Nucleus accumbens shell small conductance potassium channels underlie adolescent ethanol exposure-induced anxiety

Lili Shan,Ewa Galaj,Yao-Ying Ma

doi:10.1038/s41386-019-0415-7

Lili Shan, Ewa Galaj + Show 1 more

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https://doi.org/10.1038/s41386-019-0415-7

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Abstract

Alcohol use typically begins in adolescence, increasing the likelihood of adult mental disorders such as anxiety. However, the cellular mechanisms underlying the consequences of adolescent alcohol exposure as well as the behavioral consequences remain poorly understood. We examined the effects of adolescent or adult chronic intermittent ethanol (CIE) exposure on intrinsic excitability of striatal medium-sized spiny neurons (MSNs) and anxiety levels. Rats underwent one of the following procedures: (1) light–dark transition (LDT) and open-field (OF) tests to evaluate anxiety levels and general locomotion; (2) whole-cell patch clamp recordings and biocytin labeling to assess excitability of striatal MSNs, as well as morphological properties; and (3) western blot immunostaining to determine small conductance (SK) calcium-activated potassium channel protein levels. Three weeks, but not 2 days, after CIE treatment, adolescent CIE-treated rats showed shorter crossover latency from the light to dark side in the LDT test and higher MSN excitability in the nucleus accumbens shell (NAcS). Furthermore, the amplitude of the medium afterhyperpolarization (mAHP), mediated by SK channels, and SK3 protein levels in the NAcS decreased concomitantly. Finally, increased anxiety levels, increased excitability, and decreased amplitude of mAHP of NAcS MSNs were reversed by SK channel activator 1-EBIO and mimicked by the SK channel blocker apamin. Thus, adolescent ethanol exposure increases adult anxiety-like behavior by downregulating SK channel function and protein expression, which leads to an increase of intrinsic excitability in NAcS MSNs. SK channels in the NAcS may serve as a target to treat adolescent alcohol binge exposure-induced mental disorders, such as anxiety in adulthood.

Highlights

Alcohol is the most widely used substance of abuse and most people in the United States begin to use alcohol during adolescence [1, 2]
We found that 3 weeks after oral gavage ethanol administration, the crossover latency in Ado:: chronic intermittent ethanol (CIE) group (16.4 ± 3.0 s) was significantly shorter than that in rats with a history of Ado::chronic intermittent water (CIW) (35.0 ± 4.0 s), Adu::CIW (25.3 ± 3.3 s), or Adu::CIE (31.6 ± 5.9 s)
The specific effects of Ado::CIE on adult anxiety levels were confirmed through OF test by comparing the percent time spent in the peripheral area of the OF (Ado::CIW, 79 ± 3%; Ado::CIE, 89 ± 2%; Adu::CIW, 80 ± 4%; Adu::CIE, 76 ± 4%; CIW/CIE × Ado/Adu interaction F1,30 = 4.9, p = 0.03)

Summary

Introduction

Alcohol is the most widely used substance of abuse and most people in the United States begin to use alcohol during adolescence [1, 2]. Adolescent alcohol drinking, which can be modeled in laboratory animals by chronic intermittent ethanol (CIE) exposure, is a serious public health concern, with 7.7 million individuals between the ages of 12–20 years reporting drinking alcohol within the past month [3]. Young people (5.1 million) reported binge drinking at least once in the past month and over 90% of alcohol consumed by underage drinkers is in the form of binge-drinking episodes [2]. This prevalence of binge alcohol drinking occurs at a critical period during development when the central nervous system is undergoing rapid adaptations in structure and function that could lead to vulnerability to mental disorders, such as anxiety. In animal models, a striatum-anxiety link has emerged at both the circuit level (i.e., striatal innervation from the traditional anxiety-related brain regions) [7] and the behavioral level (e.g., open-field (OF) test, light–dark transition test) [8, 9]

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