Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts.

Despite the basic differences in their underlying biological targets, prenatal exposure to heroin or phenobarbital produces similar syndromes of neurobehavioral deficits, involving defects in septohippocampal cholinergic innervation-related behaviors. At the cellular level, these deficits are associated with cholinergic hyperactivity, characterized by increased concentrations of muscarinic receptors and enhanced second messenger activity linked to the receptors. In the present study, we determined whether the cellular changes are mechanistically linked to altered behavior, using two different approaches: neural grafting and correlations between behavior and biochemistry within the same individual animals. Mice were exposed transplacentally to phenobarbital or heroin on gestation days 9-18 and, as adults, received fetal cholinergic grafts or were sham-operated. Prenatal drug exposure resulted in deficits in behavioral performance tested in the eight-arm radial maze, accompanied by increases in hippocampal M(1)-muscarinic receptor expression and muscarinic receptor-mediated IP formation. Neural grafting reversed both the behavioral deficits and the muscarinic hyperactivity. In the drug-exposed offspring, there was a significant correlation between maze performance and carbachol-induced inositol phosphate (IP) formation. These studies indicate that deficits of cholinergic function underlie the neurobehavioral deficits seen in the hippocampus of animals exposed prenatally to heroin or phenobarbital, and consequently that the observed cholinergic hyperactivity is an unsuccessful attempt to compensate for the loss of cholinergic function. The fact that the damage can be reversed by neural grafting opens up novel approaches to the restoration of brain function after prenatal insults.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology