Effects of prenatal exposure to cocaine on the developing brain: Anatomical, chemical, physiological and behavioral consequences

Abstract

Earlier studies of human infants and studies employing animal models had indicated that prenatal exposure to cocaine produced developmental changes in the behavior of the offspring. The present paper reports on the results obtained in a rabbit model of in utero exposure to cocaine using intravenous injections (4 mg/kg, twice daily) that mimic the pharmacokinetics of crack cocaine in humans. At this dose, cocaine had no effect on the body weight gain of dams, time to delivery, litter size and body weight or other physical characteristics of the offspring. In spite of an otherwise normal appearance, cocaine-exposed neonates displayed a permanent impairment in signal transduction via the D1 dopamine receptor in caudate nucleus, frontal cortex and cingulate cortex due to an uncoupling of the receptor from its associated Gs protein. This uncoupling in the caudate nucleus was shown to have behavioral consequences in that young or adult rabbits, exposed to cocaine in utero, failed to demonstrate amphetamine-elicited motor responses normally seen after activation of D1 receptors in the caudate. The cocaine progeny also demonstrated permanent morphological abnormalities in the anterior cingulate cortex due to uncoupling of the D1 receptor and the consequent inability of dopamine to regulate neurite outgrowth during neuronal development. Consistent with the known functions of the anterior cingulate cortex, adult cocaine progeny demonstrated deficits in attentional processes. This was reflected by impairment in discrimination learning during classical conditioning that was due to an inability to ignore salient stimuli even when these were not relevant to the task. The impairment in discrimination learning also occurred in an instrumental avoidance task and could be shown to be due to an impairment of cingulothalamic learning-related neuronal coding. It was proposed that the selective loss of D1-related neurotransmission in the anterior cingulate cortex prevented an appropriate activation of GABA neurons and thus a loss of inhibitory regulation that is necessary for processes involved in associative attention. Taken together, these findings suggest that the uncoupling of the D1 receptor from its G protein may be the fundamental source of the anatomic, cognitive and motor disturbances seen in rabbits exposed to cocaine in utero. Moreover, the long-term cognitive and motor deficits observed in the rabbit model are in agreement with the recent reports indicating that persistent attentional and other behavioral deficits may be evident in cocaine-exposed children as they grow older and are challenged to master more complex cognitive tasks.

Cocaine ExposureIn UteroAlters Synaptic Plasticity in the Medial Prefrontal Cortex of Postnatal Rats

“…Cocaine exposure in utero results in molecular and cellular changes in several brain areas known to be involved in memory and attention, such as caudate nucleus (Harvey et al, 2001), prefrontal cortex (Morrow et al, 2002(Morrow et al, , 2007, and hippocampus (Little and Teyler, 1996;Harvey et al, 2001;Morrow et al, 2002Morrow et al, , 2007. For example, cocaine exposure in utero results in anatomical changes in the prefrontal cortex of postnatal rats, including a loss of inhibitory projections from parvalbumin-containing GABAergic local circuit neurons to prelimbic pyramidal neurons (Morrow et al, 2005), deficient inhibitory axoaxonic synapses on pyramidal cells (Morrow et al, 2003), and an increased number of spine synapses (Morrow et al, 2007).…”

Laurate Biosensors Image Brain Neurotransmitters In Vivo: Can an Antihypertensive Medication Alter Psychostimulant Behavior?

“…Cocaine has been shown to act on G proteins and on signalling cascades in NAc, PFC and DStr (82)(83)(84) and G proteins have been implicated in the effects of prenatal exposure to cocaine (85). Downstream in the cascade, DA and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) has been identified as a major target for DA and protein kinase A (PKA) and recently, the regulation of the specific state of DARPP-32 phosphorylation has provided an integrated mechanism for the study of dopaminoceptive neurons; both cocaine and caffeine act via DARPP-32 (cf 86 for review).…”

Developmental neurotoxicity testing in vitro: Models for assessing chemical effects on neurite outgrowth

“…Out of the 35 chemicals listed in Table 2, references for changes in axonal or dendritic outgrowth after in vivo exposure were noted for only four. Changes in axonal or dendritic morphology have been observed after developmental exposure to the neurotoxicants lead (Alfano and Petit, 1982;Campbell et al, 1982;Reuhl et al, 1989), ethanol (Burrows et al, 1995;Granato and Van Pelt, 2003;Smith and Davies, 1990), cocaine (Harvey et al, 2001;Stanwood et al, 2001) and methyl mercury (Choi et al, 1981;Stoltenburg-Didinger and Markwort, 1990). While it would be desirable to increase the data set to better understand the relationship between chemical effects on neurite outgrowth in vitro and in vivo, a one-to-one correspondence may not be necessary in the context of chemical screening.…”