Translational issues for prenatal cocaine studies and the role of environment

Abstract

Prenatal cocaine exposure produces a wide variety of effects particularly within the nervous system. While not considered a structural teratogen, preclinical studies have documented the biological effects of cocaine exposure during development; effects which to a large extent resemble those described among exposed human populations. This review evaluates the translational value of preclinical studies in terms of three factors: dose of drug administered, timing of events in brain development in the animal compared to human and pharmacokinetics of the drug in animals and humans. Cocaine's effects on cortical development are compared across non-human primate, rabbit and rodent models. Examples of studies utilizing dose–response approaches and clinically relevant plasma drug curves are presented. And lastly, the role of environment in the manifestation of prenatal cocaine effects and published neurochemical effects of enrichment are discussed. The review concludes that there is ample evidence for the biological effects of cocaine on cortical and mesolimbic dopamine system development and that manipulation of the rearing environment can dramatically alter the manifestation of these effects including function of the mesolimbic dopamine reward system.

Introduction

Dr. Vince Smeriglio first influenced my career trajectory in the early 1990s when I was asked to write a chapter on human–animal comparability for the NIDA Monograph. I spent months studying various animal models, reading the toxicological dose-scaling literature and searching for information which related human brain/behavioral development to that of the rodent. The resulting publication turned out to contribute significantly to the rapidly emerging field of research into the biological effects of cocaine exposure during pregnancy [12]. The questions which that review attempted to address were: “what are the biological effects of developmental cocaine exposure? How can we give cocaine to animals to assess the effects of cocaine exposure during human pregnancy? What constitutes a valid preclinical model?” The questions raised in 1996 still apply to the studies of today. That is; timing, dose and pharmacokinetics must be evaluated for each animal model and compared to what is known about the human pregnant cocaine abuser in order to evaluate the information derived from each animal model.

However, why do we need animal models in the first place? Clearly, administration of illegal substances to pregnant women is not an option, but there are ample, prospective clinical studies describing untoward effects of prenatal cocaine on neurobehavioral domains in the offspring (see papers by others in this issue). In particular, recent papers have documented the effects of prenatal cocaine exposure on cognitive function, attention and language development, effects which have emerged as the children undergo some degree of maturation [1], [9], [30], [37], [39], [43], [46]. While these groups have generated solid evidence for the neurobehavioral effects of prenatal cocaine, they must never the less, work with populations of children raised in sometimes chaotic surroundings, with perhaps pre and postnatal poly-drug exposure, and widely varying experiences. The animal model is necessary to establish causality of the behavioral effects of developmental cocaine exposure and in particular, control for a multitude of confounders (e.g. maternal poly-drug use, poor maternal–infant interactions, violence, etc). Animal models also provide a means to investigate the mechanisms through which cocaine produces its effects, to localize the effects to specific cerebral circuits and to provide a metric to facilitate the evaluation of possible therapeutic approaches. These goals cannot be achieved unless the animal model is physiologically relevant in terms of timing and dose of drug administration as well as utilizing appropriate pharmacokinetic factors. Several excellent reviews of brain development from the perspective of the biogenic amines and multiple licit and illicit drugs are available [18], [56].