersensitivity: a 12-week study of a novel dentifrice delivery system comparing different brushing times and assessing the efficacy for hard-to-reach molar teeth.

OBJECTIVE: This study was undertaken to confirm the efficacy of a novel 5% KNO3 gel-to-foam dentifrice, and to determine the effect of brushing duration on the relief offered from the novel dentifrice to subjects with sensitive molars. METHODS: This was a randomized, examiner-blind, two-arm, parallel-group, 12-week, longitudinal study of 141 subjects, stratified into four groups based on the number of sensitive teeth (< 6 or > or = 6) and the presence or absence of sensitive molars. Subjects brushed with the test product twice daily for either 45 seconds or two minutes for eight weeks, and then continued for four weeks with their regular dentifrice. At baseline, four, eight, and 12 weeks, subjects provided subjective evaluations of their sensitivity, and their sensitive teeth were stimulated by air and Yeaple probe. RESULTS: Both brushing groups and all four subgroups exhibited statistically significant reductions from baseline at each post-baseline visit in both their air and tactile sensitivity (p < 0.0001). Between-group comparisons revealed no statistically significant differences in air or tactile sensitivity among the groups. The two-minute group showed a small, but statistically significant increase in both air and tactile sensitivity four weeks after cessation of the test product (p < 0.04). At each post-baseline evaluation, statistically significant decreases from baseline were observed in both brushing groups for "maximum," "typical," and "minimum" subjective pain over the previous seven days (p < 0.001). There were no statistically significant differences between the brushing groups at any visit. For the subgroups with sensitive molars, there were significant decreases from baseline at each post-baseline visit, but no statistically significant differences between brushing groups. In the subgroups without sensitive molars, consistent reductions from baseline were only observed for "maximum" and "typical" pain levels, and at Week 4, the two-minute group had a statistically greater reduction in "minimum" pain level (p = 0.039). Both brushing groups and all four subgroups exhibited statistically significant reductions from baseline at each post-baseline visit in how much they were "bothered" by sensitivity in the previous week (p < 0.003). Between-group comparisons revealed no statistically significant differences. CONCLUSION: A novel gel-to-foam dentifrice with 5% potassium nitrate can provide significant reductions in dentinal hypersensitivity, and this effect extends to hard-to-reach molar teeth. This study confirms that with this new dentifrice technology, the desensitizing efficacy from a 5% KNO3 dentifrice is independent of brushing duration.

Evaluation of a desensitizing test dentifrice using an in situ erosion remineralization model.

OBJECTIVE: To evaluate, in an in situ remineralization model, the ability of a low abrasion fluoride dentifrice containing potassium nitrate to enhance the remineralization of enamel that was previously subjected to an in vitro dietary erosion challenge. METHODOLOGY: Thirteen subjects completed a single-blind (to specimen analyst) crossover design study with four randomly assigned dentifrice treatments: placebo dentifrice (0 ppm F; PD); dose response control dentifrice (250 ppm F; DD); clinically tested fluoride dentifrice (1100 ppm F; FD); and test dentifrice (1150 ppm F + 5% KNO3; TD). Each subject wore a palatal appliance holding eight bovine enamel blocks that were previously exposed for 25 minutes to an in vitro erosive challenge with grapefruit juice. Surface microhardness (SMH) was determined prior to the erosive challenge (baseline), after the in vitro erosive challenge, after in situ remineralization, and after a second in vitro erosive challenge. Statistical analyses included ANOVA and pair-wise comparisons between treatments, testing at a 5% significance level. RESULTS: The mean percent SMH recovery (SD) was 20.4 (7.7)a for PD; 27.4 (5.9)b for DD; 29.5 (8.9)bc for FD; 33.4 (6.7)c for TD. The mean percent net erosion resistance (SD) was -57.7 (10.8)a for PD; -41.3 (11.6)b for DD; -28.7 (9.7)c for FD; -23.6 (7.3)c for TD. Different superscript letters following the means imply statistically significant differences between groups for each response. CONCLUSION: The test dentifrice was shown to significantly enhance the remineralization of enamel previously subjected to an erosion challenge.