Chronic Alcohol Disrupts Dopamine Receptor Activity and the Cognitive Function of the Medial Prefrontal Cortex

Abstract

Dopamine (DA) receptors in the medial prefrontal cortex (mPFC) exert powerful effects on cognition by modulating the balance between excitatory and inhibitory neurotransmission. The present study examined the impact of chronic intermittent ethanol (CIE) exposure on cognitive function and DA receptor-mediated neurotransmission in the rat mPFC. Consistent with alterations in executive function in alcoholics, CIE-exposed rats exhibited deficits in behavioral flexibility in an operant set-shifting task. Since alterations in dopaminergic neurotransmission in the mPFC have been implicated in a number of behavioral disorders including addiction, studies were then performed in the adult acute slice preparation to examine changes in DA receptor function in the mPFC following CIE exposure. In slices obtained from control rats, DA receptor stimulation was observed to exert complex actions on neuronal firing and synaptic neurotransmission that were not only dependent upon the particular receptor subtype but also whether it was a pyramidal cell or a fast-spiking interneuron. In contrast to slices from control rats, there was a near complete loss of the modulatory actions of D2/D4 receptors on cell firing and neurotransmission in slices obtained immediately, 1 and 4 weeks after the last day of CIE exposure. This loss did not appear to be associated with changes in receptor expression. In contrast, CIE exposure did not alter D1 receptor function or mGluR1 modulation of firing. These studies are consistent with the suggestion that chronic alcohol exposure disrupts cognitive function at least in part through disruption of D2 and D4 receptor signaling in mPFC.

Behavioral and Neural Signatures of Reduced Updating of Alternative Options in Alcohol-Dependent Patients during Flexible Decision-Making

“…Low levels of D 2 receptors were linked to an impairment of re-evaluating decisions via the prefrontal cortex after negative feedback (Frank et al, 2004;Goto and Grace, 2005). Recent evidence from an animal model indicates that chronic alcohol-induced malfunction of, specifically, mPFC D 2 /D 4 receptors disrupts flexible behavioral adaptation (Trantham-Davidson et al, 2014), which is in consonance with the presented findings. Interestingly, a behavioral study in humans showed that genetic variability in dopaminergic neurotransmission relates to perseveration during reversal learning (den Ouden et al, 2013), also supporting the view that dopamine could at least partially account for the behavior observed in alcohol-dependent patients.…”

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…Although not yet completely understood, these dynamic changes in PFC/OFC neuronal function may contribute to the alterations in OFC-and PFC-based behaviors (eg, reversal learning and set-shifting) that are observed during post-WD periods similar to those examined in this study (Badanich et al, 2011;DePoy et al, 2013;Holmes et al, 2012;Kroener et al, 2012;Trantham-Davidson et al, 2014). Such changes, if present in alcohol-dependent humans, may contribute to cognitive and behavioral deficits associated with long-term alcohol abuse that underlie the inability of these individuals to exert cognitive control over their drinking in the face of adverse consequences.…”

“…However, a more parsimonious explanation is that CIE treatment induced a functional uncoupling of SK channels resulting in loss of at least one source of regulation of AP firing. Recent studies report either no change (Trantham-Davidson et al, 2014) or an increase (Pleil et al, 2015) in AP firing in prelimbic mPFC pyramidal neurons from CIE-exposed rats and mice, respectively. Increases in neuronal excitability following chronic exposure to ethanol have also been reported in other brain areas, including the VTA (Hopf et al, 2007), nucleus accumbens (Hopf et al, 2010), hippocampus (Mulholland et al, 2011), dorsal raphe (Lowery-Gionta et al, 2014), and ventral BNST (Pleil et al, 2015).…”

Habitual alcohol seeking: Modeling the transition from casual drinking to addiction

“…In addition, chronic alcohol exposure may cause a sensitized increase in dopamine and glutamate release in the nucleus accumbens in response to an alcohol challenge, suggesting altered prefrontal cortical input to the accumbens (Szumlinski et al, 2007). Recent work has shown that chronic ethanol exposure results in impaired dopamine D2/D4 (but not D1) receptor signaling in the vmPFC, which can impair behavioral flexibility (Trantham-Davidson et al, 2014). As our own work has shown that D1/D2-type signaling in the in infralimbic PFC is critical for the expression of habitual food seeking (Barker et al, 2013), we expect that dysregulation in vmPFC D2-like activity after chronic ethanol exposure could facilitate the expression of habitual reward seeking.…”