Biology subjects

Radke, A. K.

Publications and source records attributed to Radke, A. K..

5 recordsLinked to original sources

bioRxiv2023

Mu-opioid receptor knockout on Foxp2-expressing neurons leads to reduced aversion-resistant reward seeking

Mu-opioid receptors (MORs) in the amygdala and striatum are important in addictive and rewarding behaviors. The transcription factor Foxp2 is a genetic marker of intercalated (ITC) cells in the amygdala and a subset of striatal medium spiny neurons (MSNs), both of which express MORs in wild-type mice and are neuronal subpopulations of potential relevance to alcohol-drinking behaviors. For the current series of studies, we characterized the behavior of mice with genetic deletion of the MOR gene Oprm1 in Foxp2-expressing neurons (Foxp2-Cre/Oprm1fl/fl). Male and female Foxp2-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and homozygous Cre-(control) animals were tested for aversion-resistant alcohol consumption using an intermittent access (IA) task, operant responding for a sucrose reward, conditioned place aversion (CPA) to morphine withdrawal, and locomotor sensitization to morphine. The results demonstrate that deletion of MOR on Foxp2-expressing neurons renders mice more sensitive to quinine-adulterated ethanol (EtOH). Mice with the deletion (vs. Cre-controls) also consumed less alcohol during the final sessions of the IA task, responded less for sucrose under an FR3 schedule, and were less active at baseline and following morphine injection. Foxp2-MOR deletion did not impair the ability to learn to respond for reward or develop a conditioned aversion to morphine withdrawal. Together, these investigations demonstrate that Foxp2-expressing neurons may be involved in escalation of alcohol consumption and the development of compulsive-like alcohol drinking.

neuroscience↗

bioRxiv2023

Cholinergic mu-opioid receptors participate in nicotine, but not ethanol, drinking behaviors

AbstractHeavy alcohol use and binge drinking are important contributors to alcohol use disorder (AUD). The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT- Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and Cre- (control) mice were tested for alcohol and nicotine consumption. In Experiment 1, binge-like and quinine-resistant drinking was tested using 15% ethanol (EtOH) in a two- bottle, limited-access Drinking in the Dark paradigm. Experiment 2 involved a six-week intermittent access paradigm in which mice received 20% EtOH, nicotine, and then a combination of the two drugs. Experiment 3 assessed locomotor activity, sucrose preference, and quinine sensitivity. Deleting MORs in cholinergic cells did not alter consumption of EtOH in Experiment 1 or 2. In Experiment 1, the MOR deletion resulted in greater consumption of quinine-adulterated EtOH in male Cre+ mice (vs. Cre-). In Experiment 2, Cre+ mice demonstrated a significantly lower preference for nicotine but did not differ from Cre- mice in nicotine or nicotine + EtOH consumption. Overall fluid consumption was also heightened in the Cre+ mice. In Experiment 3, Cre+ females were found to have greater locomotor activity and preference for sucrose vs. Cre- mice. These data suggest that cholinergic MORs are not required for EtOH, drinking behaviors but may contribute to aversion resistant EtOH drinking in a sex- dependent manner.

neuroscience↗

bioRxiv2023

Sex, but not early life stress, effects on two-bottle choice alcohol drinking behaviors in mice

AbstractO_ST_ABSBackgroundC_ST_ABSIn humans, early life stress (ELS) is associated with an increased risk for developing both alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). We previously used an infant footshock model that produces stress-enhanced fear learning (SEFL) in rats and mice and increases aversion-resistant alcohol drinking in rats to explore this shared predisposition. The goal of the current study was to extend this model of comorbid PTSD and AUD to male and female C57BL/6J mice. MethodsAcute ELS was induced using 15 footshocks on postnatal day (PND) 17. In adulthood, alcohol drinking behavior was tested in one of three two-bottle choice drinking paradigms. In continuous access, mice were given 24 h access to 5% or 10% ethanol and water for five consecutive drinking sessions each. In limited access drinking in the dark, mice were given 2 h of access to 15% ethanol and water across 15 sessions 3 h into the dark cycle. In intermittent access, mice were presented with 20% ethanol and water Monday, Wednesday, and Friday, for four consecutive weeks. In a fifth week of intermittent access drinking, increasing concentrations of quinine (10 mg/L, 100 mg/L, and 200 mg/L) were added to the ethanol to test aversion-resistant drinking. Intermittent access drinking was tested with and without a period of adolescent drinking (PND 35). ResultsInfant footshock did not alter drinking in the continuous or limited access tasks. Adult consumption and preference were lower in the intermittent access task when adolescent drinking was included and there were ELS-induced differences in consumption of quinine-adulterated ethanol in females. ConclusionsOur results demonstrate that infant footshock followed by a period of adolescent drinking is a viable model of comorbid PTSD and AUD in rats and mice.

neuroscience↗

bioRxiv2022

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

BackgroundOne characteristic of alcohol use disorder (AUD) is compulsive drinking, or drinking despite negative consequences. When quinine is used to model such aversion-resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol (EtOH) mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in EtOH than males. Here, we aimed to determine if this female vulnerability to aversion-resistant drinking behavior is similarly observed when footshock punishment is used. MethodsMale and female C57BL/6J mice were trained to respond for 10% EtOH in an operant task on a fixed ratio 3 schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 mA footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 - 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock. ResultsMales and females continued to respond for 10% EtOH when paired with a 0.25 mA footshock. Females alone continued to respond for EtOH when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Finally, footshock sensitivity in the flinch, jump, vocalize test did not differ by sex. ConclusionsFemales continue to respond for 10% EtOH despite a 0.35 mA footshock and this behavior is not due to differences in footshock sensitivity between males and females. These results suggest that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. These results add to the literature characterizing aversion-resistant alcohol drinking behaviors in females.

neuroscience↗

bioRxiv2021

Gonadal hormones and sex chromosome complement differentially contribute to ethanol intake, preference, and relapse-like behavior in Four Core Genotypes mice

Alcohol use and high-risk alcohol drinking behaviors among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the Four Core Genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviors. FCG mice were given access to escalating concentrations of EtOH in a two-bottle, 24-h continuous access drinking paradigm to assess consumption and preference. Relapse-like behavior was measured by assessing escalated intake following repeated cycles of deprivation and re-exposure. Twenty-four hour EtOH consumption was greater in mice with ovaries (Sry-), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX vs. XY mice. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). Mice with ovaries (Sry-FCG mice and C57Bl/6J females) were also found to consume more water than mice with testes. These results demonstrate that aspects of EtOH drinking behavior may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviors is warranted.

neuroscience↗