According to the 1991 NIDA National Household Survey, over 4.0 million women of childbearing age have tried hallucinogens, including phencyclidine (PCP); an estimated 679,000 adolescents have tried PCP and/or other hallucinogens. Despite statistics that indicate significant exposure to susceptible populations, the residual behavioral and neurobiological consequences of PCP exposure in utero or during critical periods of postnatal development (e.g., adolescence) are poorly understood. Human and laboratory animal studies suggest that repeated exposure to PCP during specific stages of development produces long lasting alterations in motor function. These stages might represent critical periods when neuronal substrates through which PCP exerts its actions exhibit enhanced vulnerability to the adverse effects of PCP. Because PCP affects dopaminergic, excitatory amino acid and sigma mechanisms, it seems likely that residual behavioral effects might be a result of alterations in at least a subset of these neural systems. In male and female rats, observational and behavioral pharmacological techniques will be used to characterize the residual motor effects of subchronic developmental PCP exposure. Subchronic dosing with one high dose of PCP in initial studies will begin on postnatal day (PND) 4 or 24 and continue for 14 days. Motoric ability will be tested and observational tests, following a test dose of saline, PCP, MK-801 or d-amphetamine, will be conducted 10 and 20 days after subchronic treatment in which locomotor activity and several other behaviors will be measured. The data will provide information on the effects of subchronic PCP treatment during different ontogenetic periods on motor function, the behavioral response to specific pharmacological challenges, the ontogeny of the behavioral response to PCP, and the development of behavioral sensitization. A subset of subchronically treated male and female rats will begin training under an operant behavioral schedule on PND 67 (23 to 43 days post-subchronic treatment). Data for acquisition of the operant task will be used to compare learning curves between treatment groups. Performance under the task will assess precise timing and fine motor control of operant responses. Pilot studies will investigate residual motor effects by direct measurement of tremor while performing operant tasks. Follow-up studies will define the limits of important initial findings. Together, these studies will characterize the residual motor effects of developmental PCP exposure, determine which developmental periods are sensitive to the adverse effects of PCP, and provide data on the mechanisms of PCP-induced motor deficits. Through a better understanding of the motor deficits produced by PCP exposure during development, the long-term goal is to develop better animal models that will be useful in clinical investigations of the behavioral consequences of developmental PCP exposure.
| Anand, K J; Scalzo, F M (2000) Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate 77:69-82 |
