Effects of Monoamines on the Intrinsic Excitability of Lateral Orbitofrontal Cortex Neurons in Alcohol-dependent and Non-dependent Female Mice

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.