Epidemiological data indicate that excessive alcohol consumption is prevalent among adolescents and may have lasting neurobehavioral consequences including increased risk for the development of alcohol dependence. Sleep difficulties have also been reported to be common in human adolescents and inadequate sleep has been shown to be associated with negative outcomes. Studies from our laboratory, in rats, demonstrate that adolescent ethanol exposure via vapor can produce changes in sleep and arousal, impairments in anxiety and affective behavior as well as cortical, hippocampal, and basal forebrain neurophysiological function, well into adulthood. We have also shown that a model that employs the appetitive experience of drinking of ethanol in a runway during the adolescent period results in enhanced drinking during adulthood. Studies in this application propose to further develop a novel model that combines these two methods of adolescent alcohol exposure. In the combined model, rats are initiated to limited access alcohol drinking in a runway and are subsequently exposed to intermittent alcohol vapor during the adolescent period. The model is called ADORE (Alcohol Drinking On the Run/Ethanol vapor). The outcome variables in adulthood that we will focus on after treatment with the ADORE model are neurobehavioral (withdrawal, affective state, drinking) as well as neurophysiological measures (e.g. EEG, Event-related potentials (ERPs), Prepulse Inhibition (PPl), Sleep) that are translatable to studies in human alcohol abusers. It is also our hypothesis that ethanol may exert some of these effects on the adolescent, by inducing changes in basal forebrain and pontine cholinergic systems, as well as NPY/CRF systems in frontal cortex, hypothalamus, and amygdala. Thus, we postulate that a disruption in these neural pathways lead to disruptions in sleep and arousal and facilitates changes in tolerance to alcohol and excessive drinking. The studies outlined in this grant will establish a new model whereby the mechanisms underlying the deleterious effects of adolescent alcohol exposure can be elucidated in the adult using 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, as well as cortical, hippocampal, and basal forebrain functioning. This will pave the way for future experiments that investigate functional links between this adult altered brain activity and the increased alcohol abuse known to take place in adults exposed to alcohol during adolescence

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAA1-DD (11))
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Grandison, Lindsey
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Scripps Research Institute
La Jolla
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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; Wills, Derek N; Amodeo, Leslie et al. (2017) 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 :
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
Ehlers, Cindy L; Wills, Derek N; Desikan, Anita et al. (2014) Decreases in energy and increases in phase locking of event-related oscillations to auditory stimuli occur during adolescence in human and rodent brain. Dev Neurosci 36:175-95
Ehlers, C L; Liu, W; Wills, D N et al. (2013) Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood. Neuroscience 244:1-15
Criado, Jose R; Ehlers, Cindy L (2013) Effects of adolescent onset voluntary drinking followed by ethanol vapor exposure on subsequent ethanol consumption during protracted withdrawal in adult Wistar rats. Pharmacol Biochem Behav 103:622-30

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