RESUMEN
Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans (NA) experience some of the highest rates of substance abuse of all the US ethnic groups. The described analyses used data from a low-coverage whole genome sequence scan to conduct a genome-wide association study (GWAS) of an impulsivity phenotype in an American Indian community sample (n = 658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using emmax. Simulations were conducted to calculate empirical P-values. Genome-wide significant findings were observed for a variant 50-kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal-specific catenin, in the REG gene cluster. A meta-analysis of GWAS had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of nei endonuclease VIII-like 3 (NEIL3) on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.
Asunto(s)
Cromosomas Humanos Par 2/genética , Conducta Impulsiva , Indígenas Norteamericanos/genética , N-Glicosil Hidrolasas/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Litostatina/genética , Masculino , Persona de Mediana Edad , alfa Catenina/genéticaRESUMEN
Excessive alcohol consumption is prevalent among adolescents and may result in lasting neurobehavioral consequences. The use of animal models to study adolescent alcohol exposure has the advantage of allowing for the control necessary in order to evaluate the effects of ethanol on the brain and separate such effects from genetic background and other environmental insults. In the present study the effects of moderate ethanol vapor exposure, during adolescence, on measures of neurogenesis and behavioral measures were evaluated at two different times following ethanol withdrawal, in adulthood. The two groups of Wistar rats were both exposed to intermittent ethanol vapor (14 h on/10h off/day) for 35-36 days from PD 23 to PD 58 (average blood ethanol concentration: 163 mg%). In the first group, after rats were withdrawn from vapor they were subsequently assessed for locomotor activity, conflict behavior in the open field, and behaviors in the forced swim test (FST) and then sacrificed at 72 days of age. The second group of rats were withdrawn from vapor and injected for 5 days with Bromo-deoxy-Uridine (BrdU). Over the next 8 weeks they were also assessed for locomotor activity, conflict behavior in the open field, and behaviors in the FST and then sacrificed at 113/114 days of age. All rats were perfused for histochemical analyses. Ethanol vapor-exposed rats displayed hypoactivity in tests of locomotion and less anxiety-like and/or more "disinhibitory" behavior in the open field conflict. Quantitative analyses of immunoreactivity revealed a significant reduction in measures of neurogenesis, progenitor proliferation, as indexed by doublecortin (DCX), Ki67, and increased markers of cell death as indexed by cleaved caspase-3, and Fluoro-Jade at 72 days, and decreases in DCX, and increases in cleaved caspase-3 at 114 days in the ethanol vapor-exposed rats. Progenitor survival, as assessed by BrdU+, was reduced in the vapor-exposed animals that were sacrificed at 114 days. The reduction seen in DCX labeled in cell counts was significantly correlated with hypoactivity at 24h after withdrawal as well as less anxiety-like and/or more "disinhibitory" behavior in the open field conflict test at 2 and 8 weeks following termination of vapor exposure. These studies demonstrate that behavioral measures of disinhibitory behavior correlated with decreases in neurogenesis are all significantly and persistently impacted by periadolescent ethanol exposure and withdrawal in Wistar rats.
Asunto(s)
Etanol/administración & dosificación , Etanol/toxicidad , Hipocampo/citología , Hipocampo/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/psicología , Administración por Inhalación , Factores de Edad , Animales , Muerte Celular/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Proteína Doblecortina , Hipocampo/crecimiento & desarrollo , Pérdida de Tono Postural/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Síndrome de Abstinencia a Sustancias/fisiopatología , VolatilizaciónRESUMEN
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.
Asunto(s)
Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/toxicidad , Neuronas Colinérgicas/efectos de los fármacos , Etanol/toxicidad , Prosencéfalo/efectos de los fármacos , Animales , Colina O-Acetiltransferasa/metabolismo , Neuronas Colinérgicas/metabolismo , Masculino , Prosencéfalo/metabolismo , Ratas , Ratas Wistar , Síndrome de Abstinencia a Sustancias/metabolismoRESUMEN
BACKGROUND: Nicotine dependence has been shown to represent a heritable condition, and several research groups have performed linkage analysis to identify genomic regions influencing this disorder though only a limited number of the findings have been replicated. METHOD: In the present study, a genome-wide linkage scan for nicotine dependence was conducted in a community sample of 950 probands and 1204 relatives recruited through the University of California, San Francisco (UCSF) Family Alcoholism Study. A modified version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) with additional questions that probe nicotine use was used to derive DSM-IV nicotine dependence diagnoses. RESULTS: A locus on chromosome 2q31.1 at 184 centiMorgans nearest to marker D2S2188 yielded a logarithm (base 10) of odds (LOD) score of 3.54 (point-wise empirical p=0.000012). Additional peaks of interest were identified on chromosomes 2q13, 4p15.33-31, 11q25 and 12p11.23-21. Follow-up analyses were conducted examining the contributions of individual nicotine dependence symptoms to the chromosome 2q31.1 linkage peak as well as examining the relationship of this chromosomal region to alcohol dependence. CONCLUSIONS: The present report suggests that chromosome 2q31.1 confers risk to the development of nicotine dependence and that this region influences a broad range of nicotine dependence symptoms rather than a specific facet of the disorder. Further, the results show that this region is not linked to alcohol dependence in this population, and thus may influence nicotine dependence specifically.
Asunto(s)
Alcoholismo/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Tabaquismo/genética , Adulto , Alcoholismo/psicología , Cromosomas Humanos Par 2/genética , Femenino , Predisposición Genética a la Enfermedad/psicología , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Fenotipo , Tabaquismo/psicología , Estados UnidosRESUMEN
Substantial evidence suggests that glutamatergic neurotransmission is a critical mediator of the experience-dependent synaptic plasticity that may underlie alcohol dependence. Substance abuse typically begins in adolescence; therefore, the impact of alcohol on glutamatergic systems during this critical time in brain development is of particular importance. The N-methyl-d-aspartate receptor (NMDAR) is involved in developmental mechanisms underlying neuronal differentiation and synaptogenesis and as such may be a target system for alcohol effects during adolescence. In the present study quantitative biochemical determinations were made of the relative abundance of different protein expressions of NMDAR subunits in adolescents and adults after 2 weeks of ethanol vapor exposure, and 24 h and 2 weeks following withdrawal. After 2 weeks of ethanol vapor exposure N-methyl-d-aspartate receptor NR1 subunit (NR1), N-methyl-d-aspartate receptor NR2A subunit (NR2A), and N-methyl-d-aspartate receptor NR2B subunit (NR2B) subunit expression was found to be increased in hippocampus of the adults. In contrast, 2 weeks of ethanol exposure resulted in no significant changes in NR1 and NR2B subunits and a reduction NR2A subunit expression in hippocampus in adolescents. Twenty-four h and 2 weeks following withdrawal from ethanol vapor NR1 and NR2A subunit expression in hippocampus was decreased in adolescents, whereas in adults it had returned to control levels. In frontal cortex, 2 weeks of chronic ethanol exposure produced decreases in NR1 subunit expression in both adults and adolescents but also produced decreases in NR2A and NR2B subunit expression in adults that returned or exceeded control levels by 2 weeks following withdrawal from ethanol vapor. These results demonstrate that NMDAR subunit composition can be modulated differentially between adolescents and adults by chronic ethanol exposure and withdrawal. These developmental differences in NMDAR subunits composition may also be associated with the enhanced vulnerability of the adolescent brain to ethanol dependence.
Asunto(s)
Etanol/farmacología , Lóbulo Frontal/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Administración por Inhalación , Factores de Edad , Animales , Peso Corporal/efectos de los fármacos , Etanol/administración & dosificación , Etanol/sangre , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Masculino , Isoformas de Proteínas/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Mouse models have been developed to simulate several relevant human traits associated with alcohol use and dependence. However, the neurophysiological substrates regulating these traits remain to be completely elucidated. We have previously demonstrated that differences in the event-related potential (ERP) responses can be found that distinguish high-alcohol preferring from low alcohol preferring mice that resemble differences seen in human studies of individuals with high and low risk for alcohol dependence. Recently, evidence of genes that affect event-related oscillations (EROs) and the risk for alcohol dependence has emerged, however, to date EROs have not been evaluated in genetic mouse models of high and low alcohol preference. Therefore, the objective of the present study was to characterize EROs in mouse models of high (C57BL/6 [B6] and high alcohol preference 1 [HAP-1] mice) and low (DBA/2J [D2] and low alcohol preference-1 [LAP-1] mice) alcohol preference. A time-frequency representation method was used to determine delta, theta and alpha/beta ERO energy and the degree of phase variation in these mouse models. The present results suggest that the decrease in P3 amplitudes previously shown in B6 mice, compared to D2 mice, is related to reductions in evoked delta ERO energy and delta and theta phase locking. In contrast, the increase in P1 amplitudes reported in HAP-1 mice, compared to LAP-1 mice, is associated with increases in evoked theta ERO energy. These studies suggest that differences in delta and theta ERO measures in mice mirror changes observed between groups at high- and low-risk for alcoholism where changes in EROs were found to be more significant than group differences in P3 amplitudes, further suggesting that ERO measures are more stable endophenotypes in the study of alcohol dependence. Further studies are needed to determine the relationship between expression of these neurophysiological endophenotypes and the genetic profile of these mouse models.
Asunto(s)
Alcoholismo/genética , Alcoholismo/fisiopatología , Encéfalo/fisiopatología , Potenciales Evocados , Periodicidad , Estimulación Acústica , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Percepción Auditiva/fisiología , Modelos Animales de Enfermedad , Electroencefalografía , Predisposición Genética a la Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , Factores de Riesgo , Factores de TiempoRESUMEN
OBJECTIVE: Ethanol and neuropeptide Y (NPY) can have additive neurobehavioral effects. In the present study, the NPY Y1 receptor antagonist BIBP3226 was administered alone or in combination with a moderate dose of ethanol to determine whether it interacted with the neurobehavioral effects of ethanol. METHOD: Male Wistar rats were implanted with cortical recording electrodes and a lateral ventricular cannula. The effects of 1 nmol BIBP3226, 0.75 g/kg ethanol and the combination (BIBP3226 + EtOH) on neurophysiological activity and locomotion were then assessed. RESULTS: Ethanol significantly increased 1-2 Hz parietal cortical power and this effect was partially antagonized by BIBP3226. Peak frequencies in the parietal cortical 6-8 Hz and 8-16 Hz bands were also altered by ethanol, but these effects were not reversed by BIBP3226. BIBP3226 or ethanol, when administered alone, did not alter motor activity or cortical event-related potentials (ERPs) but administration of BIBP3226 + EtOH reduced motor activity, reduced parietal cortical N1 ERP amplitude and increased frontal cortical N1 ERP latency. CONCLUSIONS: In the present study, the most prominent effect of antagonizing central NPY Y1 receptors was a facilitation of the effects of ethanol. In particular, the effects of combined administration of BIBP3226 and ethanol are indicative of enhanced sedation and possibly cognitive impairment.
Asunto(s)
Arginina/análogos & derivados , Corteza Cerebral/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Potenciales Evocados/fisiología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Arginina/administración & dosificación , Arginina/farmacología , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Etanol/administración & dosificación , Etanol/farmacología , Lóbulo Frontal/efectos de los fármacos , Locomoción/efectos de los fármacos , Lóbulo Parietal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Neurophysiological measures, such as decreased P300 amplitude and altered EEG alpha activity, have been associated with increased alcoholism risk. The purpose of the present study was to extend the assessment of the neurophysiological indices associated with alcohol consumption to a recently developed mouse model of high ethanol consumption, the first replicate line of high alcohol preferring (HAP-1) and low alcohol preferring (LAP-1) mice. Male HAP-1, LAP-1, and HS mice from the Institute for Behavioral Genetics at the University of Colorado Health Science Center (i.e., HS/Ibg mice) were implanted with cortical electrodes. EEG activity, and event related potentials (ERPs) were then examined. Following electrophysiological assessment, ethanol preference was assessed to examine the relationship between neurophysiological indices and ethanol consumption. EEG analyses revealed that HAPs and HS/Ibgs had greater peak frequency in the 2-4-Hz band and lower peak frequency in the 6-8- and 1-50-Hz bands of the cortical EEG compared to LAPs. Compared to HAPs, LAPs and HS/Ibgs had decreased peak EEG frequency in the 8-16-Hz band. Decreased parietal cortical power from 8 to 50 Hz was associated with high initial ethanol preference in HAP mice. In regards to ERPs, P1 amplitude was greater in HAPs compared to both LAPs and HS/Ibgs and the P3 latency in LAPs was decreased compared to both HAPs and HS/Ibgs. As expected, HAPs consumed more ethanol and had higher ethanol preference than LAPs and HS/Ibgs. There were no significant differences in ethanol intake or preference between HS/Ibgs and LAPs. These data indicate that selective breeding of the HAP and LAP lines has resulted in the divergence of EEG and ERP phenotypes. The differences observed suggest that increased cortical P1 amplitude and altered cortical EEG activity in the 8-50-Hz frequency range may be neurophysiological 'risk factors' associated with high ethanol consumption in mice. Decreased P3 latency in LAPs compared to HAPs and HS/Ibgs mice may be a 'protective factor'.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Depresores del Sistema Nervioso Central/administración & dosificación , Depresores del Sistema Nervioso Central/efectos adversos , Corteza Cerebral/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Etanol/administración & dosificación , Etanol/efectos adversos , Potenciales Evocados/efectos de los fármacos , Estimulación Acústica , Alcoholismo/fisiopatología , Animales , Peso Corporal , Corteza Cerebral/fisiopatología , Modelos Animales de Enfermedad , Lóbulo Frontal/efectos de los fármacos , Masculino , Ratones , Ratones Mutantes , Lóbulo Parietal/efectos de los fármacos , Fenotipo , Factores de RiesgoRESUMEN
RATIONALE: A select number of electrophysiological findings have been demonstrated to differentiate rat lines selectively bred for high and low ethanol preference. OBJECTIVE: In the present study, EEGs and event-related potentials (ERPs) of high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats from replicate line 2 (HAD-2 and LAD-2) were assessed to determine if their neurophysiological profiles are similar to selected lines previously evaluated. METHODS: Rats obtained from Indiana University were implanted with cortical and amygdalar recording electrodes. Baseline EEG and ERPs were assessed in ethanol-naïve HAD-2 and LAD-2 rats. Animals subsequently were trained to self-administer ethanol by using a sucrose-substitution procedure. RESULTS: Compared with LAD-2 rats, HAD-2 rats displayed greater parietal cortical power in the 6 to 32 Hz frequency range of the EEG. Greater parietal cortical peak frequency in the 2 to 4 Hz range and decreased frontal, parietal, and amygdalar peak frequencies in the 16 to 32 Hz frequency range were also seen. Compared with LAD-2 rats, HAD-2 rats had decreased P2 latency of ERPs recorded in the parietal cortex. HAD-2 rats also had greater frontal, parietal, and amygdalar P2 amplitudes, greater frontal and parietal cortical P1 amplitudes, and greater parietal cortical P3 amplitudes compared with LAD-2 rats. As anticipated, HAD-2 rats consumed significantly greater levels of sucrose, sucrose-ethanol, and ethanol over the course of the sucrose-substitution procedure compared with LAD-2 rats. CONCLUSIONS: These data suggest that increased cortical power is associated with high ethanol preference in a number of selectively bred rat lines. However, unique electrophysiological characteristics may index alcohol preference in each line.
Asunto(s)
Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/fisiopatología , Potenciales Evocados/fisiología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Electroencefalografía/efectos de los fármacos , Electroencefalografía/métodos , Etanol/farmacología , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/genética , Masculino , Fenómenos Fisiológicos del Sistema Nervioso/efectos de los fármacos , Ratas , Autoadministración/psicología , Especificidad de la Especie , Sacarosa/farmacologíaRESUMEN
RATIONALE: Several studies have provided indirect evidence that neuropeptide Y (NPY) may play a role in the regulation of ethanol consumption. However, the direct effects of central NPY administration on ethanol drinking are unclear. OBJECTIVE: This study examined the effects of NPY on ethanol, sucrose, and food consumption as well as its concomitant effects on the cortical EEG. METHODS: Wistar rats were implanted with cortical recording electrodes and a cannula in the third ventricle after using a sucrose substitution procedure to establish ethanol self-administration. NPY (0-15 microg/3.0 microl) was infused into the third ventricle prior to drinking sessions, when 10% ethanol (10E), 2% sucrose (2S), 0.5% sucrose (0.5S), or food were available. Behavior and cortical EEG were monitored during the sessions. RESULTS: NPY had no effect on the intake of 10E, 2S, or 0.5S, but NPY (15 microg/3.0 microl) significantly increased food intake. Under baseline drinking conditions, EEG power in the 6-8 Hz range was significantly greater when 2S was consumed compared to 10E. NPY decreased power in the 8-16 Hz range, decreased peak frequency in the 6-8 Hz range, and increased peak frequency in the 32-50 Hz range when 10E or 2S was available. CONCLUSIONS: These data suggest that NPY administration into the third ventricle preferentially regulates feeding compared to ethanol or sucrose drinking. In addition, since NPY significantly altered the cortical EEG in the absence of effects on ethanol and sucrose consumption, these data may indicate that NPY's cortical EEG effects are more related to its sedative or anxiolytic properties, rather than any effect on consumption.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Corteza Cerebral/fisiología , Conducta de Ingestión de Líquido/fisiología , Ingestión de Alimentos/fisiología , Etanol/administración & dosificación , Neuropéptido Y/fisiología , Sacarosa/administración & dosificación , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Animales , Corteza Cerebral/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Neuropéptido Y/administración & dosificación , Neuropéptido Y/farmacología , Núcleo Hipotalámico Paraventricular/fisiología , Ratas , Ratas Wistar , AutoadministraciónRESUMEN
Native Americans have some of the highest rates of alcohol abuse and dependence, yet risk factors for problem drinking remain relatively unknown. The amplitude of the P3 component of the event-related potential (ERP) has been suggested to be an index of 'vulnerability to alcoholism', especially when it is elicited by visual tasks in younger individuals. Visual P3 tasks, however, have not been previously investigated in Native American youth. One hundred and four Mission Indian youth between the ages of 7 and 13 years participated in the study. ERPs were collected using two visual target paradigms: a facial discrimination and an estimation of line orientation task. Analyses of covariance revealed that participants with a first degree family history of alcoholism had lower P3 component amplitudes in frontal leads to the facial discrimination task. Lower P3 amplitudes, in posterior areas, were found in the line discrimination task in children who scored above the 75th percentile in delinquent behaviors on the Achenbach Child Behavior Checklist. These findings are consistent with investigations in non-Indian populations demonstrating that the late positive component of the event related potential is sensitive to both familial history of alcohol dependence as well as personal history of externalizing behaviors.
Asunto(s)
Alcoholismo/genética , Potenciales Evocados Visuales/genética , Indígenas Norteamericanos/genética , Delincuencia Juvenil/etnología , Adolescente , Alcoholismo/fisiopatología , Alcoholismo/psicología , California , Corteza Cerebral/fisiopatología , Niño , Trastornos de la Conducta Infantil/genética , Trastornos de la Conducta Infantil/fisiopatología , Trastornos de la Conducta Infantil/psicología , Hijo de Padres Discapacitados/psicología , Electroencefalografía , Potenciales Evocados Visuales/fisiología , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Indígenas Norteamericanos/psicología , Control Interno-Externo , Delincuencia Juvenil/psicología , Masculino , Factores de RiesgoRESUMEN
OBJECTIVE: Native Americans have some of the highest rates of alcohol abuse and dependence, yet potential biological risk factors associated with the problem drinking seen in many tribes remain relatively unknown. In this study, the amplitude of the P3 component of the event-related potential (ERP), a measure associated with risk for alcoholism in European-American youth, was investigated in Mission Indians. METHOD: The study participants were Mission Indian children and adolescents (N = 68, 37 male) between the ages of 7 and 13 years. ERPs were collected using two auditory "oddball" paradigms: an easy and a difficult discrimination task. P3 amplitude and latency were statistically evaluated as a function of age, gender, degree of Native American heritage (NAH) and family history (FH) of alcohol dependence. RESULTS: P3 latency was found to vary as a function of age and gender, with girls demonstrating greater decreases in latency with age than boys. suggesting a faster maturation time. Whereas there were no significant relationships between NAH and P3 latency, those participants with at least one alcoholic parent had longer P3 latencies elicited by the difficult auditory task. No significant relationships were found between P3 amplitude generated to the target tones and any of the variables (age, gender, FH, NAH). CONCLUSIONS: Mean P3 amplitudes and latencies obtained from these Mission Indian youth were within the range of those values reported in the literature for samples of children and adolescents of other ethnicities. Although the amplitude of the P3 ERP measure has been associated with FH of alcoholism in studies of predominantly European-American individuals, P3 amplitudes generated in response to these auditory tasks did not robustly differentiate Mission Indian children and adolescents who may be at higher risk for alcoholism from those presumed to be at lower risk.
Asunto(s)
Alcoholismo/epidemiología , Potenciales Relacionados con Evento P300/fisiología , Indígenas Norteamericanos/psicología , Adolescente , Alcoholismo/diagnóstico , Niño , Electroencefalografía , Femenino , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Masculino , Escalas de Valoración Psiquiátrica , Factores de Riesgo , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
Human and animal studies support the involvement of neuropeptide Y (NPY) in the pathophysiology of depression. Thus, hippocampal NPY-LI is decreased in genetic models of depression, the Flinders Sensitive Line and Fawn Hooded rats. Maternal "deprivation" has been identified as one risk factor in the development of psychopathology, including depression in adulthood. In view of these findings we hypothesized that brain NPY may also be decreased in an animal model of early life maternal deprivation. To test this hypothesis, male and female Sprague-Dawley rats were maternally separated (MS) 6 h/day or briefly handled from postnatal day 2 (PN2) to PN6 and from PN9 to PN13. At 12 weeks of age the rats were sacrificed, the brains dissected and NPY-LI measured by radioimmunoassay. MS rats had lower NPY-LI in the hippocampus. NPY-LI was also lower in female compared to male rats in hippocampus. Lastly, NPY-LI was increased in the hypothalamus of both male and female MS rats. These findings support the hypothesis that altered NPY in the limbic region is a common denominator of several models of depression and might be a trait marker of vulnerability to affective disorders.
Asunto(s)
Depresión/metabolismo , Hipocampo/metabolismo , Hipotálamo/metabolismo , Privación Materna , Neuropéptido Y/metabolismo , Animales , Animales Recién Nacidos , Depresión/fisiopatología , Modelos Animales de Enfermedad , Femenino , Lóbulo Frontal/crecimiento & desarrollo , Lóbulo Frontal/metabolismo , Hipocampo/crecimiento & desarrollo , Hipotálamo/crecimiento & desarrollo , Masculino , Embarazo , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Factores SexualesRESUMEN
BACKGROUND: Left frontal electroencephalogram (EEG) alpha dominance has been hypothesized to be related to depressed mood as well as aversive motivation and emotion. However, few studies have prospectively evaluated electroencephalogram asymmetry during development in high-risk adolescents and children. METHODS: EEG alpha asymmetry was investigated in 134 Mission Indian children who were between 7 and 13 years of age. The relationships between electroencephalogram alpha asymmetry and age, gender, parental history of alcohol dependence, Native American heritage, and mood/ approach behaviors were explored. RESULTS: No significant relationship was found between frontal alpha asymmetry and age, gender, or behavioral measures of depressed mood and/or approach behaviors. However, participants with > or = 50% Native American heritage were significantly more likely to have greater electroencephalogram alpha power in the left frontal cortex than in the right. CONCLUSIONS: The present findings suggest that the hypothesized relationship between EEG alpha asymmetry and measures of depressed mood, aversive motivation, and emotion may not be universal in all age or ethnic groups. Additionally, though the relationship between greater degrees of Native American heritage and alpha asymmetry are not as yet clear, we suggest it may be more related to substance abuse than depression in this population of Mission Indians.
Asunto(s)
Afecto , Alcoholismo/fisiopatología , Alcoholismo/psicología , Indígenas Norteamericanos , Adolescente , Alcoholismo/etnología , Niño , Electroencefalografía , Femenino , Lateralidad Funcional , Humanos , Masculino , Factores de Riesgo , Encuestas y Cuestionarios , Estados Unidos/epidemiologíaRESUMEN
Most individuals have their first experience with ethanol (EtOH) consumption as adolescents. Episodes of high EtOH drinking, lasting from hours to days (i.e. binges), are not uncommon. Thus, adolescent EtOH drinking has become a significant health concern due to the possible protracted effects of high doses of EtOH on behavior and the developing brain. This study assessed the effects of brief high levels of EtOH during periadolescence on subsequent behavior and electrophysiology in adult rats. Male Sprague-Dawley rats were exposed to EtOH vapor for 5 days (i.e. postnatal days 35-40) or 10 days (i.e. postnatal days 30-40) for 12 h/day. Locomotor activity, EEG activity, and event-related potentials (ERPs) were then assessed at 1 and 6-7 weeks post EtOH exposure. Significant differences in locomotor activity were not observed at 1 week or 6-7 weeks post-ethanol exposure. However, EtOH exposure did have long-term electrophysiological effects. EtOH exposure increased the frequency of the EEG in the 1-2 Hz range in the parietal cortex and the 16-32 Hz range in the hippocampus. EtOH exposure also increased hippocampal N2 amplitude, decreased hippocampal P3 amplitude, and decreased cortical and hippocampal P2 amplitudes. While these findings are generally similar to those reported following long-term ethanol exposure during adulthood, alcohol exposure during adolescence appears to produce more robust hippocampal effects following shorter periods of exposure. In addition, these data indicate that, in the absence of overt behavioral differences, there are long-lasting changes in the functional brain activity of adult rats briefly exposed to high levels of EtOH during the periadolescent period.
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Envejecimiento/fisiología , Etanol/farmacología , Fenómenos Fisiológicos del Sistema Nervioso/efectos de los fármacos , Animales , Electroencefalografía , Etanol/administración & dosificación , Potenciales Evocados/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Actividad Motora/efectos de los fármacos , Lóbulo Parietal/efectos de los fármacos , Lóbulo Parietal/fisiología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Many, but not all, Native American tribes have some of the highest rates of alcohol abuse and dependence. Yet, risk factors for the development of problem drinking in these high risk groups remain largely unknown. In primarily Euroamerican populations, electrophysiological variables have been associated with risk for alcoholism. The EEG has a specific developmental time course that has been described in a diverse set of ethnic groups, but it has not been described in Native American youth. In addition, the relationship between EEG development and risk for alcoholism in Indian youth has not been previously studied. METHODS: Clinical ratings and spectral characteristics of the resting EEG were investigated in 140 Native American Mission Indian children and adolescents between the ages of 7 and 13 years. The specific aims of the study were to (1) investigate the relationship of age and gender with EEG spectral variables to determine if this population conforms to similar trends from previously published data in other ethnic groups and (2) to determine whether children with a parental history of alcoholism differ from those without alcoholic parents on EEG spectral parameters. RESULTS: No excess of abnormal EEG activity was found in this sample of Native American youth. Age, but not gender, was found to have a significant effect on EEG spectral characteristics with younger children (7-11 years old), having significantly more power in slow activity (0.5-7.5 Hz) and in alpha power (8-12 Hz) as well as slower alpha frequencies than older children (12-13 years old). Consistent with other studies of Native American youth, 66% of the children and adolescents participating in this study had at least one parent who had a lifetime diagnosis of alcohol dependence. However, an ANCOVA that covaried for age and gender revealed no significant differences in power or frequency characteristics of the EEG on the basis of parental history of alcoholism. CONCLUSIONS: These studies suggest that this sample of Mission Indian children, despite high levels of parental alcohol dependence and low socioeconomic status, show normal EEG development. As yet, no relationship has been found between any specific EEG phenotype and parental history of alcoholism in this population, however, further EEG maturation may be necessary before any relationships can be fully delineated.
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Alcoholismo/genética , Electroencefalografía , Indígenas Norteamericanos/genética , Adolescente , Factores de Edad , Alcoholismo/epidemiología , Ritmo alfa , Análisis de Varianza , Ritmo beta , Niño , Femenino , Humanos , Masculino , Fenotipo , Factores SexualesRESUMEN
OBJECTIVE: Central tachykinin levels (i.e., substance P [SP], neurokinin A [NKA], neurokinin B [NKB] and neurokinin K [NKK]) have been reported to fluctuate in association with stress and anxiety. Ethanol can also modulate stress and anxiety. Further, ethanol intake can change as a result of stress and anxiety. This suggests possible interactions between ethanol and central tachykinins, i.e., changing tachykinin levels could influence ethanol intake and vice versa. However, to date few studies have assessed the potential relationship between tachykinin levels in the brain and ethanol preference. The present study was designed to determine if rodent lines selectively bred for differences in alcohol preference (i.e., alcohol-preferring [P] and non-preferring [NP] rats) have different tachykinin levels in the brain. METHOD: Tissue samples from the brains of ethanol-naive P and NP rats were collected from the frontal cortex, caudate, hippocampus, amygdala and hypothalamus. Using radioimmuno assays, concentrations of SP-like immunoreactivity (SP-LI) and neurokinin-like immunoreactivity (NK-LI, i.e., neurokinin A, B and K) in P and NP rats were determined. RESULTS: In P rats, SP-LI was significantly lower in the frontal cortex (F= 12.80, 1/26 df, p = .001) while NK-LI was significantly lower in the frontal cortex (F = 7.36, 1/26 df, p = .012) and hypothalamus (F = 5.32, 1/26 df, p = .029) compared with NP rats. CONCLUSIONS: These data indicate that endogenous SP and neurokinin levels are reduced in discrete brain regions of P rats compared with NP rats. These decreases may be associated with decreased serotonergic innervation of these brain regions in P rats compared with NP rats.
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Consumo de Bebidas Alcohólicas/metabolismo , Corteza Cerebral/metabolismo , Hipotálamo/metabolismo , Neuroquinina A/metabolismo , Neuroquinina B/metabolismo , Sustancia P/metabolismo , Consumo de Bebidas Alcohólicas/genética , Animales , Masculino , Ratas , Especificidad de la EspecieRESUMEN
BACKGROUND: Two of the class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode for multiple isozymes that differ in their kinetic properties. Polymorphisms at both of these gene loci have been linked to alcoholism and/or alcohol-induced disabilities in some populations. At the ADH2 locus, three polymorphisms are present (ADH2*1, ADH2*2, ADH2*3). ADH2*3 allele codes for a high Km and Vmax variant that has been reported to occur exclusively in African Americans and some tribes of Native Americans. In African Americans, the presence of the ADH2*3 allele is associated with protection from alcohol-related birth defects. However, its relationship to risk for alcoholism in African Americans remains relatively unexplored. METHODS: The participants were 97 African American young adults (18-25 years old). A structured interview was used to gather information on demographics, psychiatric diagnoses, personal drinking and drug use history, and familial history of alcohol use disorders. A blood sample was obtained from each participant and leukocyte DNA extracted and genotyped for the presence of ADH2*3 alleles. The specific aim of the study was to investigate the associations between the presence of the ADH2* 3 allele and personal and family history of alcohol use/abuse. RESULTS: Thirty participants (31%) had at least one ADH2*3 allele and two were homozygous for the allele. A significant association between the presence of an ADH2*3 allele and a negative family history of alcoholism was uncovered (p < 0.04). No significant associations of an ADH2*3 allele with personal history of alcohol use disorders or with current drinking were found; however, power to detect associations was limited in this population because half the population did not drink regularly. CONCLUSIONS: Because family history of alcoholism is one of the best predictors of the development of alcohol use disorders, this pilot study suggests that, in this sample of African American young adults, the ADH2*3 allele may be associated with a lowered risk for the development of alcoholism.
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Alcohol Deshidrogenasa/genética , Alcoholismo/genética , Alelos , Población Negra , Isoenzimas/genética , Adolescente , Adulto , Consumo de Bebidas Alcohólicas/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Estados UnidosRESUMEN
Despite warning labels and increases in evidence of the adverse effects of tobacco use, women continue to use tobacco products during pregnancy. Cigarette smoking has been linked to increased prenatal mortality, increased incidence of SIDS, reductions in birth weight, and disruptions in CNS and behavioral development. Animal model systems have critically established the causal relationship between nicotine and adverse developmental outcome. The present study examines the behavioral effects of nicotine exposure in the rat during the third trimester equivalent of the human brain growth spurt, a period of rapid development of the cholinergic systems and a period during which the CNS is particularly vulnerable to a number of insults. Sprague-Dawley rat pups were exposed to nicotine (6.0 mg/kg/day) from postnatal days (PD) 4-9 via an artificial rearing procedure. This procedure ensures that observed effects are not due to nutritional deficits. Two control groups were employed, an artificially reared control group and a normally reared control group. Activity level was measured on PD 18-19. Nicotine-exposed subjects were significantly overactive compared to both control groups, which did not differ significantly from one another. This behavioral alteration was observed in the absence of nicotine-induced body weight deficits. These results suggest that women who use tobacco products during late gestation may place their fetuses at risk for hyperactivity later in life, particularly during early adolescence.
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Encéfalo/efectos de los fármacos , Estimulantes Ganglionares/farmacología , Nicotina/farmacología , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Femenino , Habituación Psicofisiológica/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , DesteteRESUMEN
BACKGROUND: Specific neurophysiological profiles, such as reduced P300 amplitude or altered spectral power in the EEG, have been associated with a risk for alcoholism in several clinical populations. In certain rodent models, high versus low alcohol consumption is associated with similar neurophysiological differences. For example, alcohol-preferring (P) rats have increased spectral power and decreased P300 amplitudes compared with alcohol-nonpreferring (NP) rats. In the present study, the neurophysiological profiles of high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats were assessed (1) to determine if their electrophysiological profiles are similar to P and NP rats and (2) to examine the relationship of these neurophysiological indices to ethanol drinking. METHODS: Ethanol-naive HAD and LAD rats were implanted with cortical and amygdalar recording electrodes. Baseline EEG and event-related potentials (ERPs) then were assessed. Subsequently, all rats were trained to self-administer ethanol by using a sucrose-substitution procedure. RESULTS: Baseline EEG and ERP (i.e., pre-ethanol exposure) were assessed based on line (HAD versus LAD) and actual ethanol consumption (high drinkers versus low drinkers). At baseline, ethanol-naive HAD rats displayed significantly greater power in the cortical EEG and decreased amygdala N1 ERP amplitude compared with ethanol-naive LAD rats. Similar EEG and ERP profiles have been observed when P and NP rats are compared. No differences in P300 between lines were observed, but high-drinking rats, independent of line, had significantly decreased P300 amplitude in the amygdala compared with low-drinking rats. CONCLUSIONS: These data suggest there are some similarities in EEG and ERP profiles of P and HAD rats compared with NP and LAD rats. Furthermore, the data suggest that decreased P300 amplitude in the amygdala is associated with increased limited access ethanol drinking.