Chronic drug exposures during development in nonhuman primates: models of brain dysfunction in humans.
This review of our work presents three specific examples of how nonhuman primates (rhesus monkeys, Macaca mulatta) have been used to study the effects of chronic drug exposures on brain function during different stages of development. In all cases, exposure levels similar to those experienced by humans were employed and the focus was on long-term--not acute--effects. In the case of the marijuana studies, exposures occurred during the adolescent period; for the cocaine studies, exposures occurred in binge-like fashion entirely before birth (in utero); and for the remacemide studies, exposures occurred daily in juveniles, prior to adolescence. An automated battery of behavioral tasks, the National Center for Toxicological Research Operant Test Battery (NCTR OTB), designed to assess aspects of motivation, visual discrimination, time perception, short-term memory, and learning, was used to monitor treatment effects. Chronic marijuana smoke exposure resulted in an 'amotivational' syndrome--even in weekend-only smokers--that resolved within three months of exposure cessation. In utero cocaine exposure was shown to cause behavioral rigidity or lack of plasticity as evidenced by the difficulty of subjects to adjust to rules changes for some OTB tasks. These effects were seen in adult subjects suggesting that the effects of gestational cocaine exposure are long-term or permanent. In addition, animals exposed to cocaine in utero were less sensitive to the behaviorally-disrupting effects of cocaine as adults. Remacemide caused profound and long-lasting, perhaps permanent, changes in learning task performance and because performance of this same task by children is significantly correlated with traditional measures of intelligence (IQ), these data suggest that such treatment may provide a valuable model of chemically-induced mental retardation.
Paule
Merle G
MG
Behavioral Toxicology Laboratories, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, Arkansas 72079-9502, USA. mpaule@nctr.fda.gov
D000818:Animals; D004192:Discrimination, Psychological / Q000502:physiology*; D006803:Human Development; D006801:Humans; D007858:Learning / Q000502:physiology*; D008253:Macaca mulatta; D008570:Memory, Short-Term / Q000502:physiology*; D009042:Motivation; D013998:Time Perception / Q000502:physiology*