Escalation of alcohol intake is associated with regionally decreased insular cortex activity but not associated with changes in taste quality

Abstract

Background: Intermittent access to ethanol (EtOH) drives persistent escalation of intake and rapid transition from moderate to compulsive-like drinking. Intermittent EtOH drinking may facilitate escalation in part by altering aversion-sensitive neural substrates, such as the insular cortex (IC), thus driving greater approach toward stimuli previously treated as aversive. Methods: We conducted a series of experiments in rats to examine behavioral and neural responses associated with escalation of EtOH intake. First, taste reactivity analyses quantified the degree that intermittent brief-access ethanol exposure (BAEE) alters sensitivity to the aversive properties of EtOH. Next, we determined whether pharmacological IC inhibition facilitated EtOH escalation. Finally, given that IC is primary gustatory cortex, we employed psychophysical paradigms to assess whether escalation of EtOH intake induced changes in EtOH taste. These paradigms measured changes in sensitivity to the intensity of EtOH taste and whether escalation shifts the salient taste quality of EtOH by measuring the degree that the taste of EtOH generalized to a sucrose-like (sweet) or quinine-like (bitter) percept. Results: We found a near complete loss of aversive oromotor responses in EtOH-exposed relative to -naive rats. Additionally, we observed significantly reduced expression of EtOH-induced c-Fos expression in the posterior IC in exposed rats relative to naive rats. Inhibition of the IC resulted in a modest, but statistically reliable increase in acceptance of higher EtOH concentrations in naive rats. Finally, we found no evidence of changes in the psychophysical assessment of the taste of EtOH in exposed, relative to naive, rats. Conclusions: Our results demonstrate that neural activity within the IC adapts following escalation of EtOH intake in a manner that correlates with reduced sensitivity to the aversive hedonic properties of EtOH. These data further establish that IC may be driving exposure-induced escalations in EtOH intake and directly contributing to development of compulsive-like EtOH drinking.

Bilateral insular cortical lesions reduce sensitivity to the adverse consequences of acute ethanol intoxication in Pavlovian conditioning procedures

“…We found that EtOH-exposed rats had a near complete loss of responding to the aversive orosensory properties of EtOH (20%) as well as significantly reduced neural activation within the posterior IC, relative to EtOH-naïve controls. Furthermore, the number of elicited aversive-associated TR responses was positively correlated with the amount of Fos-like immunoreactivity in the posterior IC (Mukherjee et al, 2023). Within the present study, ibotenic acid lesions were targeted toward an area just slightly rostral to those more posterior regions (~0.3 mm posterior to bregma) in which we found these previous Fos-behavior associations.…”

“…Subsequently, the posterior IC is then thought to relay these signals to the anterior IC, where they may reach conscious awareness and undergo memory consolidation (Droutman et al, 2015). We have previously demonstrated a correlation between reduced IC activation and a loss of responding to the aversive orosensory properties of EtOH that naturally develop following repeated EtOH drinking sessions (Mukherjee et al, 2023).…”

“…Recently, we demonstrated that rats previously acclimated to EtOH show a near complete loss of behavioral responding to the aversive orosensory properties of EtOH concomitant with a reduction in EtOH-induced cFos expression within the IC, relative to EtOH-naïve rats (Mukherjee et al, 2023).…”

“…Ethanol (EtOH) remains one of the most widely misused substances in the world, likely owing to its ubiquitous social acceptance and accessibility. Although the aversive orosensory and visceral properties of EtOH likely initially serve to protect against excessive consumption (Bachmanov et al, 2003), preclinical evidence suggests that repeated exposure to EtOH may facilitate greater acceptance of, and desensitization to, these aversive effects (Kiefer et al, 1994;Kiefer & Dopp, 1989;Loney & Meyer, 2018;Mukherjee et al, 2023;Simms et al, 2008). The overall hedonic value of EtOH and its potential for misuse in the early stages of drinking is a function of the balance between the aversive and reinforcing postingestive effects (Morean & Corbin, 2010).…”

“…The overall hedonic value of EtOH and its potential for misuse in the early stages of drinking is a function of the balance between the aversive and reinforcing postingestive effects (Morean & Corbin, 2010). Across multiple species, individual differences in sensitivity to the adverse effects of EtOH is a predictive factor for future misuse (Kroenke et al, 2014;Mukherjee et al, 2023;Risinger & Cunningham, 1998, 2000Schramm-Sapyta et al, 2010). Adaptations to these adverse consequences of EtOH intoxication may serve to facilitate the development of alcohol use disorder (AUD).…”