Alcohol Elicits Functional and Structural Plasticity Selectively in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum

Abstract

Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the dorsomedial striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive "Go" or "No-Go" behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning.

Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior

“…In support of these findings are previous studies that have suggested a role of kainate, but not AMPA, receptors in mediating the reinforcing properties of alcohol (Stephens and Brown, 1999;Czachowski et al, 2012;Wang et al, 2012). However, our findings may be surprising in light of previous reports showing that pharmacological blockade of NMDARs decreases operant self-administration in rats (Sabino et al, 2013;Jeanblanc et al, 2014;Alaux-Cantin et al, 2015; but see also Piasecki et al, 1998).…”

“…Although there is growing evidence that D2-expressing MSNs mediate several effects induced by alcohol , in a recent report by Wang et al 2015)) it was demonstrated that alcohol consumption induces a long-lasting increase in AMPAR activity specifically in D1-MSNs, but not in D2-MSNs, and striatal blockade of D1R, but not D2R, activity attenuates alcohol consumption. Therefore, we studied the contribution of NMDARs and AMPARs onto D1-MSNs in mediating addictivelike behavior.…”

Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward

“…For instance, we previously showed that excessive alcohol drinking increases dendritic branch length in D1R MSNs in the DMS (Wang et al, 2015), a change that we did not observe in the NAc shell of alcohol-drinking mice. In addition, and in contrast to the data presented herein, Uys et al recently reported that chronic exposure to alcohol vapor increases the number of thin, stubby, and filopodia spines in the NAc core, and that 72 hours of withdrawal from CIE produced a reduction in the number of mushroom-type spines (Uys et al, 2016).…”

“…Image z stacks of between 15 and 20 images were acquired at a z separation of 0.3 μm. Images of spines were deconvoluted by AutoQuant X3 (Media Cybernetics) (Wang et al, 2015), and morphological properties were analyzed by using FIJI software (NIH) (Smith et al, 2009). Protrusions from dendrites were classified into 4 types based on their length and neck and head morphology (Hering and Sheng, 2001).…”

“…Thin spines were defined as protrusions < 2 μm in length that had elongated spine necks with small heads (head width < 0.5 μm). For each of the animals examined in each group, at least 7 neurons were analyzed, with at least 2 dendrites analyzed per neuron (Wang et al, 2015). The analysis was performed single-blinded by two experimenters.…”