Animal Models Of Alcohol Use Disorder Research Articles

Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats.

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.

Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse.

For most psychiatric disorders, including alcohol use disorder (AUD), approved pharmacological treatments are limited in their effectiveness, and new drugs that can easily be translated into the clinic are needed. Currently, great hope lies in the potential of psychedelics to effectively treat AUD. The primary hypothesis is that a single session of psychedelic-guided psychotherapy can restore normal brain function in AUD individuals and thereby reduce the risk of relapse in the long run. Here we applied three different treatment schedules with psilocybin/LSD in order to investigate relapse-like drinking in the alcohol deprivation effect (ADE) model. In contrast to the primary hypothesis, psychedelics had no long-lasting effects on the ADE in male and female rats, neither when administered in a high dosage regime that is comparable to the one used in clinical studies, nor in a chronic microdosing scheme. Only sub-chronic treatment with psilocybin produced a short-lasting anti-relapse effect. However, it is not a translatable treatment option to give psychedelics sub-chronically for relapse prevention. In conclusion, our results in the ADE model do not support the hypothesis that microdosing or high doses of psychedelic reduce relapse behavior. This conclusion has to be confirmed by applying other animal models of AUD. It could also well be that animal models of AUD might be unable to fully capture the therapeutic potential of psychedelic drugs and that only future large-scale clinical trials will be able to demonstrate the efficacy of psychedelics as a new treatment option for AUD.

Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on the Liver and the Brain.

Background: Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver. Aim: To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies. Methods: Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD. Results: Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties. Conclusions: CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual’s drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.

Opposing roles of Sigma‐1 and Sigma‐2 receptors in heavy alcohol drinking and associated mechanical allodynia in mice

Alcohol Use Disorder (AUD) is a serious and complex neuropsychiatric disorder characterized by excessive alcohol intake, inability to control consumption, and the emergence of a negative emotional state in the absence of alcohol. While the role of the Sigma‐1 receptor (Sig‐1R) in animal models of AUD has been demonstrated, the role of Sigma‐2 receptor/Transmembrane Protein 97 (Sig‐2R/TMEM97), which has recently been cloned, is still unclear. Using an intermittent access, 2‐bottle choice paradigm, the effects of the Sig‐2R/TMEM97 modulator JVW‐1034 (0–30 mg/kg, i.p.) on ethanol drinking in male C57Bl/6J mice were assessed. Sucrose intake was used to control for non‐specific effects of the drug on an alternate reinforcer in a separate study, and locomotor intake was also assessed. In addition, using an automated von Frey filament test, the effects of JVW‐1034 on mechanical sensitivity in alcohol drinking mice was tested during withdrawal. The effects of the Sig‐2R modulator were compared to those of BD‐1063 (0–30 mg/kg, i.p.), a preferential Sig‐1R antagonist. Results showed that JVW‐1034 reduced alcohol intake and preference in this model, without affecting water intake. Sucrose intake was not affected by the drug, suggesting selectivity of the effect for alcohol. JVW‐1034 also blocked the mechanical allodynia induced by chronic alcohol drinking without affecting sensitivity in control mice. Lastly, JVW‐1034 did not affect locomotor activity in either group. BD‐1063 had a very similar profile. These data suggest that Sig‐1R and Sig‐2R play opposite roles in the regulation of alcohol drinking and associated allodynia and hyperalgesia, and lay the foundation for more extensive studies examining the involvement of the Sig‐2R/TMEM97 system in AUD.Support or Funding InformationR01‐AA024439This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies.

Developing efficacious treatments for alcohol use disorder (AUD) has proven difficult. The insidious nature of the disease necessitates a deep understanding of its underlying biology as well as innovative approaches to ameliorate ethanol-related pathophysiology. Excessive ethanol seeking and relapse are generated by long-term changes to membrane properties, synaptic physiology, and plasticity throughout the limbic system and associated brain structures. Each of these factors can be modulated by metabotropic glutamate (mGlu) receptors, a diverse set of G protein-coupled receptors highly expressed throughout the central nervous system. Here, we discuss how different components of the mGlu receptor family modulate neurotransmission in the limbic system and other brain regions involved in AUD etiology. We then describe how these processes are dysregulated following ethanol exposure and speculate about how mGlu receptor modulation might restore such pathophysiological changes. To that end, we detail the current understanding of the behavioral pharmacology of mGlu receptor-directed drug-like molecules in animal models of AUD. Together, this review highlights the prominent position of the mGlu receptor system in the pathophysiology of AUD and provides encouragement that several classes of mGlu receptor modulators may be translated as viable treatment options.

Class I HDAC Inhibitors: Potential New Epigenetic Therapeutics for Alcohol Use Disorder (AUD).

Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.

Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment

RationaleDespite epidemiological and clinical data indicating marked gender differences in alcohol use disorders (AUDs), few preclinical studies have examined sex differences in animal models of AUDs. ObjectiveThe purpose of this study was to first characterize sex differences in ethanol consumption and reinforcement in an alcohol preferring (P) rat model of alcoholism, then use this model to screen pharmacological treatments for sex-specific effects. MethodsEthanol consumption was first assessed in male and female P rats under a three-bottle free-choice procedure. Next, ethanol's reinforcing effects were assessed under a fixed-ratio 1 (FR1) schedule followed by a progressive-ratio (PR) schedule. Finally, the effects of two pharmacological treatments for AUDs, naltrexone (1mg/kg) and topiramate (10 or 20mg/kg), alone and in combination, were tested for sex-specific differences in their efficacy at reducing ethanol's reinforcing effects. ResultsAlthough females initially had higher consumption of and preference for ethanol, male rats increased their consumption and preference over time and rapidly became equal to females. Following prolonged 24-hour/day access, males and females self-administered similar levels of ethanol under FR1 and PR schedules. In response to pharmacological treatment, we observed some sex differences and similarities, most notably, a more robust effect of the combination of naltrexone and topiramate in males as compared to females. ConclusionsThis model of selectively bred P rats may be useful for understanding sex differences in AUDs and related behavior and their underlying neurobiological mechanisms and treatment.