Effects of monoamines on the intrinsic excitability of lateral orbitofrontal cortex neurons in alcohol-dependent and non-dependent female mice

Abstract

Changes in brain reward and control systems of frontal cortical areas including the orbitofrontal cortex (OFC) are associated with alcohol use disorders (AUD). The OFC is extensively innervated by monoamines, and drugs that target monoamine receptors have been used to treat a number of neuropsychiatric diseases, including AUDs. Recent findings from this laboratory demonstrate that D2, α2-adrenergic and 5HT receptors all decrease the intrinsic excitability of lateral OFC (lOFC) neurons in naïve male mice and that this effect is lost in mice exposed to repeated cycles of chronic intermittent ethanol (CIE) vapor. As biological sex differences may influence an individual's response to alcohol and contribute to the propensity to engage in addictive behaviors, we examined whether monoamines have similar effects on lOFC neurons in control and CIE exposed female mice. Dopamine, norepinephrine and serotonin all decreased spiking of lOFC neurons in naïve females via activation of G-coupled D2, α2-adrenergic and 5HT receptors, respectively. Firing was also inhibited by the direct GIRK channel activator ML297, while blocking these channels with barium eliminated the inhibitory actions of monoamines. Following CIE treatment, evoked spiking of lOFC neurons from female mice was significantly enhanced and monoamines and ML297 no longer inhibited firing. Unlike in male mice, the enhanced firing of neurons from CIE exposed female mice was not associated with changes in the after-hyperpolarization and the small-conductance potassium channel blocker apamin had no effect on current-evoked tail currents from either control or CIE exposed female mice. These results suggest that while CIE exposure alters monoamine regulation of OFC neuron firing similarly in males and female mice, there are sex-dependent differences in processes that regulate the intrinsic excitability of these neurons.

Review of Orbitofrontal Cortex in Alcohol Dependence: A Disrupted Cognitive Map?

“…These results are consistent with past work showing reduced OFC excitability in high‐drinking nonhuman primates (Nimitvilai et al, 2017b) and lower baseline OFC activity in human alcoholics (Catafau et al, 1999; Volkow et al, 1994, 1997). However, the same group that found reduced OFC excitability in macaques has also consistently reported opposite results in CIE mice, finding increased excitability in both males and females (Nimitvilai et al, 2016, 2017a, 2018a, 2018b). Though these discrepancies are not yet fully understood, the underlying effect of altered OFC excitability remains.…”

“…Human alcoholics showed reduced OFC glucose utilization following administration of a mixed serotonin agonist/antagonist (Hommer et al, 1997). In CIE mice, monoamine application to OFC slices did not produce the normal inhibition of lateral OFC firing (Nimitvilai et al, 2017a, 2018a). In summary, chronic alcohol affects OFC function across a variety of measures, suggesting potential disrupted or compensatory mechanisms that might underlie behavioral deficits associated with alcohol.…”

Sex Differences in the Neurobiology of Alcohol Use Disorder

“…The interaction between gonadal hormones and dopamine may provide insight into the molecular mechanisms underlying sex differences in the rewarding properties of alcohol. 51 , 52 Estradiol enhances the stimulating effect of alcohol on VTA dopamine neurons. 51 In vitro extracellular recordings of dopaminergic neurons have been conducted using VTA slices obtained from female mice under the following hormonal conditions: no estradiol (ovariectomized and vehicle-treated) or low circulating levels of estradiol (gonadally intact mice in estrus) versus moderate (gonadally intact mice in diestrus II) or high (ovariectomized mice treated with proestrus-like levels of estradiol benzoate) circulating levels of estradiol.…”

Altered Activity of Lateral Orbitofrontal Cortex Neurons in Mice following Chronic Intermittent Ethanol Exposure

“…Using slice preparations, we have previously shown that the intrinsic excitability of LOFC neurons is reduced by low concentrations of ethanol (Badanich et al, 2013, Nimitvilai et al, 2020 and that withdrawal from CIE results in enhanced current-evoked spiking (Nimitvilai et al, 2016(Nimitvilai et al, , 2018. Furthermore, lesions to or chemogenetic inhibition of the LOFC promotes escalation of alcohol drinking in CIE exposed mice (den Hartog et al, 2016).…”