Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making

Abstract

Alcohol is the most commonly abused substance among adolescents, promoting the development of substance use disorders and compromised decision-making in adulthood. We have previously demonstrated, with a preclinical model in rodents, that adolescent alcohol use results in adult risk-taking behavior that positively correlates with phasic dopamine transmission in response to risky options, but the underlying mechanisms remain unknown. Here, we show that adolescent alcohol use may produce maladaptive decision-making through a disruption in dopamine network dynamics via increased GABAergic transmission within the ventral tegmental area (VTA). Indeed, we find that increased phasic dopamine signaling after adolescent alcohol use is attributable to a midbrain circuit, including the input from the pedunculopontine tegmentum to the VTA. Moreover, we demonstrate that VTA dopamine neurons from adult rats exhibit enhanced IPSCs after adolescent alcohol exposure corresponding to decreased basal dopamine levels in adulthood that negatively correlate with risk-taking. Building on these findings, we develop a model where increased inhibitory tone on dopamine neurons leads to a persistent decrease in tonic dopamine levels and results in a potentiation of stimulus-evoked phasic dopamine release that may drive risky choice behavior. Based on this model, we take a pharmacological approach to the reversal of risk-taking behavior through normalization of this pattern in dopamine transmission. These results isolate the underlying circuitry involved in alcohol-induced maladaptive decision-making and identify a novel therapeutic target.

Contrasting Regulation of Catecholamine Neurotransmission in the Behaving Brain: Pharmacological Insights from an Electrochemical Perspective

“…In agreement with this, another study found adolescent alcohol exposure enhances VTA-stimulated dopamine release in the NAc, and an ethanol challenge produces larger increases in stimulated dopamine release compared with alcohol-naive animals (Shnitko et al, 2016). Interestingly, the administration of an allosteric GABA A agonist attenuates both increased dopamine release and increased risk-taking behavior in animals with adolescent alcohol exposure (Schindler et al, 2016). These findings suggest that there is increased inhibitory tone after alcohol exposure that drives changes in dopaminergic signaling through a disinhibitory mechanism, which may contribute to the behavioral changes.…”

“…Release magnitudes are likewise suppressed in the medial PFC when ethanol is infused directly into the VTA , and a systemic ethanol challenge also reduces NAc dopamine release (Shnitko et al, 2016). In animals with adolescent alcohol exposure, tonic levels of NAc dopamine are reduced in adulthood, and these animals exhibit increased risk-taking behavior (Schindler et al, 2016). Although tonic NAc dopamine is reduced, phasic NAc dopamine release is increased in animals with adolescent alcohol exposure, in a manner dependent on stimulation location: PPTg-but not MFB-evoked phasic dopamine release is increased compared with alcoholnaive animals (Schindler et al, 2016).…”

“…In animals with adolescent alcohol exposure, tonic levels of NAc dopamine are reduced in adulthood, and these animals exhibit increased risk-taking behavior (Schindler et al, 2016). Although tonic NAc dopamine is reduced, phasic NAc dopamine release is increased in animals with adolescent alcohol exposure, in a manner dependent on stimulation location: PPTg-but not MFB-evoked phasic dopamine release is increased compared with alcoholnaive animals (Schindler et al, 2016). In agreement with this, another study found adolescent alcohol exposure enhances VTA-stimulated dopamine release in the NAc, and an ethanol challenge produces larger increases in stimulated dopamine release compared with alcohol-naive animals (Shnitko et al, 2016).…”

“…Although alcohol-predictive cues elicit dopamine release, the amplitude of release does not differ between rats consuming sweetened alcohol versus those consuming the sweetened solution alone (Shnitko and Robinson, 2015). This apparent heterogeneity in dopamine response to ethanol should be addressed because alcohol exposure has circuit-specific effects on dopaminergic transmission (Schindler et al, 2016). Although ethanol can enhance stimulated dopamine, its effects on endogenous dopamine release are conflicting.…”

Recruitment and disruption of value encoding during alcohol seeking

“…Chronic intermittent exposure to ethanol or training with an alcoholic food reward both separately enhance dopamine release to a Pavlovian CS, though combining these manipulations has no effect in comparison to controls (Fiorenza et al, 2018). Adolescent alcohol exposure has also been shown to enhance dopamine release to Pavlovian cues (Schindler et al, 2016). We are not aware of any previous investigations of ethanol effects on VP cue encoding, though ethanol injections into the ventral tegmental area have been shown to increase extracellular dopamine levels in VP (Ding et al, 2011), and systemic ethanol decreases levels of extracellular GABA in VP (Kemppainen et al, 2010).…”