Development of tolerance to alcohol is thought to reflect a critical sign of problematic alcohol involvement, and is included as one of the diagnostic criteria for alcohol dependence in the DSM IV. Yet little is known of the relationship between tolerance development and levels of alcohol consumption, although it has been speculated that emergence of tolerance to aversive effects of ethanol may permit greater consumption, increasing alcohol exposure levels and concomitant problems. Exploring the relationship between ethanol tolerance and consumption is particularly critical during adolescence, with 12-21 yr. olds not only drinking substantially more per drinking occasion than adults, but also reporting a higher incidence of ethanol tolerance than any other age group. The studies outlined in this proposal will explore this relationship using a simple and well characterized animal model of adolescence in the rat, a model that is typified by 2-3 fold high levels of ethanol consumption, expression of markedly more acute tolerance (and under some instances, chronic tolerance), and an attenuated sensitivity to various aversive effects of alcohol when animals in this developmental phase are compared with adults. The proposed work will explore the development of acute and chronic tolerance to various aversive effects of ethanol and the relationships of these adaptations to ethanol consumption during the adolescent period and following comparable manipulations in adulthood. Neural systems influencing these adaptations and whether these adaptations are causal for elevated ethanol consumption during adolescence will also be explored. Work in this proposal will answer the following questions: What are the relationships among the emergence of acute, rapid and chronic tolerance for various aversive effects of ethanol in adolescents and adults (Sp.
Aim 1) ? Do chronic exposure regimens sufficient to induce chronic tolerance to these ethanol effects lead to increases in voluntary ethanol consumption in home cage and limited access tests, with this increased consumption being particularly marked in adolescence (Sp.
Aim 2) ? What role do NMDA and opioid receptor subsystems play in the emergence of acute and chronic tolerance to ethanol during adolescence (Sp.
Aim 3) ? And, finally, are the adaptive changes associated with chronic tolerance development causal for increasing ethanol consumption in adolescence (Sp.
Aim 4) ? The proposed work will not only provide convincing evidence as to whether the emergence of chronic tolerance to ethanol leads to increases in its consumption, but will also illuminate the relationships among acute, rapid and chronic tolerance and the role of tolerance development in contributing to the elevated ethanol consumption and the insensitivity to various aversive effects of ethanol characteristic of adolescence.

Public Health Relevance

Development of alcohol tolerance is viewed as a sign of problematic alcohol involvement and is one of the criteria used to diagnose alcohol dependence, yet little is know of the relationship between tolerance development and levels of alcohol consumption. Exploring tolerance/consumption relationships is particularly critical during adolescence, given that 12-21 yr. olds not only drink substantially more per drinking occasion than adults, but they also report a higher incidence of alcohol tolerance than any other age group. The studies outlined in this proposal will use a simple and well-characterized animal model of adolescence in the rat to compare different forms of tolerance and how they change developmentally, explore the neural substrates of these adaptations to alcohol, and determine whether tolerance development is causal for inducing the high levels of alcohol consumption characteristic of the adolescent period.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA018026-05
Application #
8318750
Study Section
Special Emphasis Panel (ZAA1-CC (03))
Program Officer
Bechtholt-Gompf, Anita
Project Start
2008-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$321,320
Indirect Cost
$107,213
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
Broadwater, Margaret A; Spear, Linda P (2014) Tone conditioning potentiates rather than overshadows context fear in adult animals following adolescent ethanol exposure. Dev Psychobiol 56:1150-5
Spear, Linda Patia (2014) Adolescents and alcohol: acute sensitivities, enhanced intake, and later consequences. Neurotoxicol Teratol 41:51-9
Broadwater, Margaret; Spear, Linda P (2014) Consequences of adolescent or adult ethanol exposure on tone and context fear retention: effects of an acute ethanol challenge during conditioning. Alcohol Clin Exp Res 38:1454-60
Varlinskaya, Elena I; Truxell, Eric; Spear, Linda P (2014) Chronic intermittent ethanol exposure during adolescence: effects on social behavior and ethanol sensitivity in adulthood. Alcohol 48:433-44
Broadwater, Margaret; Spear, Linda P (2013) Age differences in fear retention and extinction in male Sprague-Dawley rats: effects of ethanol challenge during conditioning. Behav Brain Res 252:377-87
Acevedo, María Belén; Pautassi, Ricardo Marcos; Spear, Norman E et al. (2013) Age-dependent effects of stress on ethanol-induced motor activity in rats. Psychopharmacology (Berl) 230:389-98
Broadwater, Margaret; Spear, Linda P (2013) Consequences of ethanol exposure on cued and contextual fear conditioning and extinction differ depending on timing of exposure during adolescence or adulthood. Behav Brain Res 256:10-9
Varlinskaya, Elena I; Vetter-O'Hagen, Courtney S; Spear, Linda P (2013) Puberty and gonadal hormones: role in adolescent-typical behavioral alterations. Horm Behav 64:343-9
Ramirez, Ruby Liane; Varlinskaya, Elena I; Spear, Linda P (2011) Effect of the selective NMDA NR2B antagonist, ifenprodil, on acute tolerance to ethanol-induced motor impairment in adolescent and adult rats. Alcohol Clin Exp Res 35:1149-59
Robinson, D L; Zitzman, D L; Smith, K J et al. (2011) Fast dopamine release events in the nucleus accumbens of early adolescent rats. Neuroscience 176:296-307

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