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BACKGROUND: Incentives to promote drinking ("happy hour") can encourage faster rates of alcohol consumption, especially in women. Sex differences in drinking dynamics may underlie differential health vulnerabilities relating to alcohol in women versus men. Herein, we used operant procedures to model the happy hour effect and gain insight into the alcohol drinking dynamics of male and female rats. METHODS: Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which rats had access to alcohol (self-administration session length). Rats were tested twice within the 12 h of the dark cycle, first at 2 h (early phase of the dark cycle, "early sessions") and then again at 10 h into the dark cycle (late phase of the dark cycle, "late sessions") with an 8-h break between the two sessions in the home cage. RESULTS: Adult females consumed significantly more alcohol (g/kg) than males in the 30-min sessions with the FR1 schedule of reinforcement when tested late in the dark cycle. Front-loading of alcohol was the primary factor driving higher consumption in females. Changing the schedule of reinforcement from FR1 to FR3 reduced total consumption. Notably, this manipulation had minimal effect on front-loading behavior in females, whereas front-loading behavior was significantly reduced in males when more effort was required to access alcohol. Compressing drinking access to 15 min to model a happy hour drove up front-loading behavior, generating alcohol drinking patterns in males that were similar to patterns in females (faster drinking and higher intake). CONCLUSIONS: This strategy could be useful for exploring sex differences in the neural mechanisms underlying alcohol drinking and related health vulnerabilities. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.
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Consumo de Bebidas Alcohólicas , Etanol , Animales , Femenino , Masculino , Ratas , Ratas Wistar , Autoadministración , Caracteres SexualesRESUMEN
Adolescent drinking is risky because neural circuits in the frontal lobes are undergoing maturational processes important for cognitive function and behavioral control in adulthood. Previous studies have shown that myelinated axons in the medial prefrontal cortex (mPFC) are particularly sensitive to alcohol drinking, especially in males. Pro-inflammatory mediators like toll-like receptor 4 (TLR4) and interleukin-1 beta (IL1b) have been implicated in alcohol induced-inflammation and demyelination; thus, herein we test the hypothesis that voluntary alcohol drinking early in adolescence elicits a pro-inflammatory state that is more pronounced in the brain of males compared to females. Adolescent male and female Wistar rats self-administered sweetened alcohol or sweetened water from postnatal days 28-42 and separate sets of brains were processed for 1) immunolabeling for ionized calcium-binding adapter molecule 1 to analyze microglial cell morphology, or 2) qPCR analysis of gene expression of pro-inflammatory mediators. Binge drinking alcohol activated microglia in the mPFC and hippocampus of both males and females, suggesting that voluntary alcohol exposure initiates an inflammatory response. Il1b mRNA was upregulated in the mPFC of both sexes. Conversely, Tlr4 mRNA levels were elevated after drinking only in males, which could explain more robust effects of alcohol on myelin in this region in developing males compared to females. Il1b mRNA changes were not observed in the hippocampus, but alcohol elevated Tlr4 mRNA in both sexes, highlighting regional specificity in inflammatory responses to alcohol. Overall, these findings give insight into potential mechanisms by which low-to-moderate voluntary alcohol intake impacts the developing brain. This article is part of the special Issue on 'Vulnerabilities to Substance Abuse'.
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Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/patología , Interleucina-1beta/genética , Sistema Límbico/metabolismo , Receptor Toll-Like 4/genética , Consumo de Bebidas Alcohólicas/psicología , Animales , Consumo Excesivo de Bebidas Alcohólicas/genética , Consumo Excesivo de Bebidas Alcohólicas/psicología , Condicionamiento Operante , Femenino , Regulación de la Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Interleucina-1beta/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Masculino , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Autoadministración , Caracteres Sexuales , Receptor Toll-Like 4/efectos de los fármacosRESUMEN
Sex differences may play a critical role in modulating how chronic or heavy alcohol use impacts the brain to cause the development of alcohol use disorder (AUD). AUD is a multifaceted and complex disorder driven by changes in key neurobiological structures that regulate executive function, memory, and stress. A three-stage framework of addiction (binge/intoxication; withdrawal/negative affect; preoccupation/anticipation) has been useful for conceptualizing the complexities of AUD and other addictions. Initially, alcohol drinking causes short-term effects that involve signaling mediated by several neurotransmitter systems such as dopamine, corticotropin releasing factor, and glutamate. With continued intoxication, alcohol leads to dysfunctional behaviors that are thought to be due in part to alterations of these and other neurotransmitter systems, along with alterations in neural pathways connecting prefrontal and limbic structures. Using the three-stage framework, this review highlights examples of research examining sex differences in drinking and differential modulation of neural systems contributing to the development of AUD. New insights addressing the role of sex differences in AUD are advancing the field forward by uncovering the complex interactions that mediate vulnerability.
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Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/fisiopatología , Caracteres Sexuales , Adolescente , Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/psicología , Animales , Conducta Adictiva/fisiopatología , Conducta Adictiva/psicología , Etanol , Femenino , Humanos , Masculino , Ratones , RatasRESUMEN
Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7-9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28-42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II-V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking.
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Myelination of prefrontal circuits during adolescence is thought to lead to enhanced cognitive processing and improved behavioral control. However, while standard neuroimaging techniques commonly used in human and animal studies can measure large white matter bundles and residual conduction speed, they cannot directly measure myelination of individual axons or how fast electrical signals travel along these axons. Here we focused on a specific population of prefrontal axons to directly measure conduction velocity and myelin microstructure in developing male rats. An in vitro electrophysiological approach enabled us to isolate monosynaptic projections from the anterior branches of the corpus callosum (corpus callosum-forceps minor, CCFM) to the anterior cingulate subregion of the medial prefrontal cortex (Cg1) and to measure the speed and direction of action potentials propagating along these axons. We found that a large number of axons projecting from the CCFM to neurons in Layer V of Cg1 are ensheathed with myelin between pre-adolescence [postnatal day (PD)15] and mid-adolescence (PD43). This robust increase in axonal myelination is accompanied by a near doubling of transmission speed. As there was no age difference in the diameter of these axons, myelin is likely the driving force behind faster transmission of electrical signals in older animals. These developmental changes in axonal microstructure and physiology may extend to other axonal populations as well, and could underlie some of the improvements in cognitive processing between childhood and adolescence.
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Potenciales de Acción/fisiología , Axones/fisiología , Cuerpo Calloso/fisiología , Giro del Cíngulo/fisiología , Vaina de Mielina/metabolismo , Conducción Nerviosa/fisiología , Corteza Prefrontal/fisiología , Factores de Edad , Animales , Axones/metabolismo , Axones/ultraestructura , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas WistarRESUMEN
Post-traumatic stress disorder (PTSD) affects 7.7 million Americans. One diagnostic criterion for PTSD is avoidance of stimuli that are related to the traumatic stress. Using a predator odor stress conditioned place aversion (CPA) model, rats can be divided into groups based on stress reactivity, as measured by avoidance of the odor-paired context. Avoider rats, which show high stress reactivity, exhibit persistent avoidance of stress-paired context and escalated alcohol drinking. Here, we examined the potential role of corticotropin-releasing factor (CRF), a neuropeptide that promotes anxiety-like behavior in mediating avoidance and escalated alcohol drinking after stress. CRF is expressed in the medial prefrontal cortex (mPFC). The dorsal and ventral sub-regions of the mPFC (dmPFC and vmPFC) have opposing roles in stress reactivity and alcohol drinking. We hypothesized that vmPFC CRF-CRFR1 signaling contributes functionally to stress-induced avoidance and escalated alcohol self-administration. In Experiment 1, adult male Wistar rats were exposed to predator odor stress in a CPA paradigm, indexed for avoidance of odor-paired context, and brains processed for CRF-immunoreactive cell density in vmPFC and dmPFC. Post-stress, Avoiders exhibited higher CRF cell density in vmPFC, but not the dmPFC. In Experiment 2, rats were tested for avoidance of a context repeatedly paired with intra-vmPFC CRF infusions. In Experiment 3, rats were stressed and indexed, then tested for the effects of intra-vmPFC CRFR1 antagonism on avoidance and alcohol self-administration. Intra-vmPFC CRF infusion produced avoidance of a paired context, and intra-vmPFC CRFR1 antagonism reversed avoidance of a stress-paired context, but did not alter post-stress alcohol self-administration. These findings suggest that vmPFC CRF-CRFR1 signaling mediates avoidance of stimuli paired with traumatic stress.
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Reacción de Prevención/fisiología , Hormona Liberadora de Corticotropina/administración & dosificación , Corteza Prefrontal/metabolismo , Estrés Psicológico/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Infusiones Intraventriculares , Masculino , Corteza Prefrontal/efectos de los fármacos , Pirimidinas/administración & dosificación , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Estrés Psicológico/psicologíaRESUMEN
Hyperalgesia is an exaggerated response to noxious stimuli produced by peripheral or central plasticity. Stress modifies nociception, and humans with post-traumatic stress disorder (PTSD) exhibit co-morbid chronic pain and amygdala dysregulation. Predator odor stress produces hyperalgesia in rodents. Systemic blockade of corticotropin-releasing factor (CRF) type 1 receptors (CRFR1s) reduces stress-induced thermal hyperalgesia. We hypothesized that CRF-CRFR1 signaling in central amygdala (CeA) mediates stress-induced hyperalgesia in rats with high stress reactivity. Adult male Wistar rats were exposed to predator odor stress in a conditioned place avoidance paradigm and indexed for high (Avoiders) and low (Non-Avoiders) avoidance of predator odor-paired context, or were unstressed Controls. Rats were tested for the latency to withdraw hindpaws from thermal stimuli (Hargreaves test). We used pharmacological, molecular, and immunohistochemical techniques to assess the role of CRF-CRFR1 signaling in CeA in stress-induced hyperalgesia. Avoiders exhibited higher CRF peptide levels in CeA that did not appear to be locally synthesized. Intra-CeA CRF infusion mimicked stress-induced hyperalgesia. Avoiders exhibited thermal hyperalgesia that was reversed by systemic or intra-CeA injection of a CRFR1 antagonist. Finally, intra-CeA infusion of tetrodotoxin produced thermal hyperalgesia in unstressed rats and blocked the anti-hyperalgesic effect of systemic CRFR1 antagonist in stressed rats. These data suggest that rats with high stress reactivity exhibit hyperalgesia that is mediated by CRF-CRFR1 signaling in CeA.
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Núcleo Amigdalino Central/metabolismo , Hiperalgesia/patología , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Transducción de Señal/fisiología , Estrés Psicológico/fisiopatología , Análisis de Varianza , Animales , Reacción de Prevención/efectos de los fármacos , Núcleo Amigdalino Central/patología , Condicionamiento Psicológico/efectos de los fármacos , Hormona Liberadora de Corticotropina/genética , Hormona Liberadora de Corticotropina/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hiperalgesia/fisiopatología , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Odorantes , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Pirimidinas/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/genética , Transducción de Señal/efectos de los fármacosRESUMEN
UNLABELLED: A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding quantitative trait loci for gene expression and the trait of interest, has been applied in the present study. In this analysis, a novel approach was used that combined DNA-Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA-Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co-expression modules and identify biological functions that contribute to the predisposition of consuming varying amounts of alcohol. A gene co-expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in the brain, and was associated with alcohol consumption in the RI panel. This module was found to be enriched with differentially expressed genes from the selected lines of rats. The candidate genes within the module and differentially expressed genes between high and low drinking selected lines were associated with glia (microglia and astrocytes) and could be categorized as being related to immune function, energy metabolism and calcium homeostasis, as well as glial-neuronal communication. The results of the present study show that there are multiple combinations of genetic factors that can produce the same phenotypic outcome. Although no single gene accounts for predisposition to a particular level of alcohol consumption in every animal model, coordinated differential expression of subsets of genes in the identified pathways produce similar phenotypic outcomes. DATABASE: The datasets supporting the results of the present study are available at http://phenogen.ucdenver.edu.
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Consumo de Bebidas Alcohólicas/genética , Encéfalo/metabolismo , Redes Reguladoras de Genes , Animales , Bases de Datos de Ácidos Nucleicos , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Masculino , Ratas , Ratas Endogámicas BN , Ratas Endogámicas , Ratas Wistar , Recombinación Genética , TranscriptomaRESUMEN
Chronic alcohol consumption disrupts glucocorticoid signaling at multiple physiological levels to interact with several disease-related processes associated with neuroendocrine and psychiatric disorders. Excessive alcohol use produces stress-related neuroadaptations at the level of the hypothalamic-pituitary-adrenal (HPA) axis as well as within central (extra-hypothalamic) neural circuitry, including the central amygdala (CeA) and prefrontal cortex (PFC). Altered glucocorticoid receptor (GR) signaling in these areas following excessive alcohol exposure is postulated to mediate the transition from recreational drinking to dependence, as well as the manifestation of a host of cognitive and neurological deficits. Specifically, a bidirectional regulation of stress systems by glucocorticoids leads to the development of an HPA axis tolerance and a concomitant sensitization of cortical and subcortical circuitries. A greater understanding of how hypothalamic and extra-hypothalamic glucocorticoid systems interact to mediate excessive drinking and related pathologies will lead to more effective therapeutic strategies for alcohol use disorder (AUD) and closely related comorbidities.
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Alcoholismo/metabolismo , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/fisiopatología , Alcoholismo/fisiopatología , Amígdala del Cerebelo/fisiopatología , Hormona Liberadora de Corticotropina/metabolismo , Ansia , Tolerancia a Medicamentos , Regulación de la Expresión Génica , Humanos , Sistema Hipotálamo-Hipofisario/fisiopatología , Vías Nerviosas/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiopatología , Corteza Prefrontal/fisiopatología , Recurrencia , Transducción de Señal , Estrés FisiológicoRESUMEN
Teen binge drinking is associated with low frontal white matter integrity and increased risk of alcoholism in adulthood. This neuropathology may result from alcohol exposure or reflect a pre-existing condition in people prone to addiction. Here we used rodent models with documented clinical relevance to adolescent binge drinking and alcoholism in humans to test whether alcohol damages myelinated axons of the prefrontal cortex. In Experiment 1, outbred male Wistar rats self-administered sweetened alcohol or sweetened water intermittently for 2 weeks during early adolescence. In adulthood, drinking behavior was tested under nondependent conditions or after dependence induced by 1 month of alcohol vapor intoxication/withdrawal cycles, and prefrontal myelin was examined 1 month into abstinence. Adolescent binge drinking or adult dependence induction reduced the size of the anterior branches of the corpus callosum, i.e., forceps minor (CCFM), and this neuropathology correlated with higher relapse-like drinking in adulthood. Degraded myelin basic protein in the gray matter medial to the CCFM of binge rats indicated myelin was damaged on axons in the mPFC. In follow-up studies we found that binge drinking reduced myelin density in the mPFC in adolescent rats (Experiment 2) and heavier drinking predicted worse performance on the T-maze working memory task in adulthood (Experiment 3). These findings establish a causal role of voluntary alcohol on myelin and give insight into specific prefrontal axons that are both sensitive to alcohol and could contribute to the behavioral and cognitive impairments associated with early onset drinking and alcoholism.
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Alcoholismo/metabolismo , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Etanol/farmacología , Vaina de Mielina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Sustancia Blanca/efectos de los fármacos , Factores de Edad , Animales , Masculino , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Sustancia Blanca/metabolismoRESUMEN
Early life stress (ELS) is a known antecedent for the development of mood disorders such as depression. Orexin neurons drive arousal and motivated behaviors in response to stress. We tested the hypothesis that ELS alters orexin system function and leads to an altered stress-induced behavioral phenotype in adulthood. We also investigated if voluntary exercise during adolescent development could reverse the ELS-induced changes. Male and female Wistar rats were subjected to maternal separation stress on postnatal days (PND) 2-14. A subset of animals was given access to running wheels in late adolescence (1hr/day, PND40-70). In adulthood, rats were exposed to restraint stress and then tested on the open field (OF) and elevated plus maze (EPM). Brains were processed for Fos-protein and orexin or tyrosine hydroxylase immunohistochemistry. Restraint stress stimulated Fos-protein expression in perifornical area orexin cells, the paraventricular hypothalamic nucleus, and paraventricular thalamic nuclei, but this neuronal response was dampened in male and female rats exposed to ELS. ELS also reduced exploration in the OF, without affecting EPM behavior. These neural and behavioral changes are consistent with a depressive-like phenotype. Adolescent exercise reversed the orexin and behavioral deficits in ELS males. Exercise was not protective in females, although this may be due to sex differences in running behavior. Our findings highlight the inherent plasticity of the orexin system-a trait that may lead to a state of pathological rewiring but could also be treated using non-pharmacological approaches. We also highlight a need to better understand the sex-specific changes in orexin circuits and stress-related pathology.
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BACKGROUND: Two features of alcohol addiction that have been widely studied in animal models are relapse drinking following periods of alcohol abstinence and the escalation of alcohol consumption after chronic continuous or intermittent alcohol exposure. The genetic contribution to these phenotypes has not been systematically investigated. METHODS: HXB/BXH recombinant inbred (RI) rat strains were given access to alcohol sequentially as follows: alcohol (10%) as the only fluid for 1 week; alcohol (10%) and water in a 2-bottle choice paradigm for 7 weeks ("pre-alcohol deprivation effect [ADE] alcohol consumption"); 2 weeks of access to water only (alcohol deprivation); and 2 weeks of reaccess to 10% alcohol and water ("post-ADE alcohol consumption"). The periods of deprivation and reaccess to alcohol were repeated 3 times. The ADE was defined as the amount of alcohol consumed in the first 24 hours after deprivation minus the average daily amount of alcohol consumed in the week prior to deprivation. Heritability of the phenotypes was determined by analysis of variance, and quantitative trait loci (QTLs) were identified. RESULTS: All strains showed increased alcohol consumption, compared to the predeprivation period, in the first 24 hours after each deprivation (ADE). Broad-sense heritability of the ADEs was low (ADE1, 9.1%; ADE2, 26.2%; ADE3, 16.3%). Alcohol consumption levels were relatively stable over weeks 2 to 7. Post-ADE alcohol consumption levels consistently increased in some strains and were decreased or unchanged in others. Heritability of pre- and post-ADE alcohol consumption was high and increased over time (week 2, 38.5%; week 7, 51.1%; week 11, 56.8%; week 15, 63.3%). QTLs for pre- and post-ADE alcohol consumption were similar, but the strength of the QTL association with the phenotype decreased over time. CONCLUSIONS: In the HXB/BXH RI rat strains, genotypic variance does not account for a large proportion of phenotypic variance in the ADE phenotype (low heritability), suggesting a role of environmental factors. In contrast, a large proportion of the variance across the RI strains in pre- and post-ADE alcohol consumption is due to genetically determined variance (high heritability).
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Consumo de Bebidas Alcohólicas/genética , Alcoholismo/genética , Carácter Cuantitativo Heredable , Ratas Endogámicas , Consumo de Bebidas Alcohólicas/psicología , Alcoholismo/psicología , Animales , Conducta Adictiva/genética , Conducta Adictiva/psicología , Conducta de Elección , Genotipo , Masculino , Fenotipo , Sitios de Carácter Cuantitativo/genética , Ratas , Especificidad de la EspecieRESUMEN
Impulsive choice-the preference for small immediate rewards over larger delayed rewards-has been linked to various psychological conditions ranging from behavioral disorders to addiction. These links highlight the critical need to dissect the various components of this multifaceted behavioral trait. Delay discounting tasks allow researchers to study an important factor of this behavior: how the subjective value of a rewards changes over a delay period. However, existing methods of delay discounting include a confound of different reward sizes within the procedure. Here we present a new approach of using a single constant reward size to assess delay discounting. A complementary approach could hold delay constant and assess the utility of changing quantities of a reward. Isolating these behavioral components can advance our ability to explore the behavioral complexity of impulsive choice. We present in detail the methods for isolating delay, and further capitalize on this method by pairing it with a standard peak interval task to test whether individual variation in delay discounting can be explained by differences in perception of time in male and female adolescent rats. We find that rats that were more precise in discriminating time intervals were also less impulsive in their choice. Our data suggest that differences in timing and delay discounting are not causally related, but instead are more likely influenced by a common factor. Further, the mean-level change in our measure between post-natal day 28 and 42 suggests this test may be capturing a developmental change in this factor. In summary, this new method of isolating individual components of impulsive choice (delay or quantity) can be efficiently applied in either adolescent or adult animal models and may help elucidate the mechanisms underlying impulsivity and its links to psychological disorders.
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Heavy episodic drinking early in adolescence is associated with increased risk of addiction and other stress-related disorders later in life. This suggests that adolescent alcohol abuse is an early marker of innate vulnerability and/or binge exposure impacts the developing brain to increase vulnerability to these disorders in adulthood. Animal models are ideal for clarifying the relationship between adolescent and adult alcohol abuse, but we show that methods of involuntary alcohol exposure are not effective. We describe an operant model that uses multiple bouts of intermittent access to sweetened alcohol to elicit voluntary binge alcohol drinking early in adolescence (~postnatal days 28-42) in genetically heterogeneous male Wistar rats. We next examined the effects of adolescent binge drinking on alcohol drinking and anxiety-like behavior in dependent and non-dependent adult rats, and counted corticotropin-releasing factor (CRF) cell in the lateral portion of the central amygdala (CeA), a region that contributes to regulation of anxiety- and alcohol-related behaviors. Adolescent binge drinking did not alter alcohol drinking under baseline drinking conditions in adulthood. However, alcohol-dependent and non-dependent adult rats with a history of adolescent alcohol binge drinking did exhibit increased alcohol drinking when access to alcohol was intermittent. Adult rats that binged alcohol during adolescence exhibited increased exploration on the open arms of the elevated plus maze (possibly indicating either decreased anxiety or increased impulsivity), an effect that was reversed by a history of alcohol dependence during adulthood. Finally, CRF cell counts were reduced in the lateral CeA of rats with adolescent alcohol binge history, suggesting semi-permanent changes in the limbic stress peptide system with this treatment. These data suggest that voluntary binge drinking during early adolescence produces long-lasting neural and behavioral effects with implications for anxiety and alcohol use disorders.
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Consumo de Bebidas Alcohólicas , Amígdala del Cerebelo , Ansiedad , Hormona Liberadora de Corticotropina , Factores de Edad , Animales , Recuento de Células , Masculino , Ratas , Ratas WistarRESUMEN
This article highlights the research presented at the inaugural meeting of Alcoholism and Stress: A Framework for future Treatment Strategies. This meeting was held on May 6-8, 2008 in Volterra, Italy. It is an international meeting dedicated to developing preventive strategies and pharmacotherapeutic remedies for stress- and alcohol-related disorders. For the first time, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) conferred a Young Investigator Award to promote the work of young researchers and highlight their outstanding achievements in the fields of addiction medicine and stress disorders. The awardees were Dr. Katie Witkiewitz (University of Washington), Dr. Andrew Holmes (NIAAA), Dr. Lara A. Ray (Brown University), Dr. James Murphy (University of Memphis), and Dr. Heather Richardson (The Scripps Research Institute). The symposium was chaired by Drs. Fulton Crews and Antonio Noronha.
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Alcoholismo/etiología , Distinciones y Premios , Estrés Psicológico/complicaciones , Adolescente , Hormona Adrenocorticotrópica/sangre , Adulto , Animales , Hormona Liberadora de Corticotropina/fisiología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Femenino , Humanos , Hidrocortisona/sangre , Estudios Longitudinales , Masculino , Ratones , Naltrexona/farmacología , Trastornos por Estrés Postraumático/complicacionesRESUMEN
BACKGROUND: We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations. RESULTS: In the HXB/BXH recombinant inbred (RI) rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL) analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption. CONCLUSION: Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume alcohol by rats and humans. The importance of a well-defined phenotype is also illustrated. Our results also suggest that different genetic factors predispose alcohol dependence versus the phenotype of alcohol consumption.
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Consumo de Bebidas Alcohólicas/genética , Preferencias Alimentarias/fisiología , Genómica , Carácter Cuantitativo Heredable , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Encefálica , Modelos Animales de Enfermedad , Etanol/administración & dosificación , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Análisis por Micromatrices , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Ratas , Ratas Endogámicas , Especificidad de la EspecieRESUMEN
BACKGROUND: The purpose of the present investigation was to more clearly define blood-alcohol parameters associated with alcohol dependence produced by alcohol vapor inhalation and alcohol-containing liquid diet. METHODS: Alcohol levels in blood and brain were compared during and after 4 hours of acute alcohol vapor exposure; also, brain-alcohol levels were assessed in alcohol-exposed (14-day alcohol vapor) and alcohol-naïve rats during and after 4 hours of acute alcohol vapor exposure. A separate group of rats were implanted with i.v. catheters, made dependent on alcohol via vapor inhalation, and tested for operant alcohol responding; blood-alcohol levels (BALs) were measured throughout operant alcohol drinking sessions during alcohol withdrawal. A final group of rats consumed an alcohol-liquid diet until they were dependent, and those rats were then tested for operant behavior at various withdrawal time points; BALs were measured at different withdrawal time points and after operant sessions. RESULTS: Blood- and brain-alcohol levels responded similarly to vapor, but brain-alcohol levels peaked at a higher point and more slowly returned to zero in alcohol-naïve rats relative to alcohol-exposed rats. Alcohol vapor exposure also produced an upward shift in subsequent operant alcohol responding and resultant BALs. Rats consumed large quantities of alcohol-liquid diet, most of it during the dark cycle, sufficient to produce high blood-alcohol levels and elevated operant alcohol responding when tested during withdrawal from liquid diet. CONCLUSIONS: These results emphasize that the key determinants of excessive alcohol drinking behavior are the BAL range and pattern of chronic high-dose alcohol exposure.
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Alcoholismo/metabolismo , Alcoholismo/psicología , Depresores del Sistema Nervioso Central/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Condicionamiento Operante/efectos de los fármacos , Etanol/metabolismo , Etanol/farmacología , Administración por Inhalación , Animales , Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/sangre , Dieta , Etanol/sangre , Inyecciones Intravenosas , Masculino , Microdiálisis , Ratas , Ratas Wistar , AutoadministraciónRESUMEN
Experimenter-delivered alcohol decreases adult hippocampal neurogenesis and hippocampal-dependent learning and memory. The present study used clinically relevant rodent models of nondependent limited access alcohol self-administration and excessive drinking during alcohol dependence (alcohol self-administration followed by intermittent exposure to alcohol vapors over several weeks) to compare alcohol-induced effects on cortical gliogenesis and hippocampal neurogenesis. Alcohol dependence, but not nondependent drinking, reduced proliferation and survival in the medial prefrontal cortex (mPFC). Apoptosis was reduced in both alcohol groups within the mPFC, which may reflect an initiation of a reparative environment following alcohol exposure as decreased proliferation was abolished after prolonged dependence. Reduced proliferation, differentiation, and neurogenesis were observed in the hippocampus of both alcohol groups, and prolonged dependence worsened the effects. Increased hippocampal apoptosis and neuronal degeneration following alcohol exposure suggest a loss in neuronal turnover and indicate that the hippocampal neurogenic niche is highly vulnerable to alcohol.
Asunto(s)
Alcoholismo , Proliferación Celular , Hipocampo/patología , Neurogénesis/fisiología , Neuroglía/patología , Corteza Prefrontal/patología , Alcoholismo/patología , Alcoholismo/fisiopatología , Alcoholismo/psicología , Animales , Bromodesoxiuridina/metabolismo , Caspasa 3/metabolismo , Recuento de Células/métodos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Etanol/administración & dosificación , Etanol/sangre , Fluoresceínas , Antígeno Ki-67/metabolismo , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Neurogénesis/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuropéptidos/metabolismo , Compuestos Orgánicos , Ratas , Ratas Wistar , Autoadministración/métodosRESUMEN
The juxtacapsular bed nucleus of the stria terminalis (jcBNST) is activated in response to basolateral amygdala (BLA) inputs through the stria terminalis and projects back to the anterior BLA and to the central nucleus of the amygdala. Here we show a form of long-term potentiation of the intrinsic excitability (LTP-IE) of jcBNST neurons in response to high-frequency stimulation of the stria terminalis. This LTP-IE, which was characterized by a decrease in the firing threshold and increased temporal fidelity of firing, was impaired during protracted withdrawal from self-administration of alcohol, cocaine, and heroin. Such impairment was graded and was more pronounced in rats that self-administered amounts of the drugs sufficient to maintain dependence. Dysregulation of the corticotropin-releasing factor (CRF) system has been implicated in manifestation of protracted withdrawal from dependent drug use. Administration of the selective corticotropin-releasing factor receptor 1 (CRF(1)) antagonist R121919 [2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine)], but not of the CRF(2) antagonist astressin(2)-B, normalized jcBNST LTP-IE in animals with a history of alcohol dependence; repeated, but not acute, administration of CRF itself produced a decreased jcBNST LTP-IE. Thus, changes in the intrinsic properties of jcBNST neurons mediated by chronic activation of the CRF system may contribute to the persistent emotional dysregulation associated with protracted withdrawal.
Asunto(s)
Cocaína/administración & dosificación , Etanol/administración & dosificación , Heroína/administración & dosificación , Potenciación a Largo Plazo/fisiología , Núcleos Septales/fisiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Animales , Cocaína/efectos adversos , Etanol/efectos adversos , Heroína/efectos adversos , Ratas , Ratas Wistar , Autoadministración , Núcleos Septales/efectos de los fármacosRESUMEN
Dysregulation of the stress-related corticotropin-releasing factor (CRF) system has been implicated in the development of drug dependence. The present study examined the effects of administering CRF type 1 (CRF(1)) receptor antagonists on heroin self-administration in animals allowed short (1 hour) or long (8-12 hours) access to intravenous heroin self-administration sessions. The nonpeptide CRF(1) antagonists MJL-1-109-2 (1 hour versus 8 hours access) or R121919 (1 hour versus 12 hours access) were systemically injected in both short- and long-access rats. MJL-1-109-2 (10 mg/kg) and R121919 (10 and 20 mg/kg) reduced heroin self-administration in long-access animals without altering heroin intake in short-access animals. Both MJL-1-109-2 and R121919 decreased first-hour intravenous heroin self-administration selectively in long-access rats, with R121919 decreasing cumulative heroin intake across the 12-hour session. The results demonstrate that blockade of the CRF-CRF(1) receptor system attenuates the increased heroin intake of rats with extended access to the drug.