Chronic drug exposures during development in nonhuman primates: models of brain dysfunction in humans

Abstract

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.

Does cannabis affect dopaminergic signaling in the human brain? A systematic review of evidence to date

“…In this group of young (average age 20.4) mostly male (13 out of 14) regular cannabis users smoking on at least a weekly basis for 4.9 years, there was significant inverse correlation between dopamine synthesis capacity as measured using [ 18 F]-DOPA PET scan and apathy. Although this cross-sectional study does not itself establish a causal relationship, taken together these two studies from Bloomfield and colleagues suggest that a blunting of striatal dopamine synthesis capacity from chronic cannabis use may result in apathy, a key feature of the 'amotivational syndrome' that has long been associated with cannabis use (Musty and Kaback, 1995;Paule, 2005).…”

Non-Human Primates: Model Animals for Developmental Psychopathology

“…This is not to say that developmental pharmacological methods have not been applied to other disease models in both rodents and primates. Indeed, there is a well-developed descriptive literature detailing potential brain injury, emotional and cognitive deficits associated with pre-and postnatal exposure environmental toxins, pollutants and drugs of abuse in non-human primates (Buse et al, 2003;Haberny et al, 2002;Paule, 2005;Rice, 2000;Wu et al, 2008). These efforts have demonstrated that developmental pharmacological challenges might be well suited to providing discreet, quantifiable stimulation of critical pathways during development, particularly in validated risk models, to examine the potential role of unique neurotransmitter systems in subsequent pathology.…”

Neurodevelopment of children exposed to anesthesia: Design of the Mayo Anesthesia Safety in Kids (MASK) study

“…In the animal laboratory, aspects of performance of these tasks have been used as metrics for determining the acute and chronic effects of drugs and other chemicals on important aspects of brain function. 39 In the clinical setting, the instrument has been used to generate normative data for children as a function of age, 40-43 examine correlations between OTB performance and IQ, 44 characterize OTB behavioral profiles in different clinical populations (e.g., ADHD, depression, anxiety) as well as assess the ability of therapeutic agents to normalize OTB behaviors in these children, 45-47 and generate OTB behaviors for direct comparison with those obtained from laboratory animals, in particular, nonhuman primates. 45,48-51 Utilization of similar or identical behavioral tasks across species serves not only to aid in the validation of the approach but also to facilitate the interspecies extrapolation of exposure data.…”