Biology subjects

Wean, S.

Publications and source records attributed to Wean, S..

3 recordsLinked to original sources

bioRxiv2022

THE ROLE OF ALPHA- AND BETA-ADRENERGIC RECEPTORS ONCOMPULSION-LIKE ALCOHOL DRINKING

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), and this intake despite negative consequences can be a major clinical obstacle. With the quite limited treatment options available for AUD, there is a significant and critical unmet need for novel therapies. The noradrenergic system is an important hub for the stress response as well as maladaptive drives for alcohol, and pre-clinical (including our own) and clinical studies have shown that drugs targeting the 1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of {beta} ARs for treating human drinking AUD has received somewhat scant investigation, and we sought to provide pre-clinical validation for possible AR utility for CLAD. Thus, we first examined whether {beta} AR antagonist propranolol, betaxolol ({beta}1), and ICI, 118 551 ({beta}2) impacted compulsion-like intake and alcohol-only drinking (AOD) in male Wistar rats through systemic injections. The systemic highest dose of propranolol (10mg/kg) reduced both AOD and CLAD. 5mg/kg propranolol affected CLAD more than AOD, with no effects of 2.5mg/kg. Similar to propranolol, betaxolol also only decreased CLAD at the lower dose (2.5mg/kg). ICI 118.551 had no effects, suggesting propranolol regulates alcohol intake through {beta}1. Also, while AR compounds might have utility for AUD, these compounds can also lead to undesirable cardiovascular system side effects; thus, any strategy incorporating lower doses of these compounds to reduce drinking could have broad utility. Importantly, here we found that a combination of ineffective doses of propranolol and prazosin administrated together did reduce both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol into two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10g) in aINS or mPFC did not affect CLAD or AOD (although with a trend for aINS betaxolol to impact CLAD), suggesting propranolol regulation of alcohol drinking through a target other than aINS and mPFC. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.

neuroscience↗

bioRxiv2022

Anterior insular cortex firing links initial and sustained encoding during aversion-resistant alcohol consumption

Compulsive-like alcohol drinking (CLAD), where intake persists despite adverse consequences, is often a core facet of alcohol use disorder. Recent work sheds light on underlying mechanisms, but much remains unknown about CLAD etiology. Previously, we showed that projections from anterior insula (aINS), a central mediator of emotion, motivation, and interoception, promote CLAD in rodents, and heavy human drinkers exhibit similar insula-circuit recruitment under compulsion-like conditions. However, global aINS inhibition also reduces alcohol-only drinking (AOD), and one major obstacle is the lack of information on aINS firing patterns that could promote different aspects of intake. Here, we recorded single-unit activity in right aINS from 15 rats during AOD or CLAD (10mg/L or 60mg/L quinine in alcohol). Neurons with a sustained-increase or sustained-decrease phenotype (SIP, SDP) showed no firing differences across drinking conditions. In contrast, aINS neurons with a phenotype of strong firing increase at initiation of responding (IRP) showed significantly greater activity across the rest of licking during CLAD versus AOD, concurring with our previous behavioral findings suggesting quick evaluation and response strategy adjustment under CLAD. There were also no condition-related differences in firing-phenotype abundance. Further, total responding only correlated with abundance of SDP cells, but SDP firing returned to baseline during pauses in licking, while IRP and SIP sustained responding through pauses in licking. Thus, only aINS cells with a particular strong firing at licking onset showd greater sustained responding under compulsion-like conditions, while other cells likely promoted drinking more generally, providing critical new information about how aINS activity could promote alcohol consumption under different drinking conditions.

neuroscience↗

bioRxiv2022

Evidence for different greater-persistence strategies under lower and higher challenge for alcohol in female rats

Problem alcohol drinking is a substantial social and economic burden. Studies show that the misuse of alcohol is increasing in women, and that women can face higher consequences from alcohol exposure, but females have historically been understudied. Thus, there is considerable interest in understanding potential sex-different and -similar cognitive/emotional strategies, and underlying mechanisms, for alcohol responding, which would inform more effective, personalized treatments. Here, we used large cohorts of adult Wistar rats (28 females, 30 males) to provide robust assessment of potential sex differences in responding for alcohol-only and under compulsion-like drinking with moderate or higher challenge (since intake despite negative consequences can be a major obstacle to human treatment). Females had similar total licking but higher intake for all drinking conditions. However, females had significantly longer bouts under alcohol-only and moderate challenge, but not higher challenge. Further, under higher challenge, females retained several aspects of responding not seen in males, including more efficient lick volume and earlier onset of longer bouts. In addition, females overall licked slightly faster, but licking speed averaged within-bout showed no sex differences, and female intake level under alcohol-only and moderate challenge was unlinked from licking speed (unlike males, where slower licking predicted lower intake). We interpret these differences as greater persistence-like responding but not vigor per se in females, and with different strategies under lower versus higher challenge. Finally, drinking levels did not differ across the estrous cycle, although ovariectomy reduced alcohol-only and moderate-challenge intake. Together, while many aspects were sex-similar, suggesting some common drinking mechanisms, there was clear evidence for (perhaps more nuanced) sex-different alcohol strategies, which might make an outsized contribution to excessive drinking since women can have more drinking problems. Thus, our studies provide important context for future work examining sex differences in pathological drinking mechanisms.

neuroscience↗