Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption

Abstract

BACKGROUND Repeated exposure to addictive drugs and alcohol triggers glutamatergic and GABAergic plasticity in many neuronal populations. The dorsomedial striatum (DMS), a brain region critically involved in addiction, contains medium spiny neurons (MSNs) expressing dopamine D1 or D2 receptors, which form direct and indirect pathways, respectively. It is unclear how alcohol-evoked plasticity in the DMS contributes to alcohol consumption in a cell type-specific manner. METHODS Mice were trained to consume alcohol using an intermittent-access two-bottle-choice drinking procedure. Slice electrophysiology was used to measure glutamatergic and GABAergic strength in DMS D1- and D2-MSNs of alcohol-drinking mice and their controls. In vivo chemogenetic and pharmacological approaches were employed to manipulate MSN activity and their consequences on alcohol consumption were measured. RESULTS Repeated cycles of alcohol consumption and withdrawal in mice strengthened glutamatergic transmission in D1-MSNs and GABAergic transmission in D2-MSNs. In vivo chemogenetic excitation of D1-MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D2-MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D2 receptor-glycogen synthase kinase-3β (GSK3β) signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D1-MSNs or excitation of D2-MSNs. CONCLUSIONS Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiates glutamatergic strength exclusively in D1-MSNs and GABAergic strength specifically in D2-MSNs of the DMS, which concurrently contribute to alcohol consumption. These results provide insight into the synaptic and cell type-specific mechanisms underlying alcohol addiction and identify targets for the development of new therapeutic approaches to alcohol abuse.

Tipping the Scales Toward Addiction

“…However, cocaine preferentially targets D1-MSNs, while morphine targets D2-MSNs, which results in the same net shift in balance of excitation to D1- and D2-MSNs (7). These findings, together with the findings of Cheng et al (6), suggest that cocaine, morphine, alcohol, and likely other drugs of abuse all produce the same circuit shift, albeit through distinct mechanisms. It will be important to determine if this circuit shift also holds for other commonly abused drugs, such as nicotine, amphetamine, and marijuana.…”

“…These findings by Cheng et al (6) provide significant insight into the circuit mechanisms within the DMS that contribute to alcohol addiction. These findings also highlight how differential or opposing synaptic adaptations induced by drugs lead to common circuit level alterations in the striatum to produce similar circuit and behavioral outcomes.…”

“…(6) directly address these important questions by identifying specific alcohol-induced adaptations in D1- and D2-MSNs and determining how these MSN subpopulations contribute to alcohol consumption. Cheng et al (6) first examined whether N -methyl-D-aspartate receptor (NMDAR)–mediated excitatory synaptic transmission in the dorsomedial striatum (DMS) is altered in a cell type–specific manner following prolonged alcohol exposure. Following 8 weeks of intermittent access to alcohol, which resulted in excessive alcohol consumption, NMDAR-mediated excitatory postsynaptic currents were selectively increased in D1-MSNs of mice 24 hours after the last self-administration session.…”

“…To address this question, Cheng et al. (6) manipulated the activity levels of D1- and D2-MSNs within the DMS of animals during alcohol drinking sessions through chemogenetic approaches. Shifting the balance of striatal activity in favor of the direct pathway through chemogenetic activation of D1-MSNs or inhibition of D2-MSNs resulted in the same behavioral consequence—increasing the consumption of and preference for alcohol.…”

“…Lastly, Cheng et al (6) identified a mechanism underlying the alcohol-induced reduction in GABAergic transmission to D2-MSNs. Acute stimulation of D2-receptors reduced the amplitude of inhibitory postsynaptic currents in D2-MSNs, which was due to the activation of glycogen synthase kinase-3β (GSK3β), a downstream signaling target of G i -coupled D 2 receptors.…”