Results of recent studies on rats indicate a relationship among responsiveness to stress, activity of the mesolimbic dopamine system, behavioral and neurochemical responses to psychomotor stimulant and opioid drugs, and drug-seeking behaviors. Male rats separated from their mothers for 180 min/day (MS180), but not 15 min/day (MS15), on postnatal days 2-14 have an enduring increased responsiveness of their hypothalamic-pituitary-adrenal axis to a variety of stressors. In preliminary experiments, adult MS180 rats had higher locomotor activity than did MS15 rats upon initial exposure to a novel environment; they also were more sensitive to the motor-stimulating effects of morphine upon both acute and repeated administration and had a larger dopamine response in the nucleus accumbens to an IV dose of cocaine. The purpose of this exploratory/developmental project is to determine if early maternal separation results in altered responsiveness to opioid drugs in adulthood, and therefore might provide an animal model for studying factors that contribute to vulnerability to drugs of abuse. Three interrelated hypotheses will be addressed in a circumscribed series of systematic experiments in which a limited number of prototype opioid or psychomotor stimulant drugs will be tested over a range of doses in well-established procedures in animal facility reared, MS15, and MS180 rats: tests of antinociception (analgesia), motor activity, and suppression of drinking. Using morphine, the plasticity of endogenous opioid systems will be assessed in tests of tolerance and naloxone-induced sensitization to its analgesic effects, physical dependence, and sensitization to its motor-stimulating effects. Opioid modulation of effects of drugs that act via brain dopamine systems will examined in tests of cross-sensitization to motor-stimulating effects of amphetamine and cocaine and the interaction of naloxone with those drugs. Results confirming the potential value of this animal model would form the basis for a more comprehensive study of pharmacological, behavioral, and neurochemical variables contributing to vulnerability to opioids and other abused drugs.
