Understanding sex differences in the initiation to addiction are important goals as evidenced by the FOA (PAS-07-382) to which this exploratory grant is addressed. We propose a novel yet hypothesis-based approach to examine sex differences in stress responsivity and addiction using established animal procedures. Stress responsivity relates to acquisition of cocaine self-administration, an animal model of vulnerability to addiction. Stress responsivity shows sex differences but reports on self-administration are conflicting. Links between maternal care and stress responsivity of offspring are proposed; greater care relates to lower stress responsivity of adults. Maternal care differs by pup sex; male pups receive more care than female pups. Adult males show lower stress responsivity than females consistent with the link of maternal care with stress responsivity. We hypothesize that sex-dependent maternal care influences sex differences in stress responsivity and cocaine self-administration in the adult. We will test this by manipulating maternal care via altering litter gender composition (LGC; single- vs mixed-sex litters) because pups of single-sex litters receive more care than pups of mixed-sex litters. LGC influences stress responsivity in infant mice and juvenile and maternal behaviors in rats and mice. We predict both male and female adult rats of single-sex litters will show lower stress responsivity than offspring of mixed-sex litters.
In Specific Aim 1, we will confirm prior studies demonstrating sex-specific effects of maternal care. We will measure stress hormone levels after stress exposures and assess glucocorticoid feedback sensitivity. We predict the following effects of LGC on stress responsivity: mixed females>single females >=mixed males>single males. The relationship between stress responsivity and cocaine self-administration is complex and may be non-linear; both low and high stress responsivity may associate with low responding. Thus, we predict LGC will attenuate acquisition of cocaine self-administration in mixed females and single males and, overall, result in an inverted U-shaped function of stress responsivity to cocaine self-administration. Studies in Specific Aim 2 will test the effects of LGC on acquisition of cocaine self-administration with a parallel study on acquisition of food responding. Behavioral sensitivity to foot shock will also be investigated. Data will inform on contributions of stress responsivity to sex differences in vulnerability to addiction.

Public Health Relevance

The goal of this research program is to achieve a better understanding of sex differences in stress responsivity and vulnerability to addiction using animal models. Studies in this proposal will test the hypothesis that these sex differences are due to sex-dependent differences in maternal care received suggestive of epigenetic origins of the sex differences in stress and drug responses in the adult. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA020117-01A2
Application #
7532212
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Wetherington, Cora Lee
Project Start
2008-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$230,250
Indirect Cost
Name
Baylor College of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Kosten, Therese A; Nielsen, David A (2014) Litter and sex effects on maternal behavior and DNA methylation of the Nr3c1 exon 17 promoter gene in hippocampus and cerebellum. Int J Dev Neurosci 36:5-12
Kosten, Therese A; Huang, Wen; Nielsen, David A (2014) Sex and litter effects on anxiety and DNA methylation levels of stress and neurotrophin genes in adolescent rats. Dev Psychobiol 56:392-406
Kosten, Therese A; Kim, Jeansok J; Lee, Hongjoo J (2012) Early life manipulations alter learning and memory in rats. Neurosci Biobehav Rev 36:1985-2006
Nielsen, David A; Huang, Wen; Hamon, Sara C et al. (2012) Forced Abstinence from Cocaine Self-Administration is Associated with DNA Methylation Changes in Myelin Genes in the Corpus Callosum: a Preliminary Study. Front Psychiatry 3:60
Xiang, Xiaojun; Huang, Wen; Haile, Colin N et al. (2011) Hippocampal GluR1 associates with behavior in the elevated plus maze and shows sex differences. Behav Brain Res 222:326-31
Kosten, Therese A; Kehoe, Priscilla (2010) Immediate and enduring effects of neonatal isolation on maternal behavior in rats. Int J Dev Neurosci 28:53-61
Haile, Colin N; Kosten, Thomas R; Kosten, Therese A (2009) Pharmacogenetic treatments for drug addiction: cocaine, amphetamine and methamphetamine. Am J Drug Alcohol Abuse 35:161-77