Research reportPrenatal cocaine exposure specifically alters spontaneous alternation behavior
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.
References (102)
- et al.
Longitudinal investigation of task persistence and sustained attention in children with prenatal cocaine exposure
Neurotoxicol Teratol
(2001) - et al.
The effects of a mild stressor on spontaneous alternation in mice
Behav Brain Res
(2001) - et al.
Prenatal cocaine exposure alters sensitivity to the effects of idazoxan in a distraction task
Behav Brain Res
(2002) - et al.
Behavioural changes induced by early and long-term gravito-inertial force modification in the rat
Behav Brain Res
(2003) - et al.
Attention as a target of intoxication: insights and methods from studies of drug abuse
Neurotoxicol Teratol
(2000) - et al.
Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex
Neurosci Biobehav Rev
(2002) - et al.
The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning
Brain Cogn
(2004) - et al.
Attentional set-shifting in mice: modification of a rat paradigm, and evidence for strain-dependent variation
Behav Brain Res
(2002) - et al.
Brain imaging of the central executive component of working memory
Neurosci Biobehav Rev
(2002) - et al.
Prenatal cocaine and/or nicotine exposure in rats: preliminary findings on long-term cognitive outcome and genital development at birth
Neurotoxicol Teratol
(1996)
Behavioral profile of CCK2 receptor-deficient mice
Neuropsychopharmacology
Extending the spontaneous preference test of recognition: evidence of object-location and object-context recognition
Behav Brain Res
The effects of neurotoxic lesions of the perirhinal cortex combined to fornix transection on object recognition memory in the rat
Behav Brain Res
Impaired sustained attention and altered reactivity to errors in an animal model of prenatal cocaine exposure
Brain Res Dev Brain Res
Prenatal cocaine exposure does not alter working memory in adult rats
Neurotoxicol Teratol
Cocaine effects on the developing brain: current status
Neurosci Biobehav Rev
The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory
Neurosci Biobehav Rev
Effects of prenatal cocaine on Morris and Barnes maze tests of spatial learning and memory in the offspring of C57BL/6J mice
Neurotoxicol Teratol
The neurobiological basis of spontaneous alternation
Neurosci Biobehav Rev
Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds
Neurotoxicol Teratol
New evidence for neurotransmitter influences on brain development
Trend Neurosci
Prenatal intravenous cocaine adversely affects attentional processing in preweanling rats
Neurotoxicol Teratol
Mechanisms of action of drugs of abuse on the developing fetal brain
Clin Perinatol
Effects of age and gender but not prenatal cocaine on random ratio and delayed spatial alternation responding in rats
Neurotoxicol Teratol
A behavioral teratogenic model of the impact of prenatal cocaine exposure on arousal regulatory systems
Neurotoxicol Teratol
Prenatal cocaine exposure disrupts non-spatial, short-term memory in adolescent and adult male rats
Behav Brain Res
TMT, a predator odor, elevates mesoprefrontal dopamine metabolic activity and disrupts short-term working memory in the rat
Brain Res Bull
Perspectives on object-recognition memory following hippocampal damage: lessons from studies in rats
Behav Brain Res
Effects of cocaine-induced seizures during pregnancy in the rabbit
Physiol Behav
An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems
Biol Psychiatry
Prenatal cocaine exposure: effects on the development of school-age children
Neurotoxicol Teratol
Elicitation and modification of the rabbit's nictitating membrane reflex following prenatal exposure to cocaine
Pharmacol Biochem Behav
Prenatal exposure to cocaine disrupts discrimination learning in adult rabbits, Pharmacology
Biochem Behav
Intrauterine exposure to cocaine produces a modality-specific acceleration of classical conditioning in adult rabbits
Pharmacol Biochem Behav
Impaired performance of children exposed in utero to cocaine on a novel test of visuospatial working memory
Brain Cogn
Prenatal exposure to cocaine selectively disrupts motor responding to d-amphetamine in young and mature rabbits
Neuropharmacology
Neurodevelopmental effects of cocaine
Clini Perinatol
Methodological considerations in neurobehavioral teratology
Pharmacol Biochem Behav
Repeated i.v. cocaine exposure produces long-lasting behavioral sensitization in pregnant adults, but behavioral tolerance in their offspring
Neuroscience
Drug exposure early in life: functional repercussions of changing neuropharmacology during sensitive periods of brain development
Curr Opin Pharmacol
Prenatal cocaine exposure produces consistent developmental alterations in dopamine-rich regions of the cerebral cortex
Neuroscience
Recognition memory in rats–II. Neuroanatomical substrates
Prog Neurobiol
The developing neostriatum of the rabbit: correlation of fluorescence histochemistry, electron microscopy, endogenous dopamine levels, and (3H) dopamine uptake
Brain Res
Infralimbic D1 receptor agonist effects on spontaneous novelty exploration and anxiety-like defensive responding in CD-1 mice
Behav Brain Res
Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-1 mice
Prog Neuropsychopharmacol Biol Psychiatry
Intrauterine cocaine exposure of rabbits: persistent elevation of GABA-immunoreactive neurons in anterior cingulate cortex but not visual cortex
Brain Res
Development of the brain stem in the rat. V. Thymidine-radiographic study of the time of origin of neurons in the midbrain tegmentum
J Comp Neurol
Children prenatally exposed to cocaine: developmental outcomes and environmental risks at seven years of age
J Dev Behav Pediatr
Prenatal cocaine exposure increases sensitivity to the attentional effects of the dopamine D1 agonist SKF81297
J Neurosci
Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex
Neuropsychopharmacology
Cited by (47)
Fetal surgery has no additional effect to general anesthesia on brain development in neonatal rabbits
2022, American Journal of Obstetrics and Gynecology MFMCitation Excerpt :To study the effect of superimposed fetal surgery, we resorted to the rabbit model. This animal has been earlier extensively used for fetal surgery experiments16,26,27 and the study of perinatal brain development.9,11–15 The rabbit is a perinatal brain developer, that is, its brain starts developing prenatally, peaks around birth, and continues developing in the postnatal period, similar to humans.
Of mice and motion: Behavioural-EEG phenotyping of Alzheimer's disease mouse models
2019, Journal of Neuroscience MethodsCitation Excerpt :The Y-maze itself consisted of 3 open-topped corridors (A, B and C) each 60 cm in length, meeting at a triangular intersection (Plucińska et al., 2014). Testing consisted of a single 10 min trial where each sequence of 3 consecutive arm entries made by the animal was recorded by an observer as either a ‘correct alternation’ (ABC etc), an ‘incorrect alternation’ (ABA etc) or a ‘direct repetition’ (AAB) as per (Crouch et al., 2018; Thompson et al., 2005). The number of correct alternations (as a percentage of all alternations) was taken as an index of cognitive performance.
Differential effects of MDMA and cocaine on inhibitory avoidance and object recognition tests in rodents
2017, Neurobiology of Learning and MemoryMaternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex
2012, Neurobiology of Learning and MemoryCitation Excerpt :For example, an enhanced plasticity induction in the hippocampus can be correlated with spatial learning impairments (Han, Tian, Zhang, Ren, & Yang, 2011; Kaksonen et al., 2002; Moser, Krobert, Moser, & Morris, 1998). Moreover, it has been shown that prenatal cocaine exposure resulted in enhanced LTP induction in mPFC in vitro (Huang, Liang, & Hsu, 2011), and cognitive deficits including impairments in memory (Morrow, Elsworth, & Roth, 2002; Thompson, Levitt, & Stanwood, 2005) and flexibility (Garavan et al., 2000). Regarding MS models, MD also has been shown to result in a modification of synaptic plasticity in different brain regions in adulthood: i.e. it enhanced LTP in the hippocampus (Kehoe & Bronzino, 1999) and both LTP and long-term depression in basolateral amygdala-dentate gyrus pathway (Blaise, Koranda, Chow, Haines, & Dorward, 2008).
Neuroprotective effects of a traditional herbal prescription on transient cerebral global ischemia in gerbils
2011, Journal of EthnopharmacologyCitation Excerpt :It is well known that transient cerebral global ischemia leads to delayed neuronal cell death and results in memory impairment (Fox et al., 1998; Pullela et al., 2006). In the present study, we employed the Y-maze task to evaluate hippocampal-dependent short-term spatial memory and a novel object recognition task to test hippocampal-independent working recognition memory (Lelong et al., 2003; Thompson et al., 2005). We observed that transient global ischemia caused memory impairments in both the Y-maze and the novel object recognition tasks.
Early-life stress affects Mongolian gerbil interactions with conspecific vocalizations in a sex-specific manner
2023, Frontiers in Behavioral Neuroscience