Our current work in the NIAAA consortium on the Neurobiology of Adolescent Drinking in Adulthood (NADIA) has yielded four key findings of critical importance regarding the consequences of adolescent intermittent ethanol (AIE). These consequences: a) differ dramatically with exposures during early-mid versus late adolescence; b) are sex-specific; and include c) induction of social anxiety, and d) the persistence of adolescent-typical phenotypes, including adolescent-typical responses to ethanol into adulthood. Our current proposal will address critical gaps arising from this work.
Aim 1 will assess whether early-mid adolescent AIE exposure (analogous to early initiation of use in adolescence) alters social/affective/reward domains influenced by subcortical limbic systems whose activity is particularly prevalent at that time, whereas AIE in late adolescence (analogous to the late adolescent/emerging adulthood period in humans where binge drinking is particularly pronounced) produces alterations in tasks requiring integrity of late maturing prefrontal areas. Effects are predicted to be sex-specific, with early AIE effects more pronounced in males and late AIE consequences in females.
Aim 2 will focus on neural substrates underlying the marked social anxiety-like behavior induced by early AIE in males, with a focus on two peptides critically involved in social behavior: oxytocin (OXT) and vasopressin (AVP). Psychopharmacological approaches along with assessment of levels of OXT, AVP and their receptors, as well as associated epigenetic modifications in two key regions involved in social anxiety (amygdala and hypothalamus), will be used to test the hypothesis that social anxiety in males is associated with a shift in balance of OXT and AVP toward AVP. Lastly, Aim 3 will assess whether the persistence of well-characterized adolescent-typical ethanol sensitivities into adulthood following AIE relates to perturbations in excitatory-inhibitory balance. Both psychopharmacological and molecular approaches will be used to test this hypothesis, with a particular emphasis on glutamate NR2B and AMPA and extrasynaptic GABAA receptors along with vesicular transporter ratios. Studies in both Aims 2 and 3 will be conducted with an eye toward identification of pharmacotherapeutic approaches to reverse AIE effects.

Public Health Relevance

Alcoholism is a developmental disorder, with use early in adolescence and binge use later in adolescence increasing vulnerability for later alcohol problems. This project will determine mechanisms underlying the increases in social anxiety and persistence of adolescent-typical ethanol responses into adulthood that are induced by adolescent alcohol exposure, and the role of exposure timing and sex in these effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA019972-07
Application #
9133237
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Regunathan, Soundar
Project Start
2010-09-05
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
State University of NY, Binghamton
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
090189965
City
Binghamton
State
NY
Country
United States
Zip Code
13902
Dannenhoffer, Carol A; Kim, Esther U; Saalfield, Jessica et al. (2018) Oxytocin and vasopressin modulation of social anxiety following adolescent intermittent ethanol exposure. Psychopharmacology (Berl) 235:3065-3077
Varlinskaya, Elena I; Kim, Esther U; Spear, Linda P (2017) Chronic intermittent ethanol exposure during adolescence: Effects on stress-induced social alterations and social drinking in adulthood. Brain Res 1654:145-156
Hosová, Dominika; Spear, Linda Patia (2017) Voluntary Binge Consumption of Ethanol in a Sweetened, Chocolate-Flavored Solution by Male and Female Adolescent Sprague Dawley Rats. Alcohol Clin Exp Res 41:541-550
Madayag, Aric C; Stringfield, Sierra J; Reissner, Kathryn J et al. (2017) Sex and Adolescent Ethanol Exposure Influence Pavlovian Conditioned Approach. Alcohol Clin Exp Res 41:846-856
Spear, Linda Patia; Silveri, Marisa M (2016) Special Issue on the Adolescent Brain. Neurosci Biobehav Rev 70:1-3
Doremus-Fitzwater, Tamara L; Spear, Linda P (2016) Reward-centricity and attenuated aversions: An adolescent phenotype emerging from studies in laboratory animals. Neurosci Biobehav Rev 70:121-134
Shnitko, Tatiana A; Spear, Linda P; Robinson, Donita L (2016) Adolescent binge-like alcohol alters sensitivity to acute alcohol effects on dopamine release in the nucleus accumbens of adult rats. Psychopharmacology (Berl) 233:361-71
Spear, Linda Patia (2016) Consequences of adolescent use of alcohol and other drugs: Studies using rodent models. Neurosci Biobehav Rev 70:228-243
Varlinskaya, Elena I; Truxell, Eric M; Spear, Linda P (2015) Ethanol intake under social circumstances or alone in sprague-dawley rats: impact of age, sex, social activity, and social anxiety-like behavior. Alcohol Clin Exp Res 39:117-25
Varlinskaya, Elena I; Truxell, Eric M; Spear, Linda P (2015) Sex differences in sensitivity to the social consequences of acute ethanol and social drinking during adolescence. Behav Brain Res 282:6-13

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