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.
