Rationale-Whereas co-use of alcohol and marijuana is prevalent in adolescents, the effects of such drug co-exposure on ingestive and cognitive behaviors remain largely unexplored. We hypothesized that co-exposure to alcohol and Δ 9-tetrahydrocannabinol (THC), the main psychoactive constitute of marijuana, alters feeding behavior and cognition differently from either drug alone. Methods-Male rats received daily THC (3-20 mg/kg/day) or oil vehicle through subcutaneous injection or consumption of a cookie with access to saccharin or saccharin-sweetened alcohol during adolescence (P30-45). Barnes maze and sucrose preference tests were applied to assess spatial memory and behavioral flexibility and abstinence-related anhedonia, respectively. Results-Subcutaneous THC did not affect alcohol intake, but dose-dependently increased acute (3-h) chow intake and reduced weight gain. Moderate alcohol consumption reduced the acute hyperphagic effect of subcutaneous THC. By contrast, oral THC at a dose > 5 mg/kg robustly reduced alcohol intake without affecting 3-h chow intake. At this dose, some rats stopped consuming the THC-laced cookies. Furthermore, oral THC reduced weight gain, and co-exposure to alcohol alleviated this effect. Chronic subcutaneous, but not oral, THC reduced sucrose intake during abstinence. Neither treatment impaired cognitive behaviors in the Barnes maze. Conclusion-Moderate alcohol and THC consumption can interact to elicit unique outcomes on ingestive behaviors and energy balance. Importantly, this study established a novel model of voluntary alcohol and THC consumption for studying mechanisms underlying the consequences of adolescent onset co-use of the two drugs.
BackgroundThe purpose of this project was to identify short hairpin RNA (shRNA) sequences that can suppress expression of human CAPN5 in which gain-of-function mutants cause autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). We created HEK293T cells that stably express an ADNIV disease allele, CAPN5-p.R243L. Transfection protocols were optimized for neuroblastoma SHSY5Y cells. The gene silencing effect of four different shRNA plasmids that target CAPN5 was tested. RNA and protein expression was determined using quantitative RT-PCR and immunoblot analysis.FindingsTwo of four shRNA plasmids reduced mutant CAPN5 RNA in a stable cell line. Similar knockdown was observed in SH-SY5Y cells that natively express CAPN5. Lactose dehydrogenase assays showed that down-regulation of CAPN5 was not cytotoxic.ConclusionsCAPN5 expression can be suppressed by shRNA-based RNA interference. Further testing in ADNIV models will determine the potential of gene silencing as a strategy to treat, delay, or prevent blindness in ADNIV patients.
Cannabis and alcohol co-use is common, and the trend may increase further given the current popularity of cannabis legalization. However, the metabolic consequences of such co-use are unclear. Here, we investigated how co-administration of alcohol and ∆
9
-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, affects body weight and visceral adiposity, and glucose and insulin homeostasis in rats. For 16 consecutive days during adolescence, male rats drank saccharin or alcohol after receiving subcutaneous oil or THC injections in Experiment 1 and voluntarily consumed alcohol, THC edible, or both drugs in Experiment 2. Experiment 1 showed that following abstinence, drug co-exposure reduced visceral fat and the amount of insulin required to clear glucose during an oral glucose tolerance test (OGTT). In Experiment 2, rats received a high-fat diet (HFD) after 3-week abstinence. Although adolescent drug use did not interact with the HFD to worsen hyperglycemia and hyperinsulinemia during an OGTT, HFD-fed rats that co-used alcohol and THC had the lowest insulin levels 75 min after an insulin injection, suggesting an altered rate of insulin secretion and degradation. These results suggest that THC and alcohol co-exposure can distinctly alter the physiology of glucose and insulin homeostasis in a rodent model.
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