Results of studies on rodents indicate links among reactivity to stress, mesolimbic dopamine system activity, behavioral and neurochemical responses to psychomotor stimulant and opioid drugs, and drug-seeking behaviors. Male rats separated from their mother for 3 hr/day on postnatal days 2-14, as adults, are more reactive to stress than are rats from control rearing groups and have behavioral traits consistent with proposed models of drug vulnerability. They also have altered sensitivity to effects of acute and chronic morphine on pain threshold and motor activity. The principal aim of this project is to characterize further the influence of early maternal separation on opioid sensitivity by extending observations to additional procedures and drugs (e.g., kappa opioids), and to female offspring. We will address the interrelated hypotheses that mother-infant separation results in enduring changes in the functional state of endogenous opioid systems, in their plasticity, and in brain markers of opioid systems. Experiments will focus on phenomena associated with drug-induced neuronal plasticity-tolerance, physical dependence, sensitization-and on measures of drug reinforcement and abuse potential-intracranial self-stimulation, place conditioning, IV drug self- administration. Morphine and other prototypic drugs will be tested over a range of doses in adult rats that, on postnatal days 2-14, had underwent either a) 3-hr maternal separation, b) 15-min separation, or c) no separation. To identify cellular correlates of rearing-induced alterations in behavior and sensitivity to opioid drugs, opioid-related mRNAs will be measured in selected brain regions by solution hybridization and gene chip microarrays. Early mother-infant separation impacts the subsequent behavior and opioid sensitivity of the dams, too. Thus, dams will be tested in some of the same procedures as the offspring. The maternal separation paradigm affords unique animal models that can give new insights into pharmacological, behavioral, environmental, and cellular variables that affect sensitivity to opioid drugs and vulnerability to drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014122-03
Application #
6783442
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Wetherington, Cora Lee
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$305,541
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lozoff, Betsy; Jimenez, Elias; Wolf, Abraham W et al. (2009) Higher infant blood lead levels with longer duration of breastfeeding. J Pediatr 155:663-7
White, David A; Michaels, Clifford C; Holtzman, Stephen G (2008) Periadolescent male but not female rats have higher motor activity in response to morphine than do adult rats. Pharmacol Biochem Behav 89:188-99
Michaels, Clifford C; Holtzman, Stephen G (2008) Early postnatal stress alters place conditioning to both mu- and kappa-opioid agonists. J Pharmacol Exp Ther 325:313-8
Michaels, Clifford C; Holtzman, Stephen G (2007) Enhanced sensitivity to naltrexone-induced drinking suppression of fluid intake and sucrose consumption in maternally separated rats. Pharmacol Biochem Behav 86:784-96
Michaels, Clifford C; Easterling, Keith W; Holtzman, Stephen G (2007) Maternal separation alters ICSS responding in adult male and female rats, but morphine and naltrexone have little affect on that behavior. Brain Res Bull 73:310-8
Michaels, Clifford C; Holtzman, Stephen G (2006) Neonatal stress and litter composition alter sucrose intake in both rat dam and offspring. Physiol Behav 89:735-41