Differences in Behavioral Responding in Adult and Aged Rats Following Chronic Ethanol Exposure

Novier, Adelle; Ornelas, Laura C.; Diaz-Granados, Jaime L.; Matthews, Douglas B.

doi:10.1111/acer.13098

Cited by 23 publications

(21 citation statements)

References 45 publications

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“…In MWM, however, there was no effect of a history of alcohol drinking on latency to escape, suggesting that spatial learning was not affected by alcohol exposure. Previous studies demonstrating decreased MWM learning after alcohol exposure were in rats (Lukoyanov et al, 1999;Novier et al, 2016), and it is unclear why we did not observe these changes in this study, but species may be a factor. Besides species, the age of animals being studied is a potential factor.…”

Section: Chronic Voluntary Alcohol Drinking Induces Anxiety-like Behacontrasting

confidence: 74%

Chronic Voluntary Alcohol Drinking Causes Anxiety-like Behavior, Thiamine Deficiency, and Brain Damage of Female Crossed High Alcohol Preferring Mice

Liu

et al. 2021

Front. Pharmacol.

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The central nervous system is vulnerable to chronic alcohol abuse, and alcohol dependence is a chronically relapsing disorder which causes a variety of physical and mental disorders. Appropriate animal models are important for investigating the underlying cellular and molecular mechanisms. The crossed High Alcohol Preferring mice prefer alcohol to water when given free access. In the present study, we used female cHAP mice as a model of chronic voluntary drinking to evaluate the effects of alcohol on neurobehavioral and neuropathological changes. The female cHAP mice had free-choice access to 10% ethanol and water, while control mice had access to water alone at the age of 60-day-old. The mice were exposed to alcohol for 7 months then subjected to neurobehavioral tests including open field (OF), elevated plus maze (EPM), and Morris water maze (MWM). Results from OF and EPM tests suggested that chronic voluntary drinking caused anxiety-like behaviors. After behavior tests, mice were sacrificed, and brain tissues were processed for biochemical analyses. Alcohol altered the levels of several neurotransmitters and neurotrophic factors in the brain including gamma-Aminobutyric acid (GABA), corticotropin-releasing factor, cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor. Alcohol increased the expression of neuroinflammation markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor 2 (CCR2). Alcohol also induced cleaved caspase-3 and glial fibrillary acidic protein, indicative of neurodegeneration and gliosis. In addition, alcohol inhibited the expression of thiamine transporters in the brain and reduced thiamine levels in the blood. Alcohol also caused oxidative stress and endoplasmic reticulum (ER) stress, and stimulated neurogenesis.

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Section: Chronic Voluntary Alcohol Drinking Induces Anxiety-like Behacontrasting

confidence: 74%

Chronic Voluntary Alcohol Drinking Causes Anxiety-like Behavior, Thiamine Deficiency, and Brain Damage of Female Crossed High Alcohol Preferring Mice

Liu

et al. 2021

Front. Pharmacol.

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“…Aged humans show differential GABA A receptor subunit expression (Kanaumi et al., ), have higher physiological sensitivity to alcohol (Menninger, ), and are more susceptible to the deficits associated with chronic AUD (Pfefferbaum et al., ). Further, aged animals show greater EtOH‐induced memory impairment and exhibit fewer withdrawal symptoms compared with adult animals (Novier et al., ), suggesting that aged adult individuals have unique responses to chronic EtOH exposure. In this study, we also show that 3α,5α‐THP concentrations are negatively correlated with age in amygdala regions, but not in the VTA and SNM regions.…”

Section: Discussionmentioning

confidence: 99%

Cellular GABAergic Neuroactive Steroid (3α,5α)‐3‐Hydroxy‐Pregnan‐20‐One (3α,5α‐THP) Immunostaining Levels Are Increased in the Ventral Tegmental Area of Human Alcohol Use Disorder Patients: A Postmortem Study

Sait

Maldonado‐Devincci

Beattie

et al. 2017

Alcoholism Clin & Exp Res

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Background The GABAergic neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) enhances GABAergic activity and produces subjective effects similar to ethanol. The effect of chronic alcohol exposure on 3α,5α-THP concentrations has been studied in mouse, rat, and monkey limbic brain areas. Chronic ethanol exposure produced divergent brain region and cell specific changes in 3α,5α-THP concentrations in animal studies. However, 3α,5α-THP levels in similar human brain regions have never been examined in individuals diagnosed with alcohol use disorder (AUD). Therefore, we used immunohistochemistry to examine 3α,5α-THP levels in the ventral tegmental area (VTA), substantia nigra pars medialis (SNM), and amygdala of human postmortem brains of patients diagnosed with AUD compared to social drinkers. The effects of sex and liver disease on 3α,5α-THP concentrations were examined in the aforementioned brain regions. Methods Human postmortem brains of AUD patients and age-matched controls were obtained from the New South Wales Brain Tissue Resource Center. Immunohistochemistry was performed using anti-3α,5α-THP antibody on formalin fixed and paraffin embedded brain sections to detect cellular 3α,5α-THP levels. Immunoreactivity was analyzed by pixel density/mm2 for the comparison between AUD patients and controls. Results 3α,5α-THP immunoreactivity was increased by 23.2±9% in the VTA of AUD patients compared to age matched controls (p= 0.014). Moreover, a 29.6±10% increase in 3α,5α-THP immunoreactivity was observed in the SNM of male AUD patients compared to male controls (p<0.01), but not in female subjects. 3α,5α-THP immunoreactivity in the VTA and SNM regions did not differ between non-cirrhotic and cirrhotic AUD patients. A sex difference in 3α,5α-THP immunoreactivity (female 51±18% greater than male) was observed among control subjects in the SNM, but no other brain region. 3α,5α-THP immunoreactivity in the basolateral and lateral amygdala were negatively correlated with the length of the tissue fixation time as well as the age of the subjects, precluding assessment of the effect of AUD. Conclusions Cellular 3α,5α-THP levels in VTA are increased in human AUD patients, an effect that is likely independent of sex and liver disease. The differences between animal models and human studies should be factored into the interpretation of the physiological significance of elevated 3α,5α-THP levels in humans.

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“…Rats were given a week off between tests to allow for recovery from multiple blood sampling. Since previous studies have reported age-related differences in EtOH pharmacokinetics at 3.0 g/kg but not 1.5 g/kg in males (Novier et al, 2016; Ornelas et al, 2015), we chose to examine BECs following several doses of EtOH. The low dose of EtOH was utilized previously in the test of social behavior (0.75 g/kg).…”

Section: Methodsmentioning

confidence: 99%

“…Altered behavior in response to EtOH in late aging could be due simply to age differences in EtOH pharmacokinetics and/or EtOH absorption and distribution. Indeed, there are some studies demonstrating impaired clearance of high doses of EtOH (3.0 g/kg) in 18-month-old Sprague-Dawley rats (Ornelas et al, 2015), although others have shown no age differences in BECs following acute administration of lower doses of EtOH (1.5–2.5 g/kg) (Matthews and Mittleman, 2017; Novier et al, 2016). All the aforementioned studies were performed exclusively in males.…”

Section: Introductionmentioning

confidence: 99%

Late aging alters behavioral sensitivity to ethanol in a sex-specific manner in Fischer 344 rats

Perkins

Vore

Lovelock

2018

Pharmacology Biochemistry and Behavior

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Responsiveness to ethanol (EtOH) differs as a function of age. Adolescent rodents are less sensitive than adults to the sedative effects of EtOH, whereas they show enhanced sensitivity to EtOH-induced social facilitation. Late aging is associated with a natural decline in social behavior and aging-related peculiarities in sensitivity to EtOH have been largely unexplored. Whether there are sex differences in the behavioral response to EtOH during late aging remains unknown. Thus, behavioral responses to EtOH in male and female Fischer (F) 344 rats aged 4-5 months (adult) and 19-20 months (aging) were examined. First, the effects of saline and EtOH (0.5 and 0.75 g/kg) on social interaction were assessed. Social investigation and contact behavior were lower in aging animals and higher in females. Interestingly, in aged females, social contact behavior was increased following a 0.5 g/kg EtOH dose, whereas the same dose suppressed social contact in aged males. Behavioral sensitivity to the sedative effects of 3.0 and 3.5 g/kg EtOH was assessed with the loss of righting reflex (LORR) test. Although latency to LORR did not differ as a function of age or sex, aged rats showed significantly greater LORR duration and significantly lower blood ethanol concentrations (BECs) at regaining of the righting reflex relative to adults. In addition, females had a lower LORR duration, regardless of age; no sex differences were evident in BECs at awakening. In a second experiment, blood ethanol concentrations (BECs) over time were assessed following 0.75, 1.5, and 3.0 g/kg EtOH in 3-, 12-, and 18-month-old male and female F344 rats. Aged rats had higher peak BECs following 3.0 g/kg EtOH, whereas few age or sex differences were apparent at lower doses. Taken together, these data indicate that late aging is associated with altered sensitivity to the social facilitating effects and sedative effects of EtOH.

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Differences in Behavioral Responding in Adult and Aged Rats Following Chronic Ethanol Exposure

Cited by 23 publications

References 45 publications

Chronic Voluntary Alcohol Drinking Causes Anxiety-like Behavior, Thiamine Deficiency, and Brain Damage of Female Crossed High Alcohol Preferring Mice

Chronic Voluntary Alcohol Drinking Causes Anxiety-like Behavior, Thiamine Deficiency, and Brain Damage of Female Crossed High Alcohol Preferring Mice

Cellular GABAergic Neuroactive Steroid (3α,5α)‐3‐Hydroxy‐Pregnan‐20‐One (3α,5α‐THP) Immunostaining Levels Are Increased in the Ventral Tegmental Area of Human Alcohol Use Disorder Patients: A Postmortem Study

Late aging alters behavioral sensitivity to ethanol in a sex-specific manner in Fischer 344 rats

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