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Acute Ethanol Inhibition of Adult Hippocampal Neurogenesis Involves CB 1 Cannabinoid Receptor Signaling
Author(s) -
Khatri Dal,
Laroche Genevieve,
Grant Marion L.,
Jones Victoria M.,
Vetreno Ryan P.,
Crews Fulton T.,
Mukhopadhyay Somnath
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13608
Subject(s) - neurogenesis , doublecortin , dentate gyrus , cannabinoid , cannabinoid receptor , agonist , endocannabinoid system , hippocampal formation , pharmacology , rimonabant , chemistry , endocrinology , medicine , receptor , biology , neuroscience , biochemistry
Background Chronic ethanol (EtOH) exposure has been found to inhibit adult hippocampal neurogenesis in multiple models of alcohol addiction. However, acute EtOH inhibition of adult neurogenesis is not well studied. Although many abused drugs have been found to inhibit adult neurogenesis, few have studied cannabinoids or cannabinoids with EtOH, although human use of both together is becoming more common. We used an acute binge alcohol drinking model in combination with select cannabinoid receptor agonists and antagonists to investigate the actions of each alone and together on hippocampal neurogenesis. Methods Adult male Wistar rats were treated with an acute binge dose of EtOH (5 g/kg, i.g.), cannabinoid 1 receptor ( CB 1R) or cannabinoid 2 receptor ( CB 2R) agonists, as well as selective cannabinoid ( CB ) antagonists, alone or combined. Hippocampal doublecortin (DCX), Ki67, and activated cleaved caspase‐3 ( CC 3) immunohistochemistry were used to assess neurogenesis, neuroprogenitor proliferation, and cell death, respectively. Results We found that treatment with EtOH or the CB 1R agonist, arachidonoyl‐2′‐chloroethylamide ( ACEA ), and the combination significantly reduced DCX‐positive neurons ( DCX + IR ) in dentate gyrus (DG) and increased CC 3. Further, using an inhibitor of endocannabinoid metabolism, for example, JZL 195, we also found reduced DCX + IR neurogenesis. Treatment with 2 different CB 1R antagonists ( AM 251 or SR 141716) reversed both CB 1R agonist and EtOH inhibition of adult neurogenesis. CB 2R agonist HU ‐308 treatment did not produce any significant change in DCX + IR . Interestingly, neither EtOH nor CB 1R agonist produced any alteration in cell proliferation in DG as measured by Ki67 + cell population, but CC3‐positive cell numbers increased following EtOH or ACEA treatment suggesting an increase in cell death. Conclusions Together, these findings suggest that acute CB 1R cannabinoid receptor activation and binge EtOH treatment reduce neurogenesis through mechanisms involving CB 1R.