Cocaine administration in pregnant rabbits alters cortical structure and function in their progeny in the absence of maternal seizures

Abstract

Previous studies have reported that cocaine exposure in utero results in structural and functional alterations in the development of the anterior cingulate cortex (ACC). In the present study, the effects of maternal cocaine dosage and of cocaine-elicited maternal seizures on the progeny were studied. The incidence of maternal generalized tonic clonic seizures (GTCSs) elicited by cocaine was recorded. No GTCSs were elicited in pregnant rabbits by doses of 2 or 3 mg/kg of cocaine, but GTCSs were sometimes elicited by the highest dose (4 mg/kg per injection). We analyzed the offspring of cocaine-exposed and control animals using three assays of ACC development: (i) the structure of apical dendrites of pyramidal neurons, (ii) the distribution of a calcium binding protein (parvalbumin) in the dendrites of GABAergic neurons, and (iii) coupling of D 1 -like receptors and their G proteins. In all progeny of rabbits exposed to 3 or 4 mg/kg of cocaine during pregnancy, there was a significant change in the structure of apical dendrites, a significant increase in the number of dendrites of GABAergic neurons which were parvalbumin immunoreactive, and a significant reduction in D 1 /G protein coupling. In assays of apical dendrites, the effects on offspring of rabbits given 2 mg/kg cocaine were as pronounced as in offspring of rabbits given 3 or 4 mg/kg, but the effects on parvalbumin immunoreactivity and D 1 /G protein coupling were reduced at this low dose. Thus, previous findings of ACC developmental abnormalities in offspring of rabbits given a dose of 4 mg/kg were replicated, the effects were shown to be dose-related and to be independent of maternal seizures. A mechanism by which dysfunction of the D 1 receptor system could mediate cocaine-associated changes in all three parameters of ACC structure and function is discussed.

Anatomical abnormalities in dopaminoceptive regions of the cerebral cortex of dopamine D1 receptor mutant mice

“…The selectivity and extent of the morphological abnormalities in the D 1 receptor null mouse are reminiscent of those described following prenatal exposure to low doses of cocaine in the rabbit (Jones et al, , 2000Murphy et al, 1997;Stanwood et al, 2001a,b), in which the insult produces an attenuation of D 1 receptor-mediated responses through G s␣ (Friedman et al, 1996;Jones et al, 2000;Zhen et al, 2001). In this regard, rabbits exposed to cocaine prenatally exhibit enhanced dendritic growth of projection neurons, an increase in GABA detection in interneurons, and increased expression of PV in secondary and tertiary dendrites of interneurons (for review, see Levitt et al, 1997;Levitt, 2001, 2004;Harvey, 2004).…”

Pleiotropic Effects of Neurotransmission during Development: Modulators of Modularity

“…A number of studies have established that the prenatal dosing is not teratologic, nor does it impact basic developmental parameters such as kit mortality, litter size, sex or growth rates (L. Jones et al , 1996; E. H. Murphy et al , 1997; X.…”

“…B. Jones et al , 2000; E. H. Murphy et al, 1997; Stanwood & Levitt, 2001; Stanwood & Levitt, 2007; Stanwood et al , 2006; Stanwood et al, 2001b).…”

Functional MRI and Response Inhibition in Children Exposed to Cocaine in utero

“…Chronic cocaine use affects executive functions and related frontal brain regions in adults [12,13] . Animal models of prenatal cocaine exposure have documented effects on dopaminergic systems and frontal-striatal brain regions [14,15] . Although research has not yet firmly documented effects of prenatal cocaine exposure on executive functions in humans, teratogenic models predict such effects [2,3] , and recent research has found increases in externalizing behaviors in cocaine-exposed children [16] , which in turn is likely to be related to functional and structural differences in fronto-striatal brain regions [17,18] .…”