Co-reporter:Leslie R. Amodeo, Diana Kneiber, Derek N. Wills, Cindy L. Ehlers
Alcohol 2017 Volume 59(Volume 59) pp:
Publication Date(Web):1 March 2017
DOI:10.1016/j.alcohol.2016.12.002
•Rats that drank 20% ethanol as adolescents or young adults drank more as adults.•Adolescent or adult drinking did not increase future appetitive lever pressing.•Adolescents drank more and displayed more motivation to drink than adult drinkers.Binge drinking and the onset of alcohol-use disorders usually peak during the transition between late adolescence and early adulthood, and early adolescent onset of alcohol consumption has been demonstrated to increase the risk for alcohol dependence in adulthood. In the present study, we describe an animal model of early adolescent alcohol consumption where animals drink unsweetened and unflavored ethanol in high concentrations (20%). Using this model, we investigated the influence of drinking on alcohol-related appetitive behavior and alcohol consumption levels in early adulthood. Further, we also sought to investigate whether differences in alcohol-related drinking behaviors were specific to exposure in adolescence versus exposure in adulthood. Male Wistar rats were given a 2-bottle choice between 20% ethanol and water in one group and between two water bottles in another group during their adolescence (Postnatal Day [PD] 26–59) to model voluntary drinking in adolescent humans. As young adults (PD85), rats were trained in a paradigm that provided free access to 20% alcohol for 25 min after completing up to a fixed-ratio (FR) 16 lever press response. A set of young adult male Wistar rats was exposed to the same paradigm using the same time course, beginning at PD92. The results indicate that adolescent exposure to alcohol increased consumption of alcohol in adulthood. Furthermore, when investigating differences between adolescent high and low drinkers in adulthood, high consumers continued to drink more alcohol, had fewer FR failures, and faster completion of FR schedules in adulthood, whereas the low consumers were no different from controls. Rats exposed to ethanol in young adulthood also increased future intake, but there were no differences in any other components of drinking behavior. Both adolescent- and adult-exposed rats did not exhibit an increase in lever pressing during the appetitive challenge session. These data indicate that adolescent and early adult alcohol exposure can increase consumptive aspects of drinking but that adolescent exposure may preferentially influence the motivation to drink.
Co-reporter:David A. Gilder, Jennifer R. Geisler, Juan A. Luna, Daniel Calac, Peter M. Monti, Nichea S. Spillane, Juliet P. Lee, Roland S. Moore, Cindy L. Ehlers
Journal of Substance Abuse Treatment 2017 Volume 82(Volume 82) pp:
Publication Date(Web):1 November 2017
DOI:10.1016/j.jsat.2017.09.004
•Motivational Interviewing and Psycho-Education are compared in American Indian youth.•Both interventions to reduce drinking and behavior problems are effective.•Motivational Interviewing is more effective than Psycho-Education on some measures.•Gender and drinking status at baseline are covariates of intervention response.Underage drinking is an important public health issue for American Indian and Alaska Native (AI/AN) adolescents, as it is for U. S. teens of all ethnicities. One of the demonstrated risk factors for the development of alcohol use disorders in AI/AN is early age of initiation of drinking. To address this issue a randomized trial to assess the efficacy of Motivational Interviewing (MI) compared to Psycho-Education (PE) to reduce and prevent underage drinking in AI/AN youth was developed and implemented. Sixty-nine youth received MI or PE and 87% were assessed at follow-up. For teens who were already drinking, participating in the intervention (MI or PE) was associated, at follow-up, with lower quantity × frequency (q×f) of drinking (p = 0.011), fewer maximum drinks per drinking occasion (p = 0.004), and fewer problem behaviors (p = 0.009). The MI intervention resulted in male drinkers reporting a lower q×f of drinking (p = 0.048) and female drinkers reporting less depression (p = 0.011). In teens who had not started drinking prior to the intervention, 17% had initiated drinking at follow-up. As a group they reported increased quantity × frequency of drinking (p = 0.008) and maximum drinks (p = 0.047), but no change in problem behaviors. These results suggest that intervening against underage drinking using either MI or PE in AI/AN youth can result in reduced drinking, prevention of initiation of drinking, and other positive behavioral outcomes. Brief interventions that enhance motivation to change as well as Psycho-Education may provide a successful approach to reducing the potential morbidity of underage drinking in this high-risk group.
Co-reporter:Qian Peng;Nicholas J. Schork;Kirk C. Wilhelmsen
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2017 Volume 174(Issue 4) pp:435-450
Publication Date(Web):2017/06/01
DOI:10.1002/ajmg.b.32533
EEG alpha activity is the dominant oscillation in most adult humans, is highly heritable, and has been associated with a number of cognitive functions. Two EEG phenotypes, low- and high-voltage alpha (LVA & HVA), have been demonstrated to have high heritabilities. They have different prevalence depending on a population's ancestral origins. In the present study we assessed the influence of ancestry admixture on EEG alpha power, and conducted a whole genome sequencing association analysis and an ancestry-informed polygenic study on those phenotypes in a Native American (NA) population that has a high prevalence of LVA. Seven common variants, in LD with each other upstream from gene ASIC2, reached genome-wide significance (p = 2 × 10−8) having a positive association with alpha voltage. They had lower minor allele frequencies in the NAs than in a global population sample. Overall correlations between lower degrees of NA (higher degree European) ancestry and HVA, and higher degrees of NA and LVA were also found. Additionally a rare-variant gene-based study identified gene TIA1 being negatively associated with LVA. Approximately 3% of SNPs exhibited a 15-fold enrichment that explained nearly half of the total SNP-heritability for EEG alpha. These regions showed the most significant anti-correlations between NA ancestry and alpha voltage, and were enriched for genes and pathways mediating cognitive functions. Our findings suggested that these regions likely harbor causal variants for HVA, and lacking of such variants could explain the high prevalence of LVA in this NA population, possibly illuminating the ancestral origin and genetic basis for EEG alpha.
Co-reporter:Leslie R. Amodeo, Derek N. Wills, Cindy L. Ehlers
Behavioural Brain Research 2017 Volume 330(Volume 330) pp:
Publication Date(Web):14 July 2017
DOI:10.1016/j.bbr.2017.05.007
•Rats will voluntarily consume 20% ethanol at low levels.•Higher phase locking occurs in the hippocampus compared to amygdala or cortex.•Ethanol consumption reduces phase locking of event-related oscillations.•ERO energy was not changed by moderate ethanol intoxication in rats.Event-related oscillations (EROs) are rhythmic changes that are evoked by a sensory and/or cognitive stimulus that can influence the dynamics of the EEG. EROs are defined by the decomposition of the EEG signal into magnitude (energy) and phase information and can be elicited in both humans and animals. EROs have been linked to several relevant genes associated with ethanol dependence phenotypes in humans and are altered in selectively bred alcohol-preferring rats. However, pharmacological studies are only beginning to emerge investigating the impact low intoxicating doses of ethanol can have on event-related neural oscillations. The main goal of this study was to investigate the effects of low levels of voluntary consumption of ethanol, in rats, on phase locking of EROs in order to give further insight into the acute intoxicating effects of ethanol on the brain. To this end, we allow rats to self-administer unsweetened 20% ethanol over 15 intermittent sessions. This method results in a stable low-dose consumption of ethanol. Using an auditory event-related potential “oddball” paradigm, we investigated the effects of alcohol on the phase variability of EROs from electrodes implanted into the frontal cortex, dorsal hippocampus, and amygdala. We found that intermittent ethanol self-administration was sufficient to produce a significant reduction in overall intraregional synchrony across all targeted regions. These data suggest that phase locking of EROs within brain regions known to be impacted by alcohol may represent a sensitive biomarker of low levels of alcohol intoxication.
Co-reporter:Qian Peng;Ian R. Gizer;Ondrej Libiger;Chris Bizon;Kirk C. Wilhelmsen;Nicholas J. Schork
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2014 Volume 165( Issue 8) pp:673-683
Publication Date(Web):
DOI:10.1002/ajmg.b.32272
Higher rates of alcohol use and other drug-dependence have been observed in some Native American (NA) populations relative to other ethnic groups in the US. Previous studies have shown that alcohol dehydrogenase (ADH) genes and aldehyde dehydrogenase (ALDH) genes may affect the risk of development of alcohol dependence, and that polymorphisms within these genes may differentially affect risk for the disorder depending on the ethnic group evaluated. We evaluated variations in the ADH and ALDH genes in a large study investigating risk factors for substance use in a NA population. We assessed ancestry admixture and tested for associations between alcohol-related phenotypes in the genomic regions around the ADH1–7 and ALDH2 and ALDH1A1 genes. Seventy-two ADH variants showed significant evidence of association with a severity level of alcohol drinking-related dependence symptoms phenotype. These significant variants spanned across the entire 7 ADH gene cluster regions. Two significant associations, one in ADH and one in ALDH2, were observed with alcohol dependence diagnosis. Seventeen variants showed significant association with the largest number of alcohol drinks ingested during any 24-hour period. Variants in or near ADH7 were significantly negatively associated with alcohol-related phenotypes, suggesting a potential protective effect of this gene. In addition, our results suggested that a higher degree of NA ancestry is associated with higher frequencies of potential risk variants and lower frequencies of potential protective variants for alcohol dependence phenotypes. © 2014 Wiley Periodicals, Inc.
Co-reporter:Cindy L. Ehlers;Ian R. Gizer;David A. Gilder;Kirk C. Wilhelmsen
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2011 Volume 156( Issue 7) pp:772-780
Publication Date(Web):
DOI:10.1002/ajmg.b.31218
Abstract
Amphetamine-type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant “craving,” and “heavy use,” were obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant “craving,” and “heavy stimulant use,” were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant “craving” phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3-26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for “heavy stimulant use.” Additional loci with LOD scores above 2.00 were found for stimulant “craving” on chromosomes 12p13.33-13.32 and 18q22.3. These results corroborate the importance of “craving” as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes. © 2011 Wiley-Liss, Inc.
Co-reporter:Cindy L. Ehlers;Ian R. Gizer;Cassra Vieten;Kirk C. Wilhelmsen
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2010 Volume 153B( Issue 3) pp:802-811
Publication Date(Web):
DOI:10.1002/ajmg.b.31050
Abstract
Cannabis is the most widely used illicit drug in the United States. There is ample evidence that cannabis use has a heritable component, yet the genes underlying cannabis use disorders are yet to be completely identified. This study's aims were to map susceptibility loci for cannabis use and dependence and two narrower cannabis-related phenotypes of “craving” and “withdrawal” using a family study design. Participants were 2,524 adults participating in the University of California San Francisco (UCSF) Family Alcoholism Study. DSM-IV diagnoses of cannabis dependence, as well as indices of cannabis craving and withdrawal, were obtained using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms. Multipoint variance component LOD scores were obtained using SOLAR. Genome-wide significance for linkage (LOD > 3.0) was not found for the DSM-IV cannabis dependence diagnosis; however, linkage analyses of cannabis “craving” and the cannabis withdrawal symptom of “nervous, tense, restless, or irritable” revealed five sites with LOD scores over 3.0 on chromosomes 1, 3, 6, 7, and 9. These results identify new regions of the genome associated with cannabis use phenotypes as well as corroborate the importance of several chromosome regions highlighted in previous linkage analyses for other substance dependence phenotypes. © 2009 Wiley-Liss, Inc.
Co-reporter:Cindy L. Ehlers;David A. Gilder;Wendy S. Slutske;Penelope A. Lind;Kirk C. Wilhelmsen
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2008 Volume 147B( Issue 6) pp:690-698
Publication Date(Web):
DOI:10.1002/ajmg.b.30666
Abstract
Alcohol dependence is one of the leading causes of morbidity and mortality in Native Americans. Externalizing disorders such as conduct disorder (CD) and antisocial personality disorder (ASPD) have been demonstrated to have significant comorbidity with alcohol dependence in the general population. This study's aims were to: assess the comorbidity of DSM-III-R ASPD and CD with alcohol dependence, to map susceptibility loci for ASPD and CD, and to see if there is overlap with loci previously mapped for alcohol dependence phenotypes in 587 American Indians. Alcohol dependence was found to be comorbid with DSM-III-R ASPD but not CD. However, the amount of alcohol dependence in the population attributable to ASPD and/or CD is low. ASPD and the combined phenotype of participants with ASPD or CD were both found to have significant heritability, whereas no significant evidence was found for CD alone. Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 251 of the participants. Analyses of multipoint variance component LOD scores, for ASPD and ASPD/CD, revealed six locations that had a LOD score of 2.0 or above: on chromosome 13 for ASPD and on chromosomes 1, 3, 4, 14, 17, and 20 for ASPD/CD. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies for externalizing diagnoses. These results also further identify new regions of the genome, that do not overlap with alcohol dependence phenotypes previously identified in this population, that may be unique to either the phenotypes evaluated or this population of American Indians. © 2008 Wiley-Liss, Inc.
Co-reporter:Cindy L. Ehlers;David A. Gilder;Tamara L. Wall;Evelyn Phillips;Heidi Feiler;Kirk C. Wilhelmsen
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2004 Volume 129B(Issue 1) pp:
Publication Date(Web):7 JUN 2004
DOI:10.1002/ajmg.b.30057
Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain illusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians. © 2004 Wiley-Liss, Inc.
Co-reporter:Cindy L. Ehlers, Derek N. Wills, Evelyn Phillips, James Havstad
International Journal of Psychophysiology (October 2015) Volume 98(Issue 1) pp:65-75
Publication Date(Web):1 October 2015
DOI:10.1016/j.ijpsycho.2015.07.002
•EROs were used to evaluate 762 participants with and without low voltage EEGs.•Individuals with LVEEG were found to have decreased energy in their alpha EROs•LVEEG was associated with increased phase locking between cortical brain areas.•LVEEG was associated with a less intense expected response to alcohol.Low voltage EEG (LVEEG) is a heritable phenotype that differs depending on ancestral heritage, yet its impact on brain networks and cognition remain relatively unexplored. In this study we assessed energy and task related phase locking of event-related oscillation (EROs), behavioral responses, measures of IQ and personality, and expected responses to alcohol in a large sample of individuals with LVEEG compared to those with higher voltage variants. Participants (n = 762) were recruited from a Native American community and completed a diagnostic interview, the Quick Test, the Subjective High Assessment Scale Expectation Version (SHAS-E) and the Maudsley Personality Inventory. Clinical and spectral analyzed EEGs were collected for determination of the presence of a LVEEG variant. EROs were generated using a facial expression recognition task. Participants with LVEEG (n = 451) were significantly more likely to be older, married and have higher degrees of Native American heritage but did not differ in gender, income or education. Individuals with LVEEG were also found to have decreased energy in their alpha EROs, increased phase locking between stimulus trials, and increased phase-locking between cortical brain areas. No significant differences in the cognitive tests, personality variables or alcohol dependence or anxiety diagnoses were found, however, individuals with LVEEG did report a larger number of drinks ever consumed in a 24-h period and a less intense expected response to alcohol. These data suggest that alpha power in the resting EEG is highly associated with energy and cortical connectivity measures generated by event-related stimuli, as well as potentially increased risk for alcohol use.
Co-reporter:José R. Criado, Cindy L. Ehlers
Alcohol (June 2010) Volume 44(Issue 4) pp:335-342
Publication Date(Web):June 2010
DOI:10.1016/j.alcohol.2010.02.004
Co-reporter:Cindy L. Ehlers, Evelyn Phillips, Gina Finnerman, David Gilder, Philip Lau, Jose Criado
Neurotoxicology and Teratology (January–February 2007) Volume 29(Issue 1) pp:153-163
Publication Date(Web):1 January 2007
DOI:10.1016/j.ntt.2006.11.013
In adolescence, consuming a large number of drinks over a short interval of time (e.g. binging) is not an uncommon occurrence. Since adolescence is an important neurodevelopmental period, the effect of binge drinking on brain and behavior has become a significant health concern. The present study evaluated event-related potentials (ERPs) in young adult Southwest California Indians who had a history of binge drinking during their adolescence. One hundred twenty five participants who were currently 18–25 yrs of age who were free of Axis I psychiatric diagnoses were categorized as: 1) reporting no binge drinking during adolescence (> 5 drinks per occasion before age 18) or drug dependence diagnoses 2) reporting binge drinking during adolescence with no drug dependence diagnoses 3) reporting binge drinking during adolescence and drug dependence diagnoses. ERPs were collected using a facial discrimination task. Adolescent alcohol and drug exposure was found to be associated with decreases in the latency of an early P3 component (P350). Decreases in a later component amplitude (P450) were also found in young adults exposed to alcohol, and those exposed to alcohol and drugs. However, that finding appears to be a combined result of predisposing factors such as family history of alcoholism and presence of other externalizing diagnoses. Taken together these preliminary studies suggests that adolescent binge drinking may result in a decreases in P3 component latencies and amplitudes perhaps reflecting a loss or delay in the development of inhibitory brain systems.
Co-reporter:Cindy L. Ehlers, José R. Criado
Alcohol (January 2010) Volume 44(Issue 1) pp:
Publication Date(Web):1 January 2010
DOI:10.1016/j.alcohol.2009.09.033
This review discusses evidence for long-lasting neurophysiological changes that may occur following exposure to ethanol during adolescent development in animal models. Adolescence is the time that most individuals first experience ethanol exposure, and binge drinking is not uncommon during adolescence. If alcohol exposure is neurotoxic to the developing brain during adolescence, not unlike it is during fetal development, then understanding how ethanol affects the developing adolescent brain becomes a major public health issue. Adolescence is a critical time period when cognitive, emotional, and social maturation occurs and it is likely that ethanol exposure may affect these complex processes. To study the effects of ethanol on adolescent brain, animal models where the dose and time of exposure can be carefully controlled that closely mimic the human condition are needed. The studies reviewed provide evidence that demonstrates that relatively brief exposure to high levels of ethanol, via ethanol vapors, during a period corresponding to parts of adolescence in the rat is sufficient to cause long-lasting changes in functional brain activity. Disturbances in waking electroencephalogram and a reduction in the P3 component of the event-related potential (ERP) have been demonstrated in adult rats that were exposed to ethanol vapor during adolescence. Adolescent ethanol exposure was also found to produce long-lasting reductions in the mean duration of slow-wave sleep (SWS) episodes and the total amount of time spent in SWS, a finding consistent with a premature aging of sleep. Further studies are necessary to confirm these findings, in a range of strains, and to link those findings to the neuroanatomical and neurochemical mechanisms potentially underlying the lasting effects of adolescent ethanol exposure.
Co-reporter:Cindy L. Ehlers, Evelyn Phillips
Alcohol (February 2007) Volume 41(Issue 1) pp:13-20
Publication Date(Web):February 2007
DOI:10.1016/j.alcohol.2007.02.001
Co-reporter:Cindy L. Ehlers, Corinne Kim, David A. Gilder, Gina M. Stouffer, Raul Caetano, Rachel Yehuda
Journal of Psychiatric Research (December 2016) Volume 83() pp:79-85
Publication Date(Web):1 December 2016
DOI:10.1016/j.jpsychires.2016.08.009
Mexican Americans comprise one of the most rapidly growing populations in the United States, and within this population, trauma and post-traumatic stress disorder (PTSD) are associated with physical and mental health problems. Therefore, efforts to delineate factors that may uniquely contribute to increased likelihood of trauma, PTSD, and substance use disorders over the lifetime in Mexican Americans are important to address health disparities and to develop treatment and prevention programs. Six hundred fourteen young adults (age 18–30 yrs) of Mexican American heritage, largely second generation, were recruited from the community and assessed with the Semi-Structured Assessment for the Genetics of Alcoholism and an acculturation stress scale. More males (51.2%) reported experiencing traumas than females (41.1%), however, a larger proportion of females received a PTSD diagnosis (15%) than males (8%). Alcohol dependence and affective disorders, but not anxiety disorders, antisocial disorders, nicotine, marijuana, or stimulant dependence, were significantly comorbid with PTSD. Endorsing higher levels of acculturation stress was also significantly associated with both trauma exposure and a diagnosis of PTSD. Logistic regression revealed that female gender, having an affective disorder, alcohol dependence, higher levels of acculturation stress, and lower levels of education were all predictors of PTSD status. Additionally, alcohol dependence generally occurred after the PTSD diagnosis in early adulthood in this high-risk population. These studies suggest that treatment and prevention efforts should particularly focus on young adult second generation Mexican American women with higher levels of acculturation stress, who may be at higher risk for PTSD, affective disorder, and alcohol dependence following trauma exposure.
Co-reporter:Cindy L. Ehlers, Anita Desikan, Derek N. Wills
Alcohol (December 2013) Volume 47(Issue 8) pp:601-610
Publication Date(Web):December 2013
DOI:10.1016/j.alcohol.2013.09.040
Co-reporter:José R. Criado, Derek N. Wills, Brendan M. Walker, Cindy L. Ehlers
Alcohol (December 2008) Volume 42(Issue 8) pp:631-639
Publication Date(Web):December 2008
DOI:10.1016/j.alcohol.2008.08.001
Co-reporter:C.L. Ehlers, J.R. Criado, D.N. Wills, W. Liu, F.T. Crews
Neuroscience (29 December 2011) Volume 199() pp:333-345
Publication Date(Web):29 December 2011
DOI:10.1016/j.neuroscience.2011.10.011
Substance abuse typically begins in adolescence; therefore, the impact of alcohol during this critical time in brain development is of particular importance. Epidemiological data indicate that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences. Loss of cholinergic input to the forebrain has been demonstrated following fetal alcohol exposure and in adults with Wernicke–Korsakoff syndrome. In the present study, immunohistochemistry for choline acetyltransferase (ChAT) was determined to assess forebrain cholinergic neurons (Ch1-4), and behavioral changes following periadolescent alcohol exposure. Wistar rats were exposed to intermittent ethanol vapor (14 h on/10 h off/day) for 35 days from postnatal day (PD) 22 to PD 57 (average blood alcohol concentration (BAC): 163 mg%). Rats were withdrawn from vapor and assessed for locomotor activity, startle response, conflict behavior in the open field, and immobility in the forced swim test, as adults. Rats were then sacrificed at day 71/72 and perfused for histochemical analyses. Ethanol vapor–exposed rats displayed: increased locomotor activity 8 h after the termination of vapor delivery for that 24 h period at day 10 and day 20 of alcohol vapor exposure, significant reductions in the amplitude of their responses to prepulse stimuli during the startle paradigm at 24 h withdrawal, and at 2 weeks following withdrawal, less anxiety-like and/or more “disinhibitory” behavior in the open field conflict, and more immobility in the forced swim test. Quantitative analyses of ChAT immunoreactivity revealed a significant reduction in cell counts in the Ch1-2 and Ch3-4 regions of the basal forebrain in ethanol vapor–exposed rats. This reduction in cell counts was significantly correlated with less anxiety-like and/or more “disinhibitory” behavior in the open field conflict test. These studies demonstrate that behavioral measures of arousal, affective state, disinhibitory behavior, and ChAT+IR, are all significantly impacted by periadolescent ethanol exposure and withdrawal in Wistar rats.Highlights▶Adolescence ethanol exposure produces disinhibitory behavior at 2 weeks withdrawal. ▶Adolescence ethanol exposure produces depressive-like behavior at 2 weeks withdrawal. ▶Adolescent ethanol exposure reduced cholinergic neurons in basal forebrain. ▶Reduced cholinergic neurons were correlated with more disinhibitory behavior.Download high-res image (122KB)Download full-size image
Co-reporter:Manuel Sanchez-Alavez, Patricia Robledo, Derek N. Wills, James Havstad, Cindy L. Ehlers
Brain Research (22 April 2014) Volume 1559() pp:11-25
Publication Date(Web):22 April 2014
DOI:10.1016/j.brainres.2014.02.043
•A time–frequency analysis was used to evaluate the cholinergic involvement on EROs.•Medial Septum contributes to synchronization/phase re-setting between brain areas.•Nucleus Basalis Magnocellularis contributes to synchronization within a brain area.•ERO analysis provides information of cholinergic hypofunction.The cholinergic system in the brain modulates patterns of activity involved in general arousal, attention processing, memory and consciousness. In the present study we determined the effects of selective cholinergic lesions of the medial septum area (MS) or nucleus basalis magnocellularis (NBM) on amplitude and phase characteristics of event related oscillations (EROs). A time–frequency based representation was used to determine ERO energy, phase synchronization across trials, recorded within a structure (phase lock index, PLI), and phase synchronization across trials, recorded between brain structures (phase difference lock index, PDLI), in the frontal cortex (Fctx), dorsal hippocampus (DHPC) and central amygdala (Amyg). Lesions in MS produced: (1) decreases in ERO energy in delta, theta, alpha, beta and gamma frequencies in Amyg, (2) reductions in gamma ERO energy and PLI in Fctx, (3) decreases in PDLI between the Fctx–Amyg in the theta, alpha, beta and gamma frequencies, and (4) decreases in PDLI between the DHPC–Amyg and Fctx–DHPC in the theta frequency bands. Lesions in NBM resulted in: (1) increased ERO energy in delta and theta frequency bands in Fctx, (2) reduced gamma ERO energy in Fctx and Amyg, (3) reductions in PLI in the theta, beta and gamma frequency ranges in Fctx, (4) reductions in gamma PLI in DHPC and (5) reduced beta PLI in Amyg. These studies suggest that the MS cholinergic system can alter phase synchronization between brain areas whereas the NBM cholinergic system modifies phase synchronization/phase resetting within a brain area.
Co-reporter:Cindy L. Ehlers, Evelyn Phillips, Ian R. Gizer, David A. Gilder, Kirk C. Wilhelmsen
Drug and Alcohol Dependence (15 January 2010) Volume 106(Issues 2–3) pp:101-110
Publication Date(Web):15 January 2010
DOI:10.1016/j.drugalcdep.2009.07.024
Native Americans have some of the highest rates of marijuana and alcohol use and abuse, yet neurobiological measures associated with dependence on these substances in this population remain unknown. The present investigation evaluated the heritability of spectral characteristics of the electroencephalogram (EEG) and their correlation with marijuana and alcohol dependence in an American Indian community. Participants (n = 626) were evaluated for marijuana (MJ) and alcohol (ALC) dependence, as well as other psychiatric disorders. EEGs were collected from six cortical sites and spectral power determined in five frequency bands (delta 1.0–4.0 Hz, theta 4.0–7.5 Hz, alpha 7.5–12.0 Hz, low beta 12.0–20.0 Hz and high beta/gamma 20–50 Hz). The estimated heritability (h2) of the EEG phenotypes was calculated using SOLAR, and ranged from 0.16 to 0.67. Stepwise linear regression was used to detect correlations between MJ and ALC dependence and the spectral characteristics of the EEG using a model that took into account: age, gender, Native American Heritage (NAH) and a lifetime diagnosis of antisocial personality and/or conduct disorder (ASPD/CD). Increases in spectral power in the delta frequency range, were significantly correlated with gender (p < 0.001) and marijuana dependence (p < 0.003). Gender, age, NAH and ASPD/CD were all significantly (p < 0.001) correlated with theta, alpha and beta band power, whereas alcohol dependence (p < 0.01), gender (p < 0.001), and ASPD/CD (p < 0.001) were all correlated with high beta/gamma band power. These data suggest that the traits of EEG delta and high beta/gamma activity are correlated with MJ dependence and alcohol dependence, respectively, in this community sample of Native Americans.
Co-reporter:José R. Criado, Cindy L. Ehlers
Behavioural Brain Research (11 July 2010) Volume 210(Issue 2) pp:
Publication Date(Web):11 July 2010
DOI:10.1016/j.bbr.2010.02.021
Electrophysiological studies have shown that adolescent ethanol (EtOH) exposure can produce long-term changes in hippocampal EEG and ERP activity. Recently, evidence has emerged suggesting that event-related oscillations (EROs) may be good indices of alcoholism risk in humans, however, have not been evaluated for their ability to index the effects of EtOH exposure. The objective of the present study was to characterize EROs generated in hippocampus in adult rats exposed to EtOH during adolescence. Adolescent male Sprague–Dawley rats were exposed to EtOH vapor for 12 h/d for 10 days. A time–frequency representation method was used to determine delta, theta, alpha and beta ERO energy and the degree of phase variation in the hippocampus of adult rats exposed to EtOH and age-matched controls. The present results suggest that the decrease in P3 amplitudes, previously observed in adult rats exposed to EtOH during adolescence, is associated with increases in evoked theta ERO energy. These studies suggest that EROs are suitable for characterizing the long-term effects of adolescent EtOH exposure. Further studies are needed to determine the relationship between the mechanisms that regulate these neurophysiological endophenotypes and the consequences of adolescent EtOH exposure.
Co-reporter:Whitney E. Melroy-Greif, Kirk C. Wilhelmsen, Cindy L. Ehlers
Drug and Alcohol Dependence (1 September 2016) Volume 166() pp:249-253
Publication Date(Web):1 September 2016
DOI:10.1016/j.drugalcdep.2016.06.021
•Genetic variation in FAAH was associated with DSM-5 cannabis use disorder.•CNR1, MGLL, DAGLA, and DAGLB were not associated with DSM-5 cannabis use disorder.•Previous associations with rs324420 and cannabis use disorders were replicated.BackgroundCannabis is a commonly used drug and studies have shown that a significant portion of the variation in cannabis use disorders (CUDs) is heritable. Five genes known to play a role in the endocannabinoid system and CUDs were examined in a community sample of young adult Mexican Americans (MAs): CNR1, MGLL, FAAH, DAGLA, and DAGLB.MethodsGene-based tests were run to test for association between each gene and two DSM-5 cannabis phenotypes. Subsequent linear regressions were run in PLINK using an additive model to determine which single nucleotide polymorphisms (SNPs) were driving the association.ResultsFAAH was significantly associated with DSM-5 cannabis use disorder group count (DSM-5 CUD) using a gene-based test (p = 0.0035). This association survived Bonferroni correction for multiple testing at p < 0.004. Post hoc analyses suggested this association was driven by two common (minor allele frequency >5%) SNPs in moderate linkage disequilibrium, rs324420 and rs4141964, at p = 0.0014 and p = 0.0023, respectively. In both cases the minor allele increased risk for DSM-5 CUD.ConclusionsGenetic variation in FAAH was associated with DSM-5 CUD in MAs. This association was primarily driven by the missense SNP rs324420. In vitro work has provided evidence that the risk allele generates an enzyme with decreased expression and cellular stability. Although this SNP has been previously associated with substance use in the literature, this is the first association in a young adult MA sample.
Co-reporter:Jacqueline M. Otto, Ian R. Gizer, Chris Bizon, Kirk C. Wilhelmsen, Cindy L. Ehlers
Drug and Alcohol Dependence (1 October 2016) Volume 167() pp:95-102
Publication Date(Web):1 October 2016
DOI:10.1016/j.drugalcdep.2016.07.029
•Polygenic risk scores (PRS) represent additive effects of common genetic variants.•PRS for cigarettes per day (CPD) were derived from European ancestry GWAS data.•PRS predicted liability for nicotine dependence (ND) in European ancestry subjects.•PRS did not predict liability for ND in Native American ancestry subjects.•Model linkage disequilibrium when creating PRS with different ancestral populations.BackgroundRecent studies have demonstrated the utility of polygenic risk scores (PRSs) for exploring the genetic etiology of psychiatric phenotypes and the genetic correlations between them. To date, these studies have been conducted almost exclusively using participants of European ancestry, and thus, there is a need for similar studies conducted in other ancestral populations. However, given that the predictive ability of PRSs are sensitive to differences in linkage disequilibrium (LD) patterns and minor allele frequencies across discovery and target samples, the applicability of PRSs developed in European ancestry samples to other ancestral populations has yet to be determined. Therefore, the current study derived PRSs for cigarettes per day (CPD) from predominantly European-ancestry samples and examined their ability to predict nicotine dependence (ND) in a Native American (NA) population sample. Method: Results from the Tobacco and Genetics Consortium’s meta-analysis of genome-wide association studies of CPD were used to compute PRSs in a NA community sample (N = 288). These scores were then used to predict ND diagnostic status. Results: The PRS was not significantly associated with liability for ND in the full sample. However, a significant interaction between PRS and percent NA ancestry was observed. Risk scores were positively associated with liability for ND at higher levels of European ancestry, but no association was observed at higher levels of NA ancestry. Conclusion: These findings illustrate how differences in patterns of LD across discovery and target samples can reduce the predictive ability of PRSs for complex traits.
Co-reporter:David A. Gilder, Gina M. Stouffer, Philip Lau, Cindy L. Ehlers
Drug and Alcohol Dependence (1 April 2016) Volume 161() pp:222-229
Publication Date(Web):1 April 2016
DOI:10.1016/j.drugalcdep.2016.02.006
•Multi-substance use disorder was more prevalent than single use disorder.•Alcohol was the most common drug followed by stimulants and cannabis.•Multi-substance use disorder was more severe and had greater co-morbidity.BackgroundAlcohol and other substance use disorders (SUD) pose major problems of morbidity and mortality in some American Indian communities, but little is known about the clinical characteristics, risk factors, and consequences of combined alcohol and other substance use disorders (multi-substance use disorder, MSUD) in those communities.MethodsUsing the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), in a community sample of 876 American Indians, the clinical characteristics of lifetime DSM-5 moderate or severe alcohol use disorder alone (AUD alone) (n = 146) and MSUD (defined as alcohol and ≥1 other SUD) (n = 284) were evaluated and compared to 347 participants with no lifetime SUD (no SUD).ResultsThe majority (57%) of participants with a SUD had multi-substance use disorder and 94% of those were with AUD. Stimulants (cocaine and/or amphetamine) and/or cannabis were the most common other SUDs. Participants with AUD alone were more likely to be male and have an earlier age of first alcohol intoxication than those with no SUD. Those with MSUD were more likely to have dropped out of high school, have antisocial personality disorder (ASPD) or conduct disorder (CD), have earlier ages of first alcohol intoxication and first use of cannabis and stimulants, an earlier age of onset of AUD, and more of several AUD symptoms than those with AUD alone, but the same temporal course and time to remission of AUD.ConclusionsMSUD is prevalent in this sample, is associated with multiple comorbidities and denotes a more severe alcohol syndrome than AUD alone.
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