This is the fourth component of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium. This component has a focus on translatable studies on the effects of Adolescent Intermittent Ethanol (AIE) exposure on sleep and waking electrophysiology and concomitant behavioral outcomes. We have demonstrated that binge drinking in human adolescents produces persistent effects on measures of waking electrophysiology as indexed by event-related potentials and event-related oscillations (ERP/EROs). Studies from our laboratory have also demonstrated that young adults with alcohol use disorders report significant sleep deficits. Despite the clear importance of sleep disturbance in the development of alcoholism the complex relationship between insomnia and alcohol dependence continues to remain poorly understood. The reason for this is, in part, because human adolescents often have co-morbid medical, psychiatric and other substance use disorders, as well as risk factors for insomnia that may have predated their alcohol use. An additional barrier to progress in understanding the impact alcohol has on adolescent sleep homeostasis is the development of translatable animal models that would allow the control necessary to investigate the long term effects of adolescent alcohol exposure on sleep and to develop new therapeutics. Over last five years we have demonstrated in rats that AIE via vapor can produce changes in ERP measures, slow wave sleep, impairments in inhibitory behaviors, and low response to alcohol, well into adulthood, similar to the human condition. The studies outlined below will extend those studies and investigate the neural mechanisms underlying the deleterious effects of AIE on behavior, sleep and waking electrophysiology. Our current hypothesis focuses on the importance of two brain systems in alcohol-induced sleep/wake disruption: (1) the hypocretin/orexin systems located in the perifornical lateral hypothalamus (pLH) and (2) the GABAergic system in the median preoptic (MnPO) region. Additionally, we suggest that AIE also delays brain and behavioral maturity in regulatory circuitry related to arousal and reward that can lead to a retention of the adolescent phenotype (e.g.lock-in) as evidenced by: a low response to alcohol, altered responses to reward related stimuli, behavioral disinhibition and excessive drinking. We further suggest that this immaturity may be indexed by measures of synaptic spines. Finally, we propose to test targeted therapeutic agents that may ameliorate the AIE-induced sleep/wake and behavioral deficits. One that has recently been demonstrated to improve sleep disturbances seen in human alcoholics (gabapentin), as well as two new therapeutic drugs for alcohol-induced insomnia that targets Hct/OX receptors will be studied. The studies outlined will identify the mechanisms underlying AIE induced sleep pathology and new therapeutics tested using electrophysiological measures that are translatable to the human condition.

Public Health Relevance

This project tests the hypothesis that in the rat, exposure to alcohol during adolescence induces long-term changes in sleep and arousal, impairments in anxiety and affective behavior, and changes in brain connectivity over development that are in part mediated by the hypocretin/GABA systems in the hypothalamus. These studies also tests new therapeutics for adolescent alcohol-induced sleep/wake pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01AA019969-06
Application #
9026404
Study Section
Special Emphasis Panel (ZAA1-CC (01))
Program Officer
Regunathan, Soundar
Project Start
2010-09-10
Project End
2020-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
6
Fiscal Year
2015
Total Cost
$391,698
Indirect Cost
$184,997
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Sanchez-Alavez, Manuel; Wills, Derek N; Amodeo, Leslie et al. (2018) Effect of Gabapentin on Sleep and Event-Related Oscillations (EROs) in Rats Exposed to Chronic Intermittent Ethanol Vapor and Protracted Withdrawal. Alcohol Clin Exp Res 42:624-633
Sanchez-Alavez, Manuel; Nguyen, William; Mori, Simone et al. (2018) Time course of microglia activation and brain and blood cytokine/chemokine levels following chronic ethanol exposure and protracted withdrawal in rats. Alcohol 76:37-45
Amodeo, Leslie R; Wills, Derek N; Sanchez-Alavez, Manuel et al. (2018) Intermittent voluntary ethanol consumption combined with ethanol vapor exposure during adolescence increases drinking and alters other behaviors in adulthood in female and male rats. Alcohol 73:57-66
Ehlers, Cindy L; Sanchez-Alavez, Manuel; Wills, Derek (2018) Effect of gabapentin on sleep and delta and theta EEG power in adult rats exposed to chronic intermittent ethanol vapor and protracted withdrawal during adolescence. Psychopharmacology (Berl) 235:1783-1791
Amodeo, Leslie R; Wills, Derek N; Ehlers, Cindy L (2017) Acute low-level alcohol consumption reduces phase locking of event-related oscillations in rodents. Behav Brain Res 330:25-29
Amodeo, Leslie R; Kneiber, Diana; Wills, Derek N et al. (2017) Alcohol drinking during adolescence increases consumptive responses to alcohol in adulthood in Wistar rats. Alcohol 59:43-51
Sanchez-Alavez, Manuel; Ehlers, Cindy L (2016) Event-related oscillations (ERO) during an active discrimination task: Effects of lesions of the nucleus basalis magnocellularis. Int J Psychophysiol 103:53-61
Ehlers, Cindy L; Desikan, Anita; Wills, Derek N (2014) Event-related potential responses to the acute and chronic effects of alcohol in adolescent and adult Wistar rats. Alcohol Clin Exp Res 38:749-59
Desikan, Anita; Wills, Derek N; Ehlers, Cindy L (2014) Ontogeny and adolescent alcohol exposure in Wistar rats: open field conflict, light/dark box and forced swim test. Pharmacol Biochem Behav 122:279-85
Sanchez-Alavez, Manuel; Robledo, Patricia; Wills, Derek N et al. (2014) Cholinergic modulation of event-related oscillations (ERO). Brain Res 1559:11-25

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