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Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain.

Rivera P, Blanco E, Bindila L, Alen F, Vargas A, Rubio L, Pavón FJ, Serrano A, Lutz B, Rodríguez de Fonseca F, Suárez J - Front Cell Neurosci (2015)

Bottom Line: Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations.Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus.JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ.

View Article: PubMed Central - PubMed

Affiliation: UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga-Hospital Universitario Regional de Málaga Málaga, Spain.

ABSTRACT
Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence.

No MeSH data available.


Related in: MedlinePlus

Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on the cumulative ad libitum consumption of sucrose and ethanol. (A) Compared consumption of sucrose and ethanol. (B) Treatment effects on sucrose consumption. (C) Treatment effects on ethanol consumption. The histograms represents the mean + s.e.m. (n = 6) per experimental group. Bonferroni's test following repeated measures ANOVA: ###P < 0.001 vs. the backward time points; $$∕$$$P < 0.01/0.001 vs. day 10; &&∕&&&P < 0.01/0.001 vs. day 11; P < 0.01 vs. day 12. Bonferroni's test following two-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001 vs. the sucrose-vehicle or ethanol-vehicle groups at the same time point.
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Figure 2: Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on the cumulative ad libitum consumption of sucrose and ethanol. (A) Compared consumption of sucrose and ethanol. (B) Treatment effects on sucrose consumption. (C) Treatment effects on ethanol consumption. The histograms represents the mean + s.e.m. (n = 6) per experimental group. Bonferroni's test following repeated measures ANOVA: ###P < 0.001 vs. the backward time points; $$∕$$$P < 0.01/0.001 vs. day 10; &&∕&&&P < 0.01/0.001 vs. day 11; P < 0.01 vs. day 12. Bonferroni's test following two-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001 vs. the sucrose-vehicle or ethanol-vehicle groups at the same time point.

Mentions: Rats were habituated to a controlled-isocaloric pair-feeding period of sucrose and alcohol diets until a stable rate of alcoholic consumption was reached (12.4 ± 1.4 g of ethanol/kg body weight/day, up to 1 week). All rats were fed ad libitum for 6 days after habituation (Figure 1). Bonferroni's multiple comparison test following the repeated measures ANOVA analysis indicated significant increases in the cumulative intake of sucrose diet when all time points during these 6 days were compared (###P < 0.001). However, an increase in the cumulative intake of alcohol diet was detected from day 13 onward (day 13: $$P < 0.01; day 14 on: $$$P < 0.001). Two-way ANOVA analysis revealed a clear diet effect when ad libitum sucrose and alcohol consumptions were compared [average: 30.6 ± 1.3 vs. 7.3 ± 1.1 g/kg/day; Cumulative intake: F(1, 60) = 1104.4, P < 0.0001]. A time effect [F(5, 60) = 204.8, P < 0.0001] and interaction between diet and time [F(5, 60) = 97.5, P < 0.0001] were found, which indicates that the increased cumulative consumption of sucrose and alcohol were different over time. Bonferroni analysis revealed an increased sucrose intake compared to alcohol intake from the first day of ad libitum consumption (day 10: P < 0.05; day 11: P < 0.01; day 12 on: P < 0.001; Figure 2A).


Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain.

Rivera P, Blanco E, Bindila L, Alen F, Vargas A, Rubio L, Pavón FJ, Serrano A, Lutz B, Rodríguez de Fonseca F, Suárez J - Front Cell Neurosci (2015)

Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on the cumulative ad libitum consumption of sucrose and ethanol. (A) Compared consumption of sucrose and ethanol. (B) Treatment effects on sucrose consumption. (C) Treatment effects on ethanol consumption. The histograms represents the mean + s.e.m. (n = 6) per experimental group. Bonferroni's test following repeated measures ANOVA: ###P < 0.001 vs. the backward time points; $$∕$$$P < 0.01/0.001 vs. day 10; &&∕&&&P < 0.01/0.001 vs. day 11; P < 0.01 vs. day 12. Bonferroni's test following two-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001 vs. the sucrose-vehicle or ethanol-vehicle groups at the same time point.
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Figure 2: Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on the cumulative ad libitum consumption of sucrose and ethanol. (A) Compared consumption of sucrose and ethanol. (B) Treatment effects on sucrose consumption. (C) Treatment effects on ethanol consumption. The histograms represents the mean + s.e.m. (n = 6) per experimental group. Bonferroni's test following repeated measures ANOVA: ###P < 0.001 vs. the backward time points; $$∕$$$P < 0.01/0.001 vs. day 10; &&∕&&&P < 0.01/0.001 vs. day 11; P < 0.01 vs. day 12. Bonferroni's test following two-way ANOVA: *P < 0.05, **P < 0.01, ***P < 0.001 vs. the sucrose-vehicle or ethanol-vehicle groups at the same time point.
Mentions: Rats were habituated to a controlled-isocaloric pair-feeding period of sucrose and alcohol diets until a stable rate of alcoholic consumption was reached (12.4 ± 1.4 g of ethanol/kg body weight/day, up to 1 week). All rats were fed ad libitum for 6 days after habituation (Figure 1). Bonferroni's multiple comparison test following the repeated measures ANOVA analysis indicated significant increases in the cumulative intake of sucrose diet when all time points during these 6 days were compared (###P < 0.001). However, an increase in the cumulative intake of alcohol diet was detected from day 13 onward (day 13: $$P < 0.01; day 14 on: $$$P < 0.001). Two-way ANOVA analysis revealed a clear diet effect when ad libitum sucrose and alcohol consumptions were compared [average: 30.6 ± 1.3 vs. 7.3 ± 1.1 g/kg/day; Cumulative intake: F(1, 60) = 1104.4, P < 0.0001]. A time effect [F(5, 60) = 204.8, P < 0.0001] and interaction between diet and time [F(5, 60) = 97.5, P < 0.0001] were found, which indicates that the increased cumulative consumption of sucrose and alcohol were different over time. Bonferroni analysis revealed an increased sucrose intake compared to alcohol intake from the first day of ad libitum consumption (day 10: P < 0.05; day 11: P < 0.01; day 12 on: P < 0.001; Figure 2A).

Bottom Line: Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations.Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus.JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ.

View Article: PubMed Central - PubMed

Affiliation: UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga-Hospital Universitario Regional de Málaga Málaga, Spain.

ABSTRACT
Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence.

No MeSH data available.


Related in: MedlinePlus