Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats.
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ABSTRACT:
SUBMITTER: Lovelock DF
PROVIDER: S-EPMC9263963 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Previous research has established sex differences associated with nicotine intake, however a significant gap in knowledge remains regarding the molecular mechanisms that govern these differences at the transcriptional level. One critical regulator of transcription are microRNAs (miRNAs). miRNAs are a family of non-coding RNAs that regulate an array of important biological functions altered in several disease states, including neuroadaptive changes within the brain associated with drug dependence. We examined the prefrontal cortex (PFC) from male and female Sprague-Dawley rats following self-administration (22 days) of nicotine or yoked saline controls using next generation RNA-Sequencing (RNA-Seq) technology and found an array of miRNAs to be significantly and differentially regulated by nicotine self-administration. Of these, we found the expression of miR-199a and 214, which are expressed on the same cluster of chromosome 1, to be upregulated in the female rats exposed to nicotine; upregulation in this group was further validated by real time polymerase chain reaction (RT-PCR). Bioinformatics analysis to assess common targets of miR-199/214 identified Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)- dependent deacetylase that plays a role in apoptosis, neuron survival, and stress resistance. Using western-blot, we confirmed downregulation of SIRT1 and increased cleaved caspase 3 expression in the brains of nicotine-exposed female rats and no change in expression levels in the other groups. Collectively, our findings highlight a miR-199/214 regulatory network that, through SIRT1, may be associated with nicotine seeking in females which may serve as a potential therapeutic target for sex-specific treatment approaches.
| S-EPMC6269448 | biostudies-literature
Project description:Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.
| S-EPMC8477003 | biostudies-literature
Project description:RationaleAlcohol and nicotine co-dependence is common in humans, and nicotine increases alcohol drinking in humans without alcohol use disorder (AUD). Nevertheless, there is little basic research on the interactions between the reinforcing effects of these two drugs.ObjectivesThe aim of this study was to investigate the effects of chronic nicotine injections on oral alcohol self-administration in alcohol non-dependent rats.MethodsAfter stable alcohol self-administration was reached (baseline) and a period without alcohol access, adult male rats were treated with chronic nicotine or saline injections for 105 days during which time they were tested intermittently for alcohol self-administration. There were 3 experimental groups: (1) saline, rats treated with saline for 105 days; (2) early nicotine, rats treated with nicotine for 70 days, and then with saline for 35 days; and (3) late nicotine: rats treated with saline for 35 days, and then with nicotine for 70 days.ResultsOur results indicate that (1) chronic nicotine increases alcohol consumption regardless of whether exposure to alcohol was interrupted (early nicotine) or not (late nicotine) before the start of nicotine treatment, (2) the number of alcohol reinforcements correlates to blood-alcohol levels, and (3) alcohol self-administration rapidly decreases when nicotine is no longer available (early nicotine).ConclusionsThese discoveries may have clinical implications in social drinkers that use nicotine products, in that chronic nicotine can escalate alcohol drinking and cessation of nicotine exposure may decrease alcohol use.
| S-EPMC7796964 | biostudies-literature
Project description:The adolescent hippocampus is highly vulnerable to alcohol-induced damage, which could contribute to their increased susceptibility to alcohol use disorder. Altered adult hippocampal neurogenesis represents one potential mechanism by which alcohol (ethanol) affects hippocampal function. Based on the vulnerability of the adolescent hippocampus to alcohol-induced damage, and prior reports of long-term alcohol-induced effects on adult neurogenesis, we predicted adverse effects on adult neurogenesis in the adolescent brain following abstinence from alcohol dependence. Thus, we examined neurogenesis in adolescent male rats during abstinence following a 4-day binge model of alcohol dependence. Bromodeoxyuridine and Ki67 immunohistochemistry revealed a 2.2-fold increase in subgranular zone cell proliferation after 7 days of abstinence. Increased proliferation was followed by a 75% increase in doublecortin expression and a 56% increase in surviving bromodeoxyuridine-labeled cells 14 and 35 days post-ethanol exposure, respectively. The majority of newborn cells in ethanol and control groups co-localized with NeuN, indicating a neuronal phenotype and therefore a 1.6-fold increase in hippocampal neurogenesis during abstinence. Although these results mirror the magnitude of reactive neurogenesis described in adult rat studies, ectopic bromodeoxyuridine and doublecortin positive cells were detected in the molecular layer and hilus of adolescent rats displaying severe withdrawal symptoms, an effect that has not been described in adults. The presence of ectopic neuroblasts suggests that a potential defect exists in the functional incorporation of new neurons into the existing hippocampal circuitry for a subset of rats. Age-related differences in functional incorporation could contribute to the increased vulnerability of the adolescent hippocampus to ethanol.
| S-EPMC3844012 | biostudies-literature
Project description:Rodent models of human disease can be valuable for understanding the mechanisms of a disease and for identifying novel therapies. However, it is critical that these models be vetted prior to committing resources to developing novel therapeutics. Failure to confirm the model can lead to significant losses in time and resources. One model used for migraine headache is to administer nitroglycerin to rodents. Nitroglycerin is known to produce migraine-like pain in humans and is presumed to do the same in rodents. It is not known, however, if the mechanism for nitroglycerin headaches involves the same pathological processes as migraine. In the absence of known mechanisms, it becomes imperative that the model not only translates into successful clinical trials but also successfully reverse translates by demonstrating efficacy of current therapeutics. In this study female rats were given nitroglycerin and nociception was evaluated in OPADs. Estrous was not monitored. Based on the ED50 of nitroglycerin a dose of 10 mg/kg was used for experiments. Sumatriptan, caffeine, buprenorphine and morphine were administered to evaluate the reverse translatability of the model. We found that nitroglycerin did not produce mechanical allodynia in the face of the rats, which is reported to be a consequence of migraine in humans. Nitroglycerin reduced the animals' participation in the assay. The reduced activity was verified using an assay to measure exploratory behavior. Furthermore, the effects of nitroglycerin were not reversed or prevented by agents that are effective acute therapies for migraine. Two interesting findings from this study, however, were that morphine and nitroglycerin interact to increase the rats' tolerance of mechanical stimuli on their faces, and they work in concert to slow down the central motor pattern generator for licking on the reward bottle. These interactions suggest that nitroglycerin generated nitric oxide and mu opioid receptors interact with the same neuronal circuits in an additive manner. The interaction of nitroglycerin and morphine on sensory and motor circuits deserves additional examination. In conclusion, based on the results of this study the use of nitroglycerin at these doses in naïve female rats is not recommended as a model for migraine headaches.
| S-EPMC7744726 | biostudies-literature
Project description:Withdrawal from opioid painkillers can produce short-lived physical symptoms and protracted psychological symptoms including anxiety and depressive-like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self-administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self-medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating-dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating-dose morphine (5-30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2-week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females.
| S-EPMC8129895 | biostudies-literature
Project description:The study of Alcohol Use Disorders (AUD) in preclinical models is hampered by difficulty in training rodents to voluntarily consume high levels of alcohol. The intermittency of alcohol access/exposure is well known to modulate alcohol consumption (e.g., alcohol deprivation effect, intermittent-access two-bottle-choice) and recently, intermittent access operant self-administration procedures have been used to produce more intense and binge-like self-administration of intravenous psychostimulant and opioid drugs. In the present study, we sought to systematically manipulate the intermittency of operant self-administered alcohol access to determine the feasibility of promoting more intensified, binge-like alcohol consumption. To this end, 24 male and 23 female NIH Heterogeneous Stock rats were trained to self-administer 10% w/v ethanol, before being split into three different-access groups. Short Access (ShA) rats continued receiving 30-min training sessions, Long Access (LgA) rats received 16-h sessions, and Intermittent Access (IntA) rats received 16-h sessions, wherein the hourly alcohol-access periods were shortened over sessions, down to 2 min. IntA rats demonstrated an increasingly binge-like pattern of alcohol drinking in response to restriction of alcohol access, while ShA and LgA rats maintained stable intake. All groups were tested on orthogonal measures of alcohol-seeking and quinine-punished alcohol drinking. The IntA rats displayed the most punishment-resistant drinking. In a separate experiment, we replicated our main finding, that intermittent access promotes a more binge-like pattern of alcohol self-administration using 8 male and 8 female Wistar rats. In conclusion, intermittent access to self-administered alcohol promotes more intensified self-administration. This approach may be useful in developing preclinical models of binge-like alcohol consumption in AUD.
| S-EPMC10247413 | biostudies-literature
Project description:BackgroundGlucagon-like peptide1 receptor (GLP-1R) agonists have been found to reduce alcohol drinking in rodents and overweight patients with alcohol use disorder (AUD). However, the probability of low semaglutide doses, an agonist with higher potency and affinity for GLP-1R, to attenuate alcohol-related responses in rodents and the underlying neuronal mechanisms is unknown.MethodsIn the intermittent access model, we examined the ability of semaglutide to decrease alcohol intake and block relapse-like drinking, as well as imaging the binding of fluorescently marked semaglutide to nucleus accumbens (NAc) in both male and female rats. The suppressive effect of semaglutide on alcohol-induced locomotor stimulation and in vivo dopamine release in NAc was tested in male mice. We evaluated effect of semaglutide on the in vivo release of dopamine metabolites (DOPAC and HVA) and gene expression of enzymes metabolising dopamine (MAOA and COMT) in male mice.FindingsIn male and female rats, acute and repeated semaglutide administration reduced alcohol intake and prevented relapse-like drinking. Moreover, fluorescently labelled semaglutide was detected in NAc of alcohol-drinking male and female rats. Further, semaglutide attenuated the ability of alcohol to cause hyperlocomotion and to elevate dopamine in NAc in male mice. As further shown in male mice, semaglutide enhanced DOPAC and HVA in NAc when alcohol was onboard and increased the gene expression of COMT and MAOA.InterpretationAltogether, this indicates that semaglutide reduces alcohol drinking behaviours, possibly via a reduction in alcohol-induced reward and NAc dependent mechanisms. As semaglutide also decreased body weight of alcohol-drinking rats of both sexes, upcoming clinical studies should test the plausibility that semaglutide reduces alcohol intake and body weight in overweight AUD patients.FundingSwedish Research Council (2019-01676), LUA/ALF (723941) from the Sahlgrenska University Hospital and the Swedish brain foundation.
| S-EPMC10363436 | biostudies-literature
Project description:Cognitive dysfunction is a common, often long-term complaint following acquired traumatic brain injury (TBI). Cognitive deficits suggest dysfunction in hippocampal circuits. The goal of the studies described here is to phenotype in both male and female mice the hippocampal-dependent learning and memory deficits resulting from TBI sustained by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) device-a model that delivers both a contact-concussion injury as well as unrestrained rotational head movement. Mice sustained either sham procedures or four injuries (0.7 J, 24-h intervals). Spatial learning and memory skills assessed in the Morris water maze (MWM) approximately 3 weeks following injuries were significantly impaired by brain injuries; however, slower swimming speeds and poor performance on visible platform trials suggest that measurement of cognitive impairment with this test is confounded by injury-induced motor and/or visual impairments. A separate experiment confirmed hippocampal-dependent cognitive deficits with trace fear conditioning (TFC), a behavioral test less dependent on motor and visual function. Male mice had greater injury-induced deficits on both the MWM and TFC tests than female mice. Pathologically, the injury was characterized by white matter damage as observed by silver staining and glial fibrillary acidic protein (astrogliosis) in the optic tracts, with milder damage seen in the corpus callosum, and fimbria and brainstem (cerebral peduncles) of some animals. No changes in the density of GABAergic parvalbumin-expressing cells in the hippocampus, amygdala, or parietal cortex were found. This experiment confirmed significant sexually dimorphic cognitive impairments following a repeated, diffuse brain injury.
| S-EPMC8126427 | biostudies-literature
Project description:In drug self-administration procedures, extended-access test sessions allow researchers to model maladaptive patterns of excessive and escalating drug intake that are characteristic of human substance-abusing populations.The purpose of the present study was to examine the ability of aerobic exercise to decrease excessive and escalating patterns of drug intake in male and female rats responding under extended-access conditions.Male and female Long-Evans rats were obtained at weaning and divided into sedentary (no running wheel) and exercising (running wheel) groups immediately upon arrival. After 6 weeks, rats were surgically implanted with intravenous catheters and allowed to self-administer cocaine under positive reinforcement contingencies. In experiment 1, cocaine self-administration was examined during 23-h test sessions that occurred every 4 days. In experiment 2, the escalation of cocaine intake was examined during daily 6-h test sessions over 14 consecutive days.In experiment 1, sedentary rats self-administered significantly more cocaine than exercising rats during uninterrupted 23-h test sessions, and this effect was apparent in both males and females. In experiment 2, sedentary rats escalated their cocaine intake to a significantly greater degree than exercising rats over the 14 days of testing. Although females escalated their cocaine intake to a greater extent than males, exercise effectively attenuated the escalation of cocaine intake in both sexes.These data indicate that aerobic exercise decreases maladaptive patterns of excessive and escalating cocaine intake under extended-access conditions.
| S-EPMC3752981 | biostudies-literature