Fetal ethanol exposure is highly predictive of ethanol abuse in adolescence, and there is an inverse correlation between the age of first experience and the likelihood of continued abuse. How does fetal exposure alter adolescent ethanol acceptability? How does adolescent re-exposure increase adult acceptance? Are the consequences of fetal and adolescent exposure distinct? The fiavor attributes (smell, taste and oral irritation) of ethanol are important determinants of acceptance. We hypothesize that fetal ethanol exposure induces developmental changes in the neural systems involved in the perception and acceptability of ethanol's flavor, thereby increasing the risk of initial ingestion and continued adolescent abuse. Further, adolescent experience with ethanol augments the fetal effect and/or perpetuates the ethanol-induced changes into adulthood. This proposition is supported by our prior studies and compelling preliminary data demonstrating that fetal ethanol exposure: (1) reduces the peripheral neural taste response to quinine (a surrogate for ethanol's bitter taste) and (2) decreases the expression of bitter (T2r) and oral irritation (Trp) receptor genes fundamental to ethanol flavor perception and intake in adolescent rats. We also find that binge ethanol exposure in naive adolescent rats yields similar results to the prenatal T2r findings. Our long-range goal is to apply an understanding of these cellular processes to the development of clinical treatments and strategies. Applying behavioral, genomic and neurophysiologic methods, the objectives of this proposal are to understand mechanistically: (A) the ontogeny of the fetal exposure effect on oro-sensory receptor gene expression and whether the observed effects differ between fetal and adolescent exposure;(B) whether adolescent behavioral responses (following fetal exposure) are mediated by alterations in receptor gene expression;and (C) whether adolescent re-exposure augments the behavioral and receptor response to fetal exposure and/or perpetuates them into adulthood. We will also determine how alterations in the peripheral neural responses to ethanol and stimuli representing its component qualities (bitter, sweet and irritancy) parallel the foregoing behavioral and genomic effects.
Environmental exposures can alter patterns of gene expression in the developing fetus, yielding changes in neural development and function. Our proposal addresses epigenetic chemosensory mechanisms by which maternal ethanol use can be transferred to offspring, and via which, the adolescent system is primed to have the effects of fetal exposure augmented and/or preserved into adulthood. Our studies will provide results within a clinically relevant framework related to adolescent ethanol intake behavior and its progression.
|Mantella, Nicole M; Youngentob, Steven L (2014) Prenatal alcohol exposure increases postnatal acceptability of nicotine odor and taste in adolescent rats. PLoS One 9:e102255|
|Santerre, Jessica L; Gigante, Eduardo D; Landin, Justine D et al. (2014) Molecular and behavioral characterization of adolescent protein kinase C following high dose ethanol exposure. Psychopharmacology (Berl) 231:1809-20|
|Doremus-Fitzwater, Tamara L; Buck, Hollin M; Bordner, Kelly et al. (2014) Intoxication- and withdrawal-dependent expression of central and peripheral cytokines following initial ethanol exposure. Alcohol Clin Exp Res 38:2186-98|
|Gigante, Eduardo D; Santerre, Jessica L; Carter, Jenna M et al. (2014) Adolescent and adult rat cortical protein kinase A display divergent responses to acute ethanol exposure. Alcohol 48:463-70|
|Miranda-Morales, Roberto Sebastián; Nizhnikov, Michael E; Waters, Dustin H et al. (2014) New evidence of ethanol's anxiolytic properties in the infant rat. Alcohol 48:367-74|
|Fabio, Maria Carolina; Nizhnikov, Michael E; Spear, Norman E et al. (2014) Binge ethanol intoxication heightens subsequent ethanol intake in adolescent, but not adult, rats. Dev Psychobiol 56:574-83|
|Anderson, Rachel I; Morales, Melissa; Spear, Linda P et al. (2014) Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats. Psychopharmacology (Berl) 231:1687-93|
|Varlinskaya, Elena I; Mooney, Sandra M (2014) Acute exposure to ethanol on gestational day 15 affects social motivation of female offspring. Behav Brain Res 261:106-9|
|Nizhnikov, Michael E; Kozlov, Andrey P; Kramskaya, Tatiana A et al. (2014) Central effects of ethanol interact with endogenous mu-opioid activity to control isolation-induced analgesia in maternally separated infant rats. Behav Brain Res 260:119-30|
|Anderson, Rachel I; Spear, Linda P (2014) Age differences in ethanol discrimination: acquisition and ethanol dose generalization curves following multiple training conditions in adolescent and adult rats. Alcohol Clin Exp Res 38:186-94|
Showing the most recent 10 out of 40 publications