Alcohol binge drinking during adolescence or dependence during adulthood reduces prefrontal myelin in male rats

Abstract

Teen binge drinking is associated with low frontal white matter integrity and increased risk of alcoholism in adulthood. This neuropathology may result from alcohol exposure or reflect a pre-existing condition in people prone to addiction. Here we used rodent models with documented clinical relevance to adolescent binge drinking and alcoholism in humans to test whether alcohol damages myelinated axons of the prefrontal cortex. In Experiment 1, outbred male Wistar rats self-administered sweetened alcohol or sweetened water intermittently for 2 weeks during early adolescence. In adulthood, drinking behavior was tested under nondependent conditions or after dependence induced by 1 month of alcohol vapor intoxication/withdrawal cycles, and prefrontal myelin was examined 1 month into abstinence. Adolescent binge drinking or adult dependence induction reduced the size of the anterior branches of the corpus callosum, i.e., forceps minor (CCFM), and this neuropathology correlated with higher relapse-like drinking in adulthood. Degraded myelin basic protein in the gray matter medial to the CCFM of binge rats indicated myelin was damaged on axons in the mPFC. In follow-up studies we found that binge drinking reduced myelin density in the mPFC in adolescent rats (Experiment 2) and heavier drinking predicted worse performance on the T-maze working memory task in adulthood (Experiment 3). These findings establish a causal role of voluntary alcohol on myelin and give insight into specific prefrontal axons that are both sensitive to alcohol and could contribute to the behavioral and cognitive impairments associated with early onset drinking and alcoholism.

Keywords: adolescent; alcohol; binge; dependence; myelin; prefrontal.

Figure 1.

Alcohol causes reductions in prefrontal white matter that predict higher levels of relapse-like drinking in adulthood (Experiment 1). a, Schematic illustrating the alcohol exposure time line during adolescence and adulthood. Male rats underwent voluntary, binge self-administration sessions with sweetened alcohol (binge) or sweetened water (control) during early adolescence. In adulthood, rats were tested for baseline alcohol drinking, then exposed to chronic alcohol vapors (dependent) or ambient air (nondependent), and tested for relapse drinking (details in Gilpin et al., 2012). b, Schematic illustrating the anatomical location of CC_FM and CC_Genu sections. c, d, Alcohol reduced cross-sectional area of the CC_FM (c; main effect of adolescent binge drinking, ^#p = 0.004; main effect of adult alcohol dependence, *p = 0.006), but not the CC_Genu (d; all ps > 0.05). e, f, CC_FM cross-sectional area did not predict baseline alcohol intake (e), but did predict the percentage increase from baseline levels after short abstinence periods, i.e., relapse-like drinking (f; p = 0.02). Data expressed as mean ± SEM (n = 4–9 rats/group).

Figure 2.

Adolescent alcohol causes enduring damage to mPFC myelin (Experiment 1). a, Schematic illustrating the anatomical regions analyzed. b–d, Adolescent alcohol increased myelin damage, indexed by dMBP, in the gray matter just medial to the CC_FM (CC_FMmPFC; main effect of adolescent binge drinking, ^#p = 0.02). Adult dependence did not significantly increase dMBP in the CC_FMmPFC (b; p > 0.05) and neither treatment significantly increased dMBP in the center of the medial branch of the CC_FM (CC_FMCenter; c, p > 0.05) or striatum (CC_FMStriatum; d, p > 0.05). Data expressed as mean ± SEM (n = 4–9 rats/group).

Figure 3.

Adolescent alcohol decreases myelinated fiber density in the mPFC and predicts poor T-maze performance in adulthood (Experiments 2 and 3). a, Schematic illustrating the time line of alcohol exposure during adolescence and neural and behavioral measures. Male rats underwent voluntary, binge self-administration sessions with sweetened alcohol (binge) or sweetened water (control) during early adolescence. Rats were tested on the T-maze as adolescents and again in adulthood after 6 weeks of abstinence. b, Schematic illustrating the anatomical location of the myelinated fiber density measurement (left). Alcohol reduced myelinated fiber density in the mPFC (*p = 0.002). c, There was a significant negative correlation between daily adolescent consumption and percentage correct responses in the T-maze in adulthood in binge rats (left graph; p = 0.009). This relationship was not observed in control rats (right graph; p > 0.05) and no relationships were detected between drinking behavior and T-maze performance tested in adolescence (ps > 0.05; data not shown). Data expressed as mean ± SEM (b, n = 8–9 rats/group; c, n = 13–14 rats/group).