Elsevier

Behavioural Brain Research

Volume 164, Issue 1, 14 October 2005, Pages 107-116
Behavioural Brain Research

Research report
Prenatal cocaine exposure specifically alters spontaneous alternation behavior

https://doi.org/10.1016/j.bbr.2005.06.010Get rights and content

Abstract

Our laboratory has previously characterized a rabbit model of gestational cocaine exposure in which permanent alterations in neuronal morphology, cell signaling and psychostimulant-induced behavior are observed. The cellular and molecular neuroadaptations produced by prenatal cocaine occur in brain regions involved in executive function and attention, such as the anterior cingulate and medial prefrontal cortices. Therefore, in the present study, we have measured the effects of prenatal cocaine exposure on specific behavioral tasks in adult offspring whose mothers were treated with cocaine (3 mg/kg, twice a day, E16–E25). We assessed non-spatial, short-term memory in a two-object recognition task and found no deficits in memory or exploratory behaviors in cocaine-exposed offspring in this paradigm. We also evaluated a different memory task with a more robust attentional component, using spontaneous alternation in a Y maze. In this task, young adult rabbits exposed to cocaine prenatally exhibited a significant deficit in performance. Deficits in spontaneous alternation can be induced by a wide variety of behavioral and cognitive dysfunctions, but taken together with previous findings in this and other animal models, we hypothesize that prenatal exposure to cocaine alters highly specific aspects of cognitive and emotional development.

Introduction

Clinical reports of the impact of prenatal cocaine exposure have been inconsistent, as some suggest gross physical malformations, others observe specific deficits in cognitive and emotional development, and yet others indicate no effects [25], [50], [53], [78], [85]. Over the last decade, the field has come to appreciate that the variable outcomes are at least in part the result of important covariates. These confounding factors include the timing and amount of cocaine use during pregnancy, polydrug use, socioeconomic status, nutrition and the quality of pre- and postnatal care. The majority of cases involve exposure to relatively low levels of cocaine in the womb and prospective longitudinal studies of such cohorts [54], [61], [71], [79] have produced compelling reports with fewer confounds. Overall, the data suggest that there are deficits in cognition, language development, executive function and emotional reactivity in children exposed to cocaine during gestation [2], [3], [36], [47], [52], [54], [61], [62], [68], [71], [79], [80]. These disturbances are consistent with the hypothesis of disrupted functioning of frontal cortices and brain biogenic amine systems due to in utero cocaine exposure.

In light of the inherent difficulties in studying prenatal cocaine exposure in humans, animal models have been useful for clarifying the nature and molecular mechanisms of drug effects. In this regard, our group and others have shown that intravenous administration of low doses of cocaine to pregnant rabbits during a discrete period of fetal development produces specific, dose-dependent and permanent effects on the structure and function of dopamine (DA)-rich cortices of offspring (for review, see [35], [48], [85]). These changes begin prenatally and include a lengthening of the apical dendrites of pyramidal neurons [40], [41], an increased number of GABA-immunoreactive cells [86], [87], [100], and increased parvalbumin-immunoreactivity in the distal dendrites of GABAergic interneurons [86], [87], [99]. The anatomical abnormalities are accompanied by a sustained reduction in coupling of the DA D1 receptor to its G protein [41], [98], [102]. There is a strong link between medial frontal cortical areas and executive function [11], [13], [18], [19], [33], particularly the ability of mesocortical DA systems to modulate these functions [10], [27], [34], [64], [65], [101], and thus consistent with the hypothesis that cocaine-exposed offspring should exhibit deficits in working memory and attention.

Behaviorally, offspring in the rabbit model show decreased responsiveness to psychostimulants [77], [84]. Moreover, cocaine-exposed rabbits exhibit impaired discriminative neuronal activity in the anterior cingulate cortex (ACC) and diminished conditioned behavioral responses to stimuli of low salience [26], [89], confirming earlier studies of Harvey and colleagues utilizing classical conditioning of the nictitating membrane reflex [73], [74]. These studies suggest that prenatal cocaine exposure in rabbits can induce select cognitive deficits, similar to those noted in humans, which occur in more complex situations requiring a greater attentional capacity.

Rodent models have yielded complex results regarding the impact of prenatal cocaine exposure on cognitive performance. For example, investigators using an intravenous in utero cocaine model in rats demonstrated a disruption of non-spatial, short-term memory in adolescent and adult offspring [59]. However, a different intravenous rat model yielded relatively selective deficits in attention [28], [29], [31], [49], but not in working memory using a delayed alternation task [30]. Still other groups utilizing higher dose models of prenatal cocaine, employing subcutaneous or intraperitoneal injection, have reported variable outcomes on spatial and working memory [14], [38], [51].

The rabbit model, established for over a decade [67], has substantially increased our understanding of the cellular, biochemical and molecular impacts of prenatal cocaine exposure. The use of this model permits the prediction and interpretation of behavioral changes in prenatal cocaine-exposed offspring within the context of highly specific anatomical and pharmacological disruptions in neurodevelopmental trajectory. In this paper, we adapted for the rabbit specific behavioral paradigms that have been used extensively in rodents. The open field has been used to measure spontaneous locomotor activity, and disruptions in travel patterns and distance are indicative of changes in global motor activity [7], [42], [90]. The perihippocampal-mediated two-object recognition task has been used extensively to test short-term memory deficits [21], [22], [63], [88]. In comparison, the Y maze has been used to measure attention [4], [15], [32], [43], [44], [93], [94], [96], [97], and disruption in performance suggest alterations in attentional capacity, arousal and/or short-term working memory. Thus, based on a robust literature, we used these three tasks to determine whether prenatal cocaine exposure results in global disruptions of cognitive and motor performance, or rather, whether changes are limited to behaviors ascribed to dopamine-rich cortical areas.

Section snippets

Animals and prenatal exposure to cocaine

Proven breeder Dutch-belted rabbits from Myrtle's Rabbitry (Thompson Station, Tennessee) were housed individually in a 12 h light–dark cycle with access to food and water ad libitum. The day of breeding was designated as embryonic day 0 (E0) and injections of cocaine hydrochloride (3 mg/kg, supplied by the National Institute of Drug Abuse) or saline were given intravenously (through the marginal ear vein) to pregnant dams twice daily (08:00 and 15:00 h) from E16 to E25. This treatment paradigm

Open field

Animals exposed to saline and cocaine in utero displayed similar behaviors in the open field (Fig. 1). Prenatal cocaine exposure did not affect latency to leave the center squares in the open field test (data not shown). Additionally, a repeated measures ANOVA did not find a main effect for group (F1,10 = 0.08, ns), a significant effect for center squares versus perimeter squares was found (F1,10 = 36.7, p < 0.01), and no significant interaction was found (F1,10 = 0.57, ns). All animals, independent of

Discussion

We observed a significant deficit of spontaneous alternation performance in young adult rabbits exposed to cocaine prenatally. Spontaneous alternation is an ethologically based test, which, like the object recognition test, does not involve reward delivery and takes advantage of an animal's willingness to explore novel environmental stimuli in a systematic way. Rates of spontaneous alternation are dependent on working memory, attention and an intact prefrontal cortex (for reviews, see [37], [45]

Acknowledgements

Support was provided by DA11165 (PL) and the Vanderbilt Kennedy Center NICHD core grant P30HD15052. We thank Joshua Parlaman for technical assistance, Jennifer Schwartz for assistance with video analysis, Dr. Warren Lambert for statistical consultation (service core C), and Bruce Williams and Roger Williams (service core B) for construction of the rabbit behavioral testing equipment.

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