Reinstating Over-Pouring Behavior: Importance of the Imagined Drinking Context.

BACKGROUND: College students significantly over-pour more than a standard drink in a free-pour simulated alcohol-pouring task. Due to this effect, it is likely that much of the self-report alcohol consumption data incorrectly or underreport actual alcohol consumption. Objective: We sought to determine factors that influence over-pouring. Specifically, in two studies we sought to determine the effect of different factors on the amount of fluid subjects pour in a simulated alcohol-pouring task. Methods: Data were collected from 217 undergraduate students (105 subjects in study 1 and 112 different subjects in study 2). In study one, subjects were asked to pour what they consider to be a standard beer for themselves and an unfamiliar peer. In study two subjects were instructed to pour a beer for themself and the experimenter as if they were at an off-campus party. Results: In study one, we found that size of the cup used to pour into significantly impacted the amount of fluid poured. In addition, subjects poured significantly less for themselves than the unfamiliar peer. In study two, the imagined context in which subjects poured significantly increased the amount of fluid poured demonstrating the importance of imagined contextual cues on alcohol use behavior. Conclusions/Importance: Imagined drinking context, presence of an unfamiliar peer, and cup size affect the amount of fluid poured in a simulated alcohol free pour task. Given the various factors that impact free pouring in college students, self-report alcohol data should be considered with caution.

Differences in Behavioral Responding in Adult and Aged Rats Following Chronic Ethanol Exposure.

BACKGROUND: Research suggests symptoms of chronic alcoholism, and withdrawal may be more severe in elderly compared with younger adults. However, examination of the effects of long-term ethanol (EtOH) consumption and withdrawal is limited in aged rodents. We thus investigated EtOH withdrawal and potential deficits in cognitive and motor behavior in young adult and aged rats. We also examined the effects of acute allopregnanolone as a potential mechanism contributing to age-related differences in EtOH's cognitive-impairing effects. METHODS: Male young adult (postnatal days 70 to 72) and aged (approximately 18 months) Sprague-Dawley rats were treated with liquid EtOH diet in a modified chronic intermittent EtOH (modified-CIE) paradigm. The severity of EtOH withdrawal was determined using a 4-item rating scale, and withdrawal-induced anxiety-like behavior was assessed in the elevated plus maze (EPM) and open field. After a 14-day EtOH-free period, spatial performance was assessed in the Morris water maze (MWM) during sober acquisition and in response to a subsequent EtOH and allopregnanolone challenge. RESULTS: Modified-CIE adults consumed more EtOH during treatment and exhibited robust EtOH withdrawal using a behavioral rating scale compared to aged rats. In the EPM, adult and aged modified-CIE groups spent increased time in the closed arms, while aged animals also made significantly more closed arm entries, fewer open arm entries, and spent less time in the open arms during withdrawal compared to controls. Modified-CIE decreased MWM performance of adult and aged rats, but did not result in motor impairments in either age group. Finally, acute allopregnanolone increased time to the MWM platform in adults but not aged animals. CONCLUSIONS: The elderly may be vulnerable to EtOH withdrawal as modified-CIE aged rats displayed anxiety-like behavior compared to controls during withdrawal despite achieving lower blood EtOH concentrations during treatment than younger adults. Our data also indicate that modified-CIE and EtOH withdrawal cause persistent cognitive impairments in both age groups. The results from this study provide further evidence indicating the elderly may be sensitive to the effects of alcohol.

Chronic intermittent ethanol exposure produces persistent anxiety in adolescent and adult rats.

BACKGROUND: Ethanol (EtOH) dependence and tolerance in the adult are marked by increased function of NMDA receptors and decreased function of GABAA receptors, which coincide with altered receptor subunit expression in specific brain regions. Adolescents often use EtOH at levels greater than adults, yet the receptor subunit expression profiles following chronic intermittent EtOH (CIE) exposure in adolescents are not known. Persistent age-dependent changes in receptor subunit alterations coupled with withdrawal-related anxiety may help explain the increase in alcohol abuse following adolescent experimentation with the drug. METHODS: Adolescent and adult rats received 10 intraperitoneal administrations of 4.0 g/kg EtOH or saline every 48 hours. At either 24 hours or 12 days after the final exposure, anxiety-like behavior was assessed on the elevated plus maze and tissue was collected. Western blotting was used to assess changes in selected NMDA and GABAA receptor subunits in whole cortex and bilateral hippocampus. RESULTS: CIE exposure yields a persistent increase in anxiety-like behavior in both age groups. However, selected NMDA and GABAA receptor subunits were not differentially altered by this CIE exposure paradigm in adolescents or adults. CONCLUSIONS: CIE exposure produced persistent anxiety-like behavior, which has important implications for alcohol cessation. Given the reported behavioral and neuropeptide expression changes in response to this dose of EtOH, it is important for future work to consider the circumstances under which these measures are altered by EtOH exposure.

Age-related effects of alcohol from adolescent, adult, and aged populations using human and animal models.

BACKGROUND: This review incorporates current research examining alcohol's differential effects on adolescents, adults, and aged populations in both animal and clinical models. METHODS: The studies presented range from cognitive, behavioral, molecular, and neuroimaging techniques, leading to a more comprehensive understanding of how acute and chronic alcohol use affects the brain throughout the life span. RESULTS: Age of life is a significant factor in determining the effect of alcohol on brain functioning. Adolescents and aged populations may be more negatively affected by heavy alcohol use when compared to adults. CONCLUSIONS: Investigations limiting alcohol effects to a single age group constrains understanding of differential trajectories and outcomes following acute and chronic use. To meaningfully address the sequencing and interaction effects of alcohol and age, the field must incorporate collaborative and integrated research efforts focused on interdisciplinary questions facilitated by engaging basic and applied scientists with expertise in a range of disciplines including alcohol, neurodevelopment, and aging.

Increased anxiolytic effect in aged female rats and increased motoric behavior in aged male rats to acute alcohol administration: Comparison to younger animals.

The population of most countries in the world is increasing and understanding risk factors that can influence the health of the older population is critical. Older adults consume alcohol often in a risky, binge manner. Previous work has demonstrated that aged rats are more sensitive to many of the effects of acute ethanol. In the current project aged, adult, and adolescent female and male rats were tested on the elevated plus maze and open field following either a 1.0 g/kg alcohol injection or a saline injection. We report sex- and age-dependent effects whereas aged female rats, but not aged male rats, showed an increased anxiolytic effect of alcohol in the elevated plus maze while aged male rats, but not aged female rats, showed increased stimulatory movement in the open field. In addition, significant age effects were found for both female and male rats. It is proposed that the sex- and age-dependent effects reported in the current studies may be due to differential levels of alcohol-induced allopregnanolone for the anxiolytic effects and differential levels of alcohol-induced dopamine for the stimulatory effects. The current work provides insights into factors influencing alcohol consumption in older adults.

Acute alcohol produces ataxia and cognitive impairments in aged animals: a comparison between young adult and aged rats.

BACKGROUND: Aging in both humans and rodents appears to be accompanied by physiological changes that increase biologic sensitivity to ethanol (EtOH) intoxication. However, animal models designed to investigate this increased alcohol sensitivity have yet to be established. For this reason, we sought to determine whether acute EtOH administration produces differential effects on motor coordination and spatial cognition in young adult and aged rats. METHODS: Male young adult (postnatal day 70 to 72) and aged (~18 months) Sprague-Dawley rats were assessed on 2 motor tasks (the accelerating rotarod [RR] and the aerial righting reflex [ARR]) and a single cognitive performance task (the Morris water maze [MWM]). Following acute EtOH exposure via intraperitoneal injection, animals' performance was reassessed. RESULTS: Aged rats showed a dramatic increase in EtOH-induced ataxia on the RR and the ARR relative to young adult animals. Similarly, results from the MWM revealed that aged animals had slightly greater EtOH-induced impairments compared with young adult animals. Importantly, the increased impairments produced by EtOH were not due to differential blood EtOH levels. CONCLUSIONS: We demonstrate for the first time that aged rats show greater EtOH-induced deficits compared with young adults in tasks of motor and cognitive performance. The possible role of protein kinase C as a mechanism for increased sensitivity to the motor-impairing effects of EtOH is discussed. Given the high prevalence of alcohol use among the elderly, increased vulnerability to alcohol-induced deficits may have a profound effect on injury in this population.

Singaporean college students overpour drinks similar to Western populations: influence of peer presence in a simulated alcohol-pouring task.

BACKGROUND: College drinking is a global health concern. However, most studies originate from countries with high alcohol consumption. In the United States, college students overpour a standard alcoholic drink, yet it is unclear if this remains true in countries with low alcohol consumption. Additionally, in college, peer influence is the greatest predictor of drinking behavior, yet it is unknown if social norms affect how students pour drinks. This study examined how male college students, in a country with low alcohol consumption, define standard drinks, and if the presence of an unfamiliar peer affects how students pour during a simulated alcohol-pouring task. METHODS: Male undergraduate students (n = 105) underwent baseline assessments of impulsivity, self-monitoring, religiosity, and drinking characteristics. Participants poured fluid into empty cups of different sizes to equal a standard serving of beer or shot of liquor. There were 2 groups based on gender of experimenter. Within each group, participants were randomly assigned to Alone or Dyad condition. In the Alone condition, students were instructed to pour only for themselves. In the Dyad condition, students were instructed to pour for themselves and the experimenter. The volumes poured by the students were compared with standards used in Singapore and the United States. RESULTS: Collapsed across container size, students overpoured shots by 50% and beer by 100% when compared to the standard drink definition in Singapore. When using a more liberal definition, students overpoured beer by 25%, but did not overpour shots. In the presence of an unfamiliar peer, overpouring decreased by 10% for beer. CONCLUSIONS: The current data show that college students, in a country with low alcohol consumption, overestimate standard alcoholic drinks similar to their Western counterparts and use social norms to determine how much to pour for a drink when confronted with an unfamiliar peer. Efforts toward creating internationally recognized standard drink definitions should be considered.

Using animal models to identify clinical risk factors in the older population due to alcohol use and misuse.

The number of people over the age of 65 years old is increasing and understanding health risks associated with the aged population is important. Recent research has revealed that alcohol (ethanol) consumption levels in older demographics remains elevated and often occurs in a dangerous binge pattern. Given ethical constraints on investigating high level or binge pattern alcohol consumption in humans, animal models are often used to study the effects of ethanol. The current review highlights ongoing work revealing that aged rats are often more sensitive to the effects of acute ethanol compared to younger rats. Specifically, aged rats are more sensitive to the motor impairing, hypnotic, hypothermic, and often the cognitive effects of ethanol compared to younger rats. In addition, the development of ethanol tolerance following chronic exposure may have a different temporal pattern in aged rats compared to younger rats. However, the neurobiological mechanisms that cause the increased sensitivity to ethanol in aged animals have yet to be identified. Furthermore, the differential age effects of ethanol highlight clinical risk factors for alcohol misuse in the older human population. Future work is needed to determine underlying CNS mechanisms producing altered effects of ethanol in aged subjects and also the development of educational material concerning ethanol's effects across ages for health care providers working with the aged population.

Chronic intermittent ethanol exposure during adolescence produces sex- and age-dependent changes in anxiety and cognition without changes in microglia reactivity late in life.

Binge-like ethanol exposure during adolescence has been shown to produce long lasting effects in animal models including anxiety-like behavior that can last into young adulthood and impairments in cognition that can last throughout most of the lifespan. However, little research has investigated if binge-like ethanol exposure during adolescence produces persistent anxiety-like behavior and concomitantly impairs cognition late in life. Furthermore, few studies have investigated such behavioral effects in both female and male rats over the lifespan. Finally, it is yet to be determined if binge-like ethanol exposure during adolescence alters microglia activation in relevant brain regions late in life. In the present study female and male adolescent rats were exposed to either 3.0 or 5.0 g/kg ethanol, or water control, in a chronic intermittent pattern before being tested in the elevated plus maze and open field task over the next ∼18 months. Animals were then trained in a spatial reference task via the Morris water maze before having their behavioral flexibility tested. Finally, brains were removed, sectioned and presumptive microglia activation determined using autoradiography for [3H]PK11195 binding. Males, but not females, displayed an anxiety-like phenotype initially following the chronic intermittent ethanol exposure paradigm which resolved in adulthood. Further, males but not females had altered spatial reference learning and impaired behavioral flexibility late in life. Conversely, [3H]PK11195 binding was significantly elevated in females compared to males late in life and the level of microglia activation interacted as a function of sex and brain regions, but there was no long-term outcome related to adolescent alcohol exposure. These data further confirm that binge-like ethanol exposure during adolescence produces alterations in behavior that can last throughout the lifespan. In addition, the data suggest that microglia activation late in life is not exacerbated by prior binge-like ethanol exposure during adolescence but the expression is sex- and brain region-dependent across the lifespan.

Chronic Intermittent Ethanol Administration during Adolescence Produces Sex Dependent Impairments in Behavioral Flexibility and Survivability.

Chronic intermittent ethanol exposure during adolescence produces behavioral impairments and neurobiological changes that can last into young adulthood. One such behavioral impairment is reduced behavioral flexibility, a behavioral impairment that has been correlated with the risk for increased ethanol intake. In the current study, we investigated if chronic intermittent ethanol exposure during adolescence alters cognition, including behavioral flexibility, over a 22-month testing period. Female and male rats were treated with either 3.0 g/kg or 5.0 g/kg ethanol via gavage in a chronic intermittent fashion during adolescence and then tested every 4 to 5 months on a series of cognitive measures in the Morris water maze. Chronic intermittent ethanol selectively impaired behavioral flexibility in both female and male rats, although the pattern of results was different as a function of sex. In addition, female, but not male, rats were impaired in a short-term relearning test. Finally, male rats administered ethanol during adolescence were significantly more likely to not survive the 22-month experiment compared to female rats administered ethanol during adolescence. The current results demonstrate that adolescence is a unique period of development where chronic intermittent ethanol exposure produces long-lasting, selective cognitive impairments across the lifespan.

Chronic Intermittent Ethanol Exposure Alters Behavioral Flexibility in Aged Rats Compared to Adult Rats and Modifies Protein and Protein Pathways Related to Alzheimer's Disease.

Repeated excessive alcohol consumption increases the risk of developing cognitive decline and dementia. Hazardous drinking among older adults further increases such vulnerabilities. To investigate whether alcohol induces cognitive deficits in older adults, we performed a chronic intermittent ethanol exposure paradigm (ethanol or water gavage every other day 10 times) in 8-week-old young adult and 70-week-old aged rats. While spatial memory retrieval ascertained by probe trials in the Morris water maze was not significantly different between ethanol-treated and water-treated rats in both age groups after the fifth and tenth gavages, behavioral flexibility was impaired in ethanol-treated rats compared to water-treated rats in the aged group but not in the young adult group. We then examined ethanol-treatment-associated hippocampal proteomic and phosphoproteomic differences distinct in the aged rats. We identified several ethanol-treatment-related proteins, including the upregulations of the Prkcd protein level, several of its phosphosites, and its kinase activity and downregulation in the Camk2a protein level. Our bioinformatic analysis revealed notable changes in pathways involved in neurotransmission regulation, synaptic plasticity, neuronal apoptosis, and insulin receptor signaling. In conclusion, our behavioral and proteomic results identified several candidate proteins and pathways potentially associated with alcohol-induced cognitive decline in aged adults.

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.

Orphan glutamate receptor delta1 subunit required for high-frequency hearing.

The function of the orphan glutamate receptor delta subunits (GluRdelta1 and GluRdelta2) remains unclear. GluRdelta2 is expressed exclusively in the Purkinje cells of the cerebellum, and GluRdelta1 is prominently expressed in inner ear hair cells and neurons of the hippocampus. We found that mice lacking the GluRdelta1 protein displayed significant cochlear threshold shifts for frequencies of >16 kHz. These deficits correlated with a substantial loss of type IV spiral ligament fibrocytes and a significant reduction of endolymphatic potential in high-frequency cochlear regions. Vulnerability to acoustic injury was significantly enhanced; however, the efferent innervation of hair cells and the classic efferent inhibition of outer hair cells were unaffected. Hippocampal and vestibular morphology and function were normal. Our findings show that the orphan GluRdelta1 plays an essential role in high-frequency hearing and ionic homeostasis in the basal cochlea, and the locus encoding GluRdelta1 represents a candidate gene for congenital or acquired high-frequency hearing loss in humans.

Acute ethanol administration produces larger spatial and nonspatial memory impairments in 29-33 month old rats compared to adult and 18-24 month old rats.

The average age of the population in many countries is continuing to increase. Older people continue to consume alcohol, often in a binge like fashion. Previous research has demonstrated that older human subjects and aged animal subjects have an increased sensitivity to the effects of ethanol on a variety of behaviors. However, it has yet to be determined if acute ethanol exposure impairs spatial and/or nonspatial memory to a greater extent in aged rats compared to adult rats. In the current studies we trained male rats ranging in age from young adult (2 months of age) to aged rats (29-33 months of age) in the standard nonspatial task followed by the standard spatial task in the Morris water maze. Only animals deemed "cognitively-spared", that is aged animals that learn as well as young animals, were administered one of two doses of moderate ethanol and had their memory tested 30 min later. Acute ethanol administration produced similar performance impairments in spatial and nonspatial memory in all cognitively-spared animals except for the 29-33 month old animals which showed a significantly greater cognitive impairment in both tasks. In addition, blood ethanol levels were similar across all ages. The present work adds to the growing literature on the selective effects of acute ethanol exposure in aged animals.

Impact of acute ethanol exposure on body temperatures in aged, adult and adolescent male rats.

The mean population age of the United States continues to increase, and data suggest that by the year 2060 the population of people over the age of 65 will more than double, providing a potentially massive strain on health care systems. Research demonstrates individuals 65 and older continue to consume ethanol, often at high levels. However, preclinical animal models are still being developed to understand how ethanol might interact with the aged population. The current experiments investigated differential body temperature responses in aged rats compared to adult rats and adolescent rats. Aged (19 months of age), adult (70 days of age), or adolescent (30 days of age) male Sprague Dawley rats were administered 1.0 g/kg, 2.0 g/kg, or 3.0 g/kg ethanol, intraperitoneally (i.p.), in a balanced Latin square design. Prior to ethanol administration, a core body temperature via an anal probe was obtained, and then repeatedly determined every 60 min following ethanol exposure for a total of 360 min. In addition, a blood sample was obtained from a tail nick 60, 180, and 300 min following the ethanol injection to investigate the relationship of ethanol levels and body temperature in the same animals. Aged rats had significantly greater reductions in body temperature compared to either adult or adolescent rats following both the 2.0 g/kg and 3.0 g/kg ethanol injection. Additionally, adolescent rats cleared ethanol significantly faster than aged or adult animals. These experiments suggest body temperature regulation in aged rats might be more sensitive to acute ethanol compared to adult rats or adolescent rats. Future studies are needed to identify the neurobiological effects underlying the differential sensitivity in aged rats to ethanol.

Acute alcohol and cognition: Remembering what it causes us to forget.

Addiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders, it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry. In general, exposure to ethanol doses that produce intoxicating effects causes consistent impairments in learning and memory processes mediated by specific brain circuitry, whereas lower doses either have no effect or produce a facilitation of memory under certain task conditions. Therefore, acute ethanol does not produce a global impairment of learning and memory, and can actually facilitate particular types of memory, perhaps particular types of memory that facilitate the development of excessive alcohol use. In addition, the effects on cognition are dependent on brain region, task demands, dose received, pharmacokinetics, and tolerance. Additionally, we explore the underlying alterations in neurophysiology produced by acute alcohol exposure that help to explain these changes in cognition and highlight future directions for research. Through understanding the impact that acute alcohol intoxication has on cognition, the preliminary changes potentially causing a problematic addiction memory can better be identified.

I can't drink what I used to: The interaction between ethanol and the aging brain.

The population of most countries is increasing and the United Nations predicts that by the year 2050 those over the age of 60 years old will increase from 900 million individuals to approximately 2.1 billion individuals (United Nations, 2015). The increase in the number of older individuals will place a strain on many national health care systems making it important to investigate behaviors in the aged that may negatively impact general health in this demographic. Recent work has shown that older adults consume alcohol, often at levels that exceed the legal limit of intoxication. Unfortunately, consumption of high levels of ethanol in the older population is associated with many health consequences and may negatively impact the brain. Given ethical constraints found in many biomedical studies, animal models are needed to investigate the possible negative impact of high ethanol use in aged populations. However, few studies have investigated the effect of ethanol exposure in aged animals compared to ethanol exposure in younger animals and consequently the impact of ethanol in the aged population is not well understood. The current review summarizes initial work establishing the impact of ethanol in aged animals. The reviewed research studies support the working hypothesis that ethanol exposure produces significantly greater effects in aged animals compared to younger animals on many, if not all, behavioral tasks. In addition, the review proposes several initial, promising avenues of research to explore the neurobiological mechanisms that underly greater effects on ethanol-induced ataxia, cognition and sleep time. It is hoped that this effort will not only lead to a better understanding of behaviors impacted by ethanol in aged animals, but also improve the understanding brain mechanisms of the reported increased sensitivity to ethanol in the aged population.

The impact of low to moderate chronic intermittent ethanol exposure on behavioral endpoints in aged, adult, and adolescent rats.

The average age of the population in the United States and other countries is increasing. Understanding the health consequences in the aged population is critical. Elderly individuals consume ethanol, often at elevated rates, and in some cases in a binge episode. The present study sought to investigate whether binge-like ethanol exposure in aged male rats produced differential health and behavioral effects compared to adult male and adolescent male rats. Subjects were exposed to either 1.0 g/kg or 2.0 g/kg ethanol every other day via intraperitoneal injection for 20 days, and tested on a variety of behavioral measures and body weight. Binge-like ethanol exposure produced differential effects on body weight between aged and adolescent and adult rats. In addition, aged rats had a significantly longer loss of righting reflex and demonstrated a trend toward tolerance following the 2.0-g/kg exposure. No significant effects on anxiety-like behavior as measured by open arm entries, depressive-like symptoms as measured by immobility in the forced swim test, or cognitive performance as measured by latency and path length in the Morris water maze were found. These results demonstrate that aged animals are differentially sensitive to the impact of chronic intermittent ethanol exposure in some, but not all behaviors. Future research is needed to understand the mechanisms of these differential effects.

Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice.

Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that gamma-aminobutyric acidA (GABA(A)) receptor alpha1-/- mice exhibit postural and kinetic tremor and motor incoordination that is characteristic of essential tremor disease. We tested mice with essential-like tremor using current drug therapies that alleviate symptoms in essential tremor patients (primidone, propranolol, and gabapentin) and several candidates hypothesized to reduce tremor, including ethanol; the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801; the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA); the GABA(A) receptor modulators diazepam, allopregnanolone, and Ro15-4513; and the L-type Ca2+ channel antagonist nitrendipine. Primidone, propranolol, and gabapentin reduced the amplitude (power) of the pathologic tremor. Nonsedative doses of ethanol eliminated tremor in mice. Diazepam, allopregnanolone, Ro15-4513, and nitrendipine had no effect or enhanced tremor, whereas MK-801 and CCPA reduced tremor. To understand the etiology of tremor in these mice, we studied the electrophysiological properties of cerebellar Purkinje cells. Cerebellar Purkinje cells in GABA(A) receptor alpha1-/- mice exhibited a profound loss of all responses to synaptic or exogenous GABA, but no differences in abundance, gross morphology, or spontaneous synaptic activity were observed. This genetic animal model elucidates a mechanism of GABAergic dysfunction in the major motor pathway and potential targets for pharmacotherapy of essential tremor.