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, 110 (36), 14783-8

Chronic Alcohol Produces Neuroadaptations to Prime Dorsal Striatal Learning

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Chronic Alcohol Produces Neuroadaptations to Prime Dorsal Striatal Learning

Lauren DePoy et al. Proc Natl Acad Sci U S A.

Abstract

Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptor-dependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.

Keywords: PFC; abuse; cannabinoid; dependence; touchscreen.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Chronic intermittent EtOH exposure. (A) Representative blood EtOH concentrations obtained in sentinel mice on the first to the second CIE cycle. (B) CIE increased EtOH drinking in a two-bottle choice test. Air controls showed a transient increase in drinking (EtOH deprivation effect). Data are means ± SEM, *P < 0.05 CIE vs. air, #P < 0.05 vs. pre-CIE/same group.
Fig. 2.
Fig. 2.
CIE causes DLS dendritic hypertrophy and altered DLS synaptic plasticity. (A) CIE increased dendritic length. (B) DLS neuron reconstructions in air and CIE mice. (Scale bar: 50 µm.) (C and D) CIE increased terminal dendritic length and number. (E) CIE prevented induction of LTD induced by local afferent high-frequency stimulation (HFS, denoted by arrows) of cortical inputs to DLS. (F) Traces from E. (G) CIE decreased CB1R agonist-stimulated functional binding in DLS. (H and I) CIE increased levels of 2-AG, not AEA, in DLS. Data are means ± SEM, *P < 0.05 CIE vs. air, #P < 0.05 vs. pre-HFS1 baseline.
Fig. 3.
Fig. 3.
CIE facilitates DLS-dependent learning. (AC) CIE before pairwise visual discrimination training decreased the number of errors and correction errors to criterion performance. (DF) CIE before reversal training decreased the number of errors and correction errors to criterion performance, specifically during the late testing stage when percent correct performance was greater than chance. (GI) CIE before Pavlovian conditioned approach testing produced a more rapid decrease in approaches during omission training. (J and K) CIE before stimulus–reward extinction training produced faster extinction. Data are means ± SEM, *P < 0.05 CIE vs. air.
Fig. 4.
Fig. 4.
CIE augments learning-related DS single-unit activity. (A) Multielectrode arrays were implanted in DLS and a medial/DLS intermediate zone before CIE and reversal. (B) Recordings were made on early, mid, and late stages of reversal, matching CIE and air groups for percent correct performance. (C) Example raster plots during each state of reversal. (D) CIE produced a sustained increase in unit firing during late reversal. Data are means ± SEM, *P < 0.05 CIE vs. air.

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