Binge-Like Alcohol Exposure of Neonatal Rats Via Intragastric Intubation Induces Both Purkinje Cell Loss and Cortical Astrogliosis

Binge-like alcohol exposure in neonatal rats on postnatal days 4 to 9 via artificial rearing results in a well-documented transient astrogliosis in the cerebral cortex. A recent study, which replicated the astrogliosis using artificial rearing, found that alcohol administered via daily exposure cycles in a vapor inhalation chamber on postnatal days 4 to 9 failed to elicit the effect, thus suggesting that the gliosis was an interactive effect of the artificial rearing administration and not specific to alcohol. The present study evaluated the effects in an intragastric intubation model that replicated the dosing parameters of the artificial rearing while avoiding the stress of surgery and extended maternal separation. In coronal frozen sections through parietal cortex labeled immunohistochemically for glial fibrillary acidic protein, the pups exposed to alcohol by intubation had a significantly greater density of glial fibrillary acidic protein-positive astrocytes per unit volume, compared with liiermate controls intubated with a maltose-dextrin formula; alcohol also induced fibrillary hypertrophy of the labeled astrocytes. In the cerebellum, alcohol induced a significant reduction in Purkinje cell number as determined using the optical disector method. These outcomes extend previous findings that neonatal binge alcohol exposure induces acute cortical astrogliosis and Purkinje cell loss, and confirm that the alcohol-induced amgliosis is not an artifact of artificial rearing.     

Exposure of Neonatal Rats to Alcohol by Vapor Inhalation Demonstrates Specificity of Microcephaly and Purkinje Cell Loss But Not Astrogliosis

The artificial rearing model (AR) of fetal alcohol syndrome (FAS) has been shown to induce several major pathologies in the early postnatal rat brain development: microcephaly, selective neuronal cell loss, and activation of astroglia in the neocortex. The purpose of this study was to determine whether these pathologies were specific to the action of alcohol or, in contrast, could result from confounds attributed to this model of FAS. For this purpose, the pathological effects of AR were compared with those of a vapor inhalation (VI) model of FAS. Our studies showed that the microcephaly that developed after exposure to periodic blood alcohol levels (BALs) of 300–350 mg% during postnatal days 4–9 could be achieved by both AR and VI models of FAS, and thus is independent of the method of alcohol administration. In contrast, the gliosis measured by glial fibrillary acidic protein (GFAP) mRNA levels in cortex, as well as by immuno-histochemical staining for GFAP, was found only in the AR-FAS model, but not in the VI model. However, the lack of gliosis in VI was apparently not due to a less intrusive intervention of alcohol, because VI exposure resulted in a reduction in Purkinje cell number comparable with that found after AR or intragastric intubation of alcohol. Based on these observations, we conclude that the activation of gliosis observed after AR is not a specific effect of alcohol, but rather is caused by an interaction of alcohol with as yet unidentified factors present in AR.     

Therapeutic Motor Training Increases Parallel Fiber Synapse Number Per Purkinje Neuron in Cerebellar Cortex of Rats Given Postnatal Binge Alcohol Exposure: Preliminary Report

Because therapeutic approaches to fetal alcohol effects in humans have been rare, this study explored the rehabilitative effect of complex motor training on an animal model of binge drinking in the third trimester of human pregnancy. Neonatal alcohol exposure induces significant and permanent reductions in Purkinje and granule cell number accompanied by impaired motor behavior in rats. The purpose of this study was to determine: (1) whether the motor skill impairment caused by exposure to alcohol in the early postnatal period could be ameliorated by the learning of a set of complex motor tasks that had been demonstrated to cause synaptogenesis in the cerebellar cortex; and (2) the extent to which cerebellar neurons in alcohol-exposed (AE) rats exhibit synaptic plasticity. The AE group was given 4.5 g/kg/day of ethanol from postnatal days 4 to 9 via an artificial rearing procedure producing a mean peak blood alcohol level of 257 mg/dl. Control groups consisted of a gastrostomy control (GC) group, that received an isocaloric mixture of maltose/dextrin instead of ethanol, and a suckle control (SC) group, that was reared normally by dams. At ?6 months of age, animals from the three groups were assigned either to a rehabilitation condition (RC; that received 10 days of training on the motor tasks) or to an inactive condition (IC; where rats stayed in isolation in their cages). Although SC rats were significantly faster to complete the course in the first 5 days of training, there were no differences in ability to perform among animals from all three groups—SC, GC, and AE—at the end of the training period. Unbiased stereological techniques were used to obtain estimates of the number of parallel fiber synapses/Purkinje cell within the cerebellar paramedian lobule. Results showed that the RC rats from the SC and AE groups had significantly more synapses/Purkinje cell than corresponding IC animals. These data demonstrate that rehabilitative intervention (complex motor training) can improve motor performance impaired by postnatal alcohol exposure and that surviving Purkinje neurons retain the capacity for synaptic plasticity.     

Effects of Early Postnatal Alcohol Exposure on Learning in the Developing Rat: Replication With Intubation Method of Delivery

Early postnatal exposure to alcohol during early development produces deficits in learned persistence, as reflected in the partial reinforcement extinction effect (PREE) in weanling rats, and deficits memory-based learning, as shown by patterned single alternation (PSA) discrimination learning in preweanling rats. We report a partial replication of these effects using the intubation method instead of artificial rearing. Rat pups were intubated once per day with 4.5 g/kg/day alcohol in a milk-based diet or control diet on postnatal days (PNDs) 4 to 9, and then assessed for the PREE on PNDs 20 and 21 or PSA learning on PNDs 17 and 18. Compared with previous artificial rearing reports, the intubation method produced healthier and heavier pups, and yielded a consistently lower and less variable blood alcohol levels. Even with the lower alcohol levels, intubation with alcohol eliminated the PREE. Intubation with alcohol had a weaker but still detrimental effect on PSA learning. These results suggest that alcohol exposure during development can produce behavioral deficits in the absence of the more severe effects on brain and body growth typically associated with fetal alcohol syndrome.     

Alcohol-Induced Purkinje Cell Loss with a Single Binge Exposure in Neonatal Rats: A Stereological Study of Temporal Windows of Vulnerability

Previous research has shown that the early neonatal period of rats is one of enhanced vulnerability to cerebellar Purkinje cell loss associated with binge-like alcohol exposure, with a prominent sensitive period during the first neonatal week. In this study, an unbiased count of the total number of Purkinje cells was obtained using the stereological optical fractionator, in groups of rats given a single binge-like alcohol exposure either during the most vulnerable neonatal period [postnatal day (PD) 4] or during a later, less vulnerable period (PD 9). Using artificial rearing methods, rats were given 6.6 g/kg of alcohol either on PD 4 or on PD 9, delivered as a 15% (v/v) solution in milk formula on two consecutive feedings of the designated day. Control groups included an artificially reared gastrostomy control and a normally reared suckle control. The mean peak blood alcohol concentrations were not different between the PD 4 and PD 9 alcohol groups, averaging 374 and 347 mg/dl, respectively. The rats were perfused on PD 27. A uniform random sample of sections was obtained from serial frozen sections through the cerebellum, stained with thionin, and Purkinje cells were counted from a uniform random sample of locations on each section with the three-dimensional optical fractionator. The number of Purkinje cells in the suckle control and gastrostomy control groups did not differ from each other, averaging 3.94 (±0.19) and 3.58 (±0.22) ± 10⁵ cells, respectively. Binge exposure on PD 4 induced significant cell loss (mean of 2.05 ± 0.20 ± 10⁵ Purkinje cells), whereas binge exposure on PD 9 did not induce significant Purkinje cell loss (3.70 ± 0.39 ± 10⁵ Purkinje cells). These findings confirm that a single neonatal binge alcohol exposure produces pathological Purkinje cell loss, provided that it occurs during the period of enhanced vulnerability coinciding with the early stages of dendritic outgrowth.     

Intragastric Intubation: Important Aspects of the Model for Administration of Ethanol to Rat Pups During the Postnatal Period

One technique for the controlled delivery of ethanol to neonatal rat pups is intragastric intubation. Often, the vehicle used for delivery of ethanol is composed of a nutrient mixture to compensate for decreased suckling or other possible nutritional compromise. This study analyzed the selection of nutrient vehicle, the combination of experimental treatment groups within a litter, and the overall litter size on the growth rate of ethanol-intubated and intubated-control pups, compared with mother-raised control pups. Sprague-Dawley rat pups were raised in litters of 8 or 10, and administered ethanol by intragastric intubation with 20% (v/v) Sustacalm or 80% (v/v) Intralipid-II® nutrient vehicle. Pups were treated between postnatal days 2 and 10, and body weight was analyzed on day 10. Pups were assigned to a treatment group as either intubated ethanol, intubated control, or nonintubated mother-raised controls. Experimental comparison by statistical analyses was performed to identity the optimal treatment design (mixed treatment groups in a single litter or a single treatment group per litter), the optimal vehicle (Sustacal® or Intralipid-II®), and the optimal number of pups per litter (8 vs. 10). The analyses demonstrate that the mixing of intubated control, intubated ethanol, and nonintubated mother-raised control treatment groups within a single litter introduced an uncontrolled variable that confounded measurement of ethanol-specific alterations. The sensitivity of treatment groups to inclusion in mixed litters was dependent on the nutrient vehicle and thus nutritional adequacy. Our results suggest that an optimal design was achieved with eight pups per litter. Furthermore, ethanol intubated and intubated control pups grow at a rate identical to parallel litters of eight mother-raised control pups when Intralipid-II® is used as nutrient vehicle, and a single treatment group is present in a litter. Optimization of these experimental parameters has provided an excellent neonatal rat model for analysis of specific ethanol effects on brain development during the third trimester.     

Effects of Alcohol Exposure and Artificial Rearing During Development on Septal and Hippocampal Neurotransmitters in Adult Rats

The effect of alcohol exposure during the early postnatal period in the rat on the hippocampus and septal region was investigated. The alcohol group was given 5 g/kg/day of ethanol from postnatal days 4 to 10 via an artificial rearing procedure. Control groups consisted of a gastrostomy control group that was treated in the same manner as the alcohol group, but not exposed to alcohol and a suckle control group that was reared normally by dams. Between 90 and 100 days of age, the hippocampus and septal region were assayed under non-stressed or stressed conditions using HPLC with electrochemical detection. Alcohol-exposed female rats exhibited increased hippocampal noradrenaline concentrations under stressed conditions, increased septal serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) concentrations under nonstressed conditions, and decreased septal dopamine concentrations under stressed conditions. Artificially reared male rats (regardless of alcohol exposure) exhibited an increase in hippocampal noradrenaline concentrations under stressed conditions; a decrease in hippocampal 5-HIAA concentrations under nonstressed conditions; and a decrease in septal noradrenaline, serotonin, 5-HIAA, and dopamine concentrations under nonstressed conditions. The results suggest that female rats may be more susceptible to alcohol exposure during the postnatal period than male rats and that male rats may be more susceptible to the effects of artificial rearing than female rats.     

Purkinje Cell Vulnerability to Developmental Ethanol Exposure in the Rat Cerebellum

BACKGROUND: Ethanol exposure is a consistent and reliable producer of neuronal toxicity, especially during periods of enhanced neuronal vulnerability. For rat cerebellar Purkinje cells, the postnatal period during the time of the brain growth spurt exhibits the greatest vulnerability to ethanol. Analyses of studies completed over more than 20 years provides sufficient detail to allow for the determination of the specific vulnerable window for ethanol-induced loss of Purkinje cells. METHODS: Data reporting Purkinje cell counts after ethanol exposure were compiled from 18 studies published since 1975. We conducted linear regression analysis between peak blood ethanol concentration (BEC) and percent reduction in Purkinje cells for the following individual postnatal (PN) days: PN4, PN5. PN6, PN7, and PN8 or beyond (+). The slope of the regression and the coefficients of determination (r2) were the primary factors of interest. Analysis of variance of the regressions was conducted to identify whether the slopes were significantly different from zero, or from each other. RESULTS: Exposures involving the PN4-6 period demonstrated the greatest significance in the relationship between BEC and reduction of Purkinje cell number. No significant differences were identified between different ethanol exposure techniques or for different Purkinje cell counting techniques. In addition, the initial day of exposure and the duration of exposure were not identified as critical variables. CONCLUSIONS: The literature database, developed over the past 20 years is clear in its direction that studies designed to identify the ethanol-specific mechanisms of Purkinje cell death are best designed to involve ethanol exposure during the vulnerable window of postnatal days 4-6.     

Cell Population Depletion Associated with Fetal Alcohol Brain Damage: Mechanisms of BAC-Dependent Cell Loss

Neuronal death is one of the most serious consequences of alcohol exposure during development. Studies described in this paper used a neonatal rat model to address factors affecting neuronal death following alcohol exposure during the period of rapid brain growth, and relate them to possible mechanisms of damage. The profile of blood alcohol concentrations (BACs) is an important variable influencing both brain growth deficits and neuronal death--a smaller daily dose of alcohol can be more damaging than a larger daily dose, if it is consumed in a binge-like pattern that produces relatively higher BACs. Alcohol exposure for a single day also can be damaging, producing both brain growth deficits and neuron loss, if high BACs are obtained. Various brain regions and different neuronal populations within a given brain area exhibit different degrees of vulnerability. Some neuronal loss clearly is a function of cell death due to direct effects of alcohol, while other deficits may be due to either primary or secondary effects of the alcohol insult. In the cerebellum, a maturational or metabolic factor also appears to be involved with alcohol-induced neuronal death. Immunocytochemical studies using a monoclonal antibody against microtubule-associated protein 2 (MAP2) indicated that cerebellar lobules containing Purkinje cells that are in the process of extending dendrites are ones that are more vulnerable to alcohol than lobules containing Purkinje cells that mature later. Alcohol exposure during brain development may be producing neuron attrition in multiple ways, including disruption of membrane integrity, inhibition of protein synthesis or other alterations such as lipid solubility, or by disruption of cytoskeletal elements.     

Electrophysiological Characterization of Cerebellar Neurons from Adult Rats Exposed to Ethanol during Development

The purpose of this study was to investigate the spontaneous activity of mature rat cerebellar neurons that had been exposed to ethanol (EtOH) during postnatal days 4 to 10, which corresponds to the third trimester in humans. Newborn Sprague-Dawley rats were implanted with gastric feeding tubes and were artificially reared from postnatal days 4 to 10 with two different diets. The experimental group received 4.5 g/kg/day of EtOH delivered in a milk solution. Controls received similar feeding with an isocaloric supplement replacing the EtOH. Electrophysiological evaluations were performed after an EtOH-free rearing period. Although lobules IX and X of the cerebellar vermis appeared morphologically smaller in the animals neonatally exposed to EtOH, compared with controls, extracellular recordings from both Purkinje cells and Golgi interneurons in adult rats showed no differences in spontaneous activity or firing pattern between the control and EtOH-exposed animals. Similarly, excitations and inhibitions of Purkinje neuron activity evoked by parallel pathway stimulation appeared unaffected by the developmental EtOH exposure. However, we did observe a significant decrease in the proportion of Purkinje neurons generating complex spike bursts in the group exposed to EtOH neonatally. These data suggest that, although fewer Purkinje neurons may survive the brain growth spurt if exposed to EtOH during this critical period of development, those that do survive appear to function normally. The observed abnormality in complex spike production may result from EtOH effects on developing neurons in the inferior olive that give rise to the climbing fibers that cause this bursting pattern in Purkinje neurons.     

Effects of Long Durations of Ethanol Treatment during Aging on Dendritic Plasticity in Fischer 344 Rats

Twelve-month-old Fischer 344 rats were fed a liquid diet containing 35% ethanol until they were 18 or 24 months old. Pair-fed and chow-fed control rats were matched to each ethanol-fed rat for concurrent treatment. Cerebellar Purkinje cell networks were measured in half of the rats at the end of the ethanol treatment and in the remaining rats after a subsequent 2-month recovery period. Chronic ethanol consumption resulted in significant elongation of terminal segments in the networks, and the unpaired terminal segments were the predominant sites of this growth. An increase in the duration of ethanol consumption from 24 to 48 weeks caused significantly greater segment elongation in the ethanol-fed rats in spite of the fact that circulating blood levels of ethanol declined markedly with the increased duration of treatment. During the same period of time, a pattern of terminal segment regression followed by terminal segment regrowth characterized age-induced changes in these networks. Thus the effects of long-term ethanol consumption were distinct from effects of concurrent aging processes in the Purkinje cell networks. There were significant interactions between the diets and the longer duration of treatment, such that as segments elongated in the ethanol-fed rats, they shortened in the pair-fed rats, and between the diets and the recovery period, such that as segments elongated during recovery in the pair-fed rats, they shortened in the ethanol-fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiological Interactions of Ethanol with GABAergic Mechanisms in the Rat Cerebellum in Vivo

Biochemical studies indicate that ethanol (EtOH) will facilitate the activation of the GABA_A/CI^– channel, and behavioral studies demonstrate that EtOH-induced sedative and incoordinating effects can be potentiated by GABA mimetics and blocked by GABA antagonists. It has been difficult, however, to demonstrate an EtOH-induced potentiation of the depressant electrophysiological effects of locally applied GABA in mammalian brain in vivo. Similarly, in this study, local EtOH applications only infrequently caused potentiations of the depressant effects of microiontophoretically applied GABA on cerebellar Purkinje neurons, and this interaction was modest when present. The predominant interaction of locally applied EtOH was an antagonism of GABA-induced depressions of neuronal activity. However, the GABA_A receptor antagonist bicuculline reversibly and apparently competitively blocked the depressant effects of locally applied EtOH on single cerebellar Purkinje neurons. Our data suggest that EtOH potentiation of GABA responses alone is insufficient to account for EtOH-induced depressions of cerebellar Purkinje neurons. However, these data clearly imply that activation of a GABA_A receptor is required for the expression of EtOH-induced depressions of neuronal activity in this brain area. It is less clear how lower, nondepressant doses of EtOH interact with GABA mechanisms. We hypothesize that either the GABA_A receptor mechanism must be sensitized to the potentiative effects of EtOH through the influences of neuromodulatory and/or hormonal regulation, or that EtOH interacts directly with these regulatory processes.     

Revisiting Intragastric Ethanol Intubation as a Dependence Induction Method for Studies of Ethanol Reward and Motivation in Rats

Background: The purpose of this study was to re‐examine intragastric ethanol intubation as a dependence induction method that effectively induces physical dependence upon ethanol over a short time period, is devoid of intrinsic stress artifacts, inexpensive, and easy to implement. Methods: Male Wistar rats were subjected to ethanol dependence induction via intragastric ethanol intubation. Ethanol solution (final concentration 20%, made up in a dietary liquid vehicle consisting of powdered milk, sucrose, and water) was intubated 4 times per day, at 4‐hour intervals, for 6 consecutive days (for a total of 10 g/kg/day). The utility of this procedure was evaluated for inducing physical dependence, determined by daily and final withdrawal ratings. Anxiety‐like behavior associated with ethanol dependence history was examined using the elevated plus‐maze (EPM) test, conducted 5 days after ethanol withdrawal. To evaluate whether potential stress‐like effects of intragastric intubation per se produce lasting effects on behavior, experimentally naive rats were compared with vehicle‐intubated rats for anxiety‐like behavior on the EPM. Results: Blood alcohol levels reached stable levels between 200 and 250 mg%, measured 1 hour after the second and third ethanol intubation on days 2, 4, and 6. Ethanol‐treated rats developed significant somatic withdrawal signs, recorded daily between 10 and 12 hours after the last ethanol administration. At 5 days postwithdrawal, ethanol‐treated rats showed significant anxiety‐like behavior, measured by decreased open arm time and open arm entries on the EPM, compared with vehicle controls. Additionally, ethanol postdependent rats showed decreased open arm time compared with experimentally naive rats. EPM performance did not differ between vehicle‐intubated and naive rats. No withdrawal seizures were observed and mortality rate was near zero. Conclusions: These findings suggest that intragastric ethanol administration produces a behavioral profile consistent with ethanol dependence (i.e., significant withdrawal signs after termination of ethanol exposure and elevated anxiety‐like behavior persisting beyond completion of physical withdrawal), and that the intubation procedure itself does not produce lasting nonspecific anxiety‐like effects. Thus, under the conditions employed here, this procedure provides an effective tool for inducing and evaluating the consequences of ethanol dependence in animal models of ethanol reward and motivation.     

胃运动功能对乙醇所致大鼠胃黏膜损伤的影响

目的研究普瑞博斯对乙醇所致胃黏膜损伤的影响,以阐明胃运动功能对胃黏膜的保护作用。方法实验包括两部分,实验1：雄性Wistar大鼠24只,随机分为对照组、普瑞博斯小剂量组和大剂量组,分别给予生理盐水、普瑞博斯0．5mg/kg和普瑞博斯1mg／kg灌胃,然后各组均给予无水乙醇灌胃,检测胃黏膜损伤的面积和深度;实验2：大鼠分组同上,实验前所有大鼠均行幽门结扎术,术后给药及胃黏膜损伤的检测方法刚上。结果于末结扎幽门的大鼠中,大剂量普瑞博斯可显著减少无水乙醇所致的胃黏膜损伤深度和面积,小剂量普瑞博斯也可减少胃黏膜损伤的深度。结扎幽门后,普瑞博斯对无水乙醇所致胃黏膜损伤的保护作用消失。结论普瑞博斯对无水乙醇所致的胃黏膜损伤有保护作用,该作用与普瑞博斯促进胃排空有关,提示胃运动功能对胃黏膜的保护作用。     

Ethanol Decreases Glial Derived Neurotrophic Factor (GDNF) Protein Release but Not mRNA Expression and Increases GDNF-Stimulated Shc Phosphorylation in the Developing Cerebellum

BACKGROUND: Ethanol exposure during development leads to substantial neuronal loss in multiple regions of the brain. Although differentiating Purkinje cells of the cerebellum are particularly vulnerable to ethanol exposure, the mechanisms underlying ethanol-induced Purkinje cell loss have not been well defined. Our previous research indicated that exogenous Glial-Derived Neurotrophic Factor (GDNF) attenuated ethanol-induced Purkinje cell loss in cerebellar explant cultures, which suggests that ethanol, in turn, may decrease endogenous trophic factor-mediated survival mechanisms. METHODS: The present experiments used an explant culture model of the developing rat cerebellum to test the hypothesis that ethanol decreases endogenous trophic support by limiting the availability of trophic factors, such as GDNF, or by altering the activation of key adapter proteins such as Shc (Src homology domain carboxy-terminal) that couple GDNF binding to multiple intracellular signaling pathways. GDNF mRNA and protein levels were measured by reverse northern blot analysis and sandwich enzyme-linked immunosorbent assay respectively, whereas Shc phosphorylation was measured by immunoprecipitation/western immunoblot analysis. RESULTS: The developing cerebellum expresses both GDNF mRNA and protein in vitro. Ethanol exposure (68, 103, or 137 mM) had no effect on cerebellar levels of GDNF mRNA. However, ethanol (68 and 137 mM) decreased levels of GDNF protein released into culture medium. In addition, ethanol itself had no effect on She phosphorylation. However, in the presence of the highest dose of ethanol (137 mM) GDNF did stimulate Shc phosphorylation. CONCLUSIONS: Together, these results suggest that ethanol decreases GDNF-mediated trophic support of Purkinje cells in the developing cerebellum. However, GDNF in turn activates intracellular signaling pathways throughout the developing cerebellum as part of its Purkinje cell-selective neuroprotective response to ethanol exposure.     

碘元素缺乏大鼠小脑的研究

本实验通过在实验室中复制大鼠地克病模型,造成仔鼠胚胎期和哺乳期的缺碘环境,形成甲低。用微型计算机处理所得照片,观察了大鼠小脑各层发育的变化。发现:低碘组大鼠小脑矢状切面面积值均小于加碘组和对照组。低碘组小脑皮质面积、皮质分子层面积、蒲金野细胞和颗粒层面积值也都小于加碘组和对照组。小脑髓质面积与对照组相比无显著差异。而加碘组大鼠的各观察指标与对照组相比均无显著差异。     

Behavioral Effects of Ethanol in Cerebellum Are Age Dependent: Potential System and Molecular Mechanisms

Background: Adolescent rats are less sensitive to the motor‐impairing effects of ethanol than adults. However, the cellular and molecular mechanisms underlying this age‐dependent effect of ethanol have yet to be fully elucidated. Method: Male rats of various ages were used to investigate ethanol‐induced ataxia and its underlying cellular correlates. In addition, Purkinje neurons from adolescent and adult rats were recorded both in vivo and in vitro. Finally, protein kinase C (PKCγ) expression was determined in 3 brain regions in both adolescent and adult rats. Results: The present multi‐methodological investigation confirms that adolescents are less sensitive to the motor‐impairing effects of ethanol, and this differential effect is not because of differential blood ethanol levels. In addition, we identify a particular cellular correlate that may underlie the reduced motor impairment. Specifically, the in vivo firing rate of cerebellar Purkinje neurons recorded from adolescent rats was insensitive to an acute ethanol challenge, while the firing rate of adult cerebellar Purkinje neurons was significantly depressed. Finally, it is demonstrated that PKCγ expression in the cortex and cerebellum mirrors the age‐dependent effect of ethanol: adolescents have significantly less PKCγ expression compared to adults. Conclusions: Adolescents are less sensitive than adults to the motor‐impairing effects of ethanol, and a similar effect is seen with in vivo electrophysiological recordings of cerebellar Purkinje neurons. While still under investigation, PKCγ expression mirrors the age effect of ethanol and may contribute to the age‐dependent differences in the ataxic effects of ethanol.