Biology subjects

Doyle, M. R.

Publications and source records attributed to Doyle, M. R..

6 recordsLinked to original sources

bioRxiv2025

Ivermectin Reduces Withdrawal-Induced Alcohol Intake via CeA GABAergic Enhancement

Although FDA-approved medications for alcohol use disorder (AUD) are available, their efficacy varies across patients, highlighting the need for novel therapeutics that address inter-individual differences in disease etiology and treatment response. Genetic models, particularly heterogeneous stock (HS) rats, recapitulate human-like genetic diversity and behavioral heterogeneity, enabling the dissection of individual differences in vulnerability to AUD and pharmacotherapeutic sensitivity. P2X4 receptors, which are encoded by the gene P2rx4, are ATP-gated ion channels inhibited by ethanol and abundantly expressed in neurons found in reward and stress circuits. P2X4 receptors have emerged as key modulators of ethanol sensitivity and consumption in preclinical models. Here, we genetically predicted P2rx4 expression in whole brain in a cohort of 130 HS rats exposed to chronic intermittent ethanol (CIE) vapor and phenotyped for self-administration during acute abstinence. Rats were dichotomized into high- and low-predicted expression groups. Higher predicted P2rx4 expression was associated with increased post-vapor intake and escalation. In 32 CIE-escalated rats, ivermectin, a positive allosteric modulator of P2X4 receptors, dose-dependently reduced drinking. We stratified rats into three groups: non-responders, mild responders, and high responders. Electrophysiological recordings from CeA slices revealed that ivermectin differentially enhanced GABAergic IPSCs: high-responders exhibited sustained increases in IPSC frequency and selective amplitude reductions, while the two other groups showed transient frequency increases. All groups displayed prolonged rise times, however non-responders showed extended decay times. These findings suggest that P2rx4 upregulation serves as a vulnerability marker for dependence-like behaviors, with ivermectin attenuating withdrawal-driven alcohol consumption by enhancing CeA GABAergic inhibition.

pharmacology and toxicology↗

bioRxiv2025

A Preclinical Alcohol BioBank: Samples from Behaviorally Characterized HS Rats for AUD Research

Alcohol use disorder (AUD) imposes a significant global health burden, yet effective treatments remain limited due to the scarcity of well-characterized biological sample repositories. To address this gap, we established the UCSD Alcohol BioBank, a comprehensive resource containing thousands of samples from over 700 genetically diverse heterogeneous stock (HS) rats. Modeled after successful cocaine and oxycodone biobanks, this repository utilizes the chronic intermittent ethanol vapor exposure (CIE) model, paired with oral self-administration, to characterize AUD-like behaviors, including ethanol consumption, preference, motivation, and withdrawal symptoms such as allodynia and anxiety-like behavior. Longitudinal samples (blood, urine, and feces) are collected before, during, and after ethanol exposure, while terminal samples (brain, heart, liver, kidneys, cecum, reproductive organs, adrenal glands, peripheral blood mononuclear cells) are obtained at intoxication, acute withdrawal, protracted abstinence, or from naive controls. Samples are preserved via snap-freezing or paraformaldehyde fixation to support diverse applications, including genomics, transcriptomics, proteomics, and neuroanatomy. The genetic diversity of HS rats enables genome-wide association studies (GWAS) to identify AUD-related genetic variants. Freely available to non-profit organizations at www.alcoholbiobank.org, with genetic and behavioral data deposited in public repositories, the Alcohol BioBank facilitates collaborative research to uncover biomarkers and develop novel therapies for AUD, addressing a critical need in addiction science.

animal behavior and cognition↗

bioRxiv2025

CircRNA hypomethylation in the human amygdala implicates FKBP5 in alcohol use disorder

Genome- and phenome-wide association studies implicate the RNA demethylase FTO in alcohol use disorder (AUD), yet the RNA methylation landscape in AUD remains poorly characterized. Analyzing postmortem human basolateral amygdala (BLA) tissue, a key brain region in AUD-related behaviors, we found extensive m6A hypomethylation uniquely affecting circular RNAs (circRNAs). Notably, FKBP5-hosted circRNAs (circFKBP5s) exhibited pronounced hypomethylation correlating with elevated expression of FKBP5 mRNA isoforms. These findings were replicated in an animal model of alcohol dependence. Predictive analyses suggest that circFKBP5s influence genes involved in neurodevelopmental processes and neuronal identity. These findings uncover a novel aspect of AUD neurobiology linked to circRNA methylation.

molecular biology↗

bioRxiv2025

High Incidence of Estrous Cycle Irregularities in Heterogeneous Stock (HS) Rats is Associated with Severe Cocaine Addiction-like Behaviors

Hormonal fluctuations throughout the estrous cycle have been hypothesized to influence drug-related behaviors. Preclinical models show that some cocaine-related behaviors are influenced by the estrous cycle. However, the extent to which the estrous cycle modulates cocaine self-administration in outbred heterogeneous stock (HS) rats, a population that captures human genetic diversity, is unknown. This study aimed to examine the relationship between estrous phases and cocaine self-administration behavior in HS rats using a model of extended access to cocaine self-administration. We focused on the escalation of intake, breaking point, and resistance to foot shock. Using vaginal swabbing and lavage techniques, we first characterized the relationship between estrous phase and cocaine intake. We then comprehensively evaluated estrous cycling patterns in young adult and adult HS rats, comparing them with Wistar rats. Contrary to our hypothesis, estrous phase showed no association with cocaine self-administration in HS rats. HS rats exhibited irregular estrous cycling with variability to the phase length, even in the absence of drug exposure, a phenomenon not observed in the Wistar strain. Irregular estrous cycle was associated with high cocaine-related behaviors. This study provides the first evidence that some female HS rats exhibit irregular estrous cycling. Moreover, rats with severe addiction-like behaviors had more instances of irregular cycling. These results demonstrate that, in HS rats, the estrous phase per se has no major influence on cocaine self-administration, but that the severity of addiction-like behaviors are associated with more irregularity of the estrus cycle. As HS rats gain popularity in behavioral and genome-wide studies, understanding these cycle disruptions is crucial as they may reveal genetic links into female vulnerability to drugs.

neuroscience↗

bioRxiv2024

Investigating the Role of Glyoxalase 1 as a Therapeutic Target for Cocaine and Oxycodone Use Disorder

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABAA receptors. MG that is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption. The goal of these studies was to determine if GLO1 inhibition could alter cocaine-or oxycodone-induced locomotor activation and/or conditioned place preference (CPP) to cocaine or oxycodone. We used both pharmacological and genetic manipulations of GLO1 to address this question. Administration of the GLO1 inhibitor s-bromobenzylglutathione cyclopentyl diester (pBBG) did not alter the locomotor response to cocaine or oxycodone. Additionally, pBBG had no significant effect on place preference for cocaine or oxycodone. Genetic knockdown of Glo1, which is conceptually similar to pharmacological inhibition, did not have any significant effects on cocaine place preference, nor did Glo1 overexpression affect locomotor response to cocaine. In summary, our results show that neither pharmacological nor genetic manipulations of GLO1 influence locomotor response or CPP to cocaine or oxycodone.

neuroscience↗

bioRxiv2024

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of substance use vary across individuals. Yet, when rats are allowed to self-administer drugs such as cocaine under short-access conditions, their behavior tends to be well-regulated and homogeneous in nature; though individual differences can emerge when rats are provided long- or intermittent-access to cocaine. In contrast to cocaine, significant individual differences emerge when rats are allowed to self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein [~]30% of rats rapidly transition to high levels of drug-taking. This study assessed the SUD-like phenotypes of male and female Sprague Dawley rats self-administering MDPV (0.032 mg/kg/infusion) or cocaine (0.32 mg/kg/infusion) by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to test the hypotheses that: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administered cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. After short-access, rats that self-administered MDPV exhibited a more severe phenotype than rats that self-administered cocaine. Though long- and intermittent-access to cocaine and MDPV self-administration altered drug-taking patterns, manipulating access conditions did not systematically alter their SUD-like phenotype. Evidence from behavioral and quantitative autoradiography studies suggest that these differences are unlikely due to changes in expression levels of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT 2A, or 5-HT2C receptors, though these possibilities cannot be ruled out. These results show that the phenotype exhibited by rats self-administering MDPV differs from that observed for rats self-administering cocaine, and suggests that individuals that use MDPV and/or related cathinones may be at greater risk for developing a SUD, and that short-access MDPV self-administration may provide a useful method to understand the factors that mediate the transition to problematic or disordered substance use in humans.

pharmacology and toxicology↗