Inactivation of the lateral orbitofrontal cortex increases drinking in ethanol-dependent but not non-dependent mice

Abstract

Long-term consumption of ethanol affects cortical areas that are important for learning and memory, cognition, and decision-making. Deficits in cortical function may contribute to alcohol-abuse disorders by impeding an individual’s ability to control drinking. Previous studies from this laboratory show that acute ethanol reduces activity of lateral orbitofrontal cortex (LOFC) neurons while chronic exposure impairs LOFC-dependent reversal learning and induces changes in LOFC excitability. Despite these findings, the role of LOFC neurons in ethanol consumption is unknown. To address this issue, we examined ethanol drinking in adult C57Bl/6J mice that received an excitotoxic lesion or viral injection of the inhibitory DREADD (designer receptor exclusively activated by designer drug) into the LOFC. No differences in ethanol consumption were observed between sham and lesioned mice during access to increasing concentrations of ethanol (3–40%) every other day for 7 weeks. Adulterating the ethanol solution with saccharin (0.2%) or quinine (0.06 mM) enhanced or inhibited, respectively, consumption of the 40% ethanol solution similarly in both groups. Using a chronic intermittent ethanol (CIE) vapor exposure model that produces dependence, we found no difference in baseline drinking between sham and lesioned mice prior to vapor treatments. CIE enhanced drinking in both groups as compared to air-treated animals and CIE treated lesioned mice showed an additional increase in ethanol drinking as compared to CIE sham controls. This effect persisted during the first week when quinine was added to the ethanol solution but consumption decreased to control levels in CIE lesioned mice in the following 2 weeks. In viral injected mice, baseline drinking was not altered by expression of the inhibitory DREADD receptor and repeated cycles of CIE exposure enhanced drinking in DREADD and virus control groups. Consistent with the lesion study, treatment with clozapine-N-oxide (CNO) further enhanced consumption only in CIE exposed DREADD mice with no change in air-treated mice. These results suggest that the LOFC is not critical for the initiation and maintenance of ethanol drinking in non-dependent mice, but may regulate the escalated drinking observed during dependence.

Knock‐in Mice Expressing an Ethanol‐Resistant GluN2A NMDA Receptor Subunit Show Altered Responses to Ethanol

“…Interestingly, studies with rats have reported an increase in alcohol intake over time in the 2‐bottle choice 24‐hour intermittent access paradigm (Bito‐Onon, Simms et al, ; Mill, Bito‐Onon et al, ; Simms, Steensland et al, ). However, this phenomenon is less consistent in mice with increases being reported in some studies (Hwa, Nathanson et al, ; Melendez, ), but not others (Crabbe, Harkness et al, ) including previous studies from our laboratory (den Hartog, Beckley et al, , den Hartog, Zamudio‐Bulcock et al, ). Together, these findings suggest that EtOH‐sensitive GluN2A‐containing NMDARs are not critical for regulating voluntary alcohol consumption in non‐dependent animals.…”

Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue‐induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats

“…Outside of reinstatement, at least 2 other studies have found an impact of OFC manipulation on motivation for EtOH. In these studies, however, lesions or DREADD inhibition of OFC increased drinking in rats (Ray et al, 2018) and mice treated with chronic EtOH (den Hartog et al, 2016). In the study by den Hartog and colleagues, mice with OFC lesions increased EtOH consumption after, but not before, chronic intermittent EtOH (CIE) vapor treatment.…”

“…Inhibition of OFC reduces cue-and context-induced reinstatement of alcohol seeking (Arinze and Moorman, 2020;Bianchi et al, 2018), and disruption of mTORC1 signaling in OFC decreased alcohol seeking during extinction (Morisot et al, 2019). In other studies, however, lesions or DREADD (designer receptor exclusively activated by designer drugs; (Armbruster et al, 2007)) inhibition of OFC increased drinking in rats (Ray et al, 2018) and mice treated with chronic ethanol (EtOH;den Hartog et al, 2016). Despite some conflicting results, these data indicate a clear involvement of OFC in alcohol seeking.…”

Region specific activation of the AKT and mTORC1 pathway in response to excessive alcohol intake in rodents

“…Alcohol vapor exposure also induces an increase in excitability, synaptic plasticity and spine density in lateral OFC neurons that may contribute to the OFC-dependent behavioral-deficits (McGuier et al, 2015). A recent study showed that inactivation of the lateral OFC by excitotoxic lesion or in response to the activation of inhibitory DREADD (designer receptor exclusively activated by designer drug) reduced alcohol drinking in mice previously exposed to vapor, revealing a role for the OFC in alcohol-related behaviors (Hartog et al, 2016). In addition, we previously found that a short period of reconsolidation of alcohol memories resulted in mTORC1 activation in the OFC (but not in the NAc) of rats, and that systemic administration of rapamycin following reactivation of alcohol memories disrupted reconsolidation leading to reduction in alcohol seeking on the following day (Barak et al, 2013).…”