Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: Cellular mechanisms and the reversal of deficits by neural grafts
Ra. Steingart et al., Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: Cellular mechanisms and the reversal of deficits by neural grafts, DEV BRAIN R, 122(2), 2000, pp. 125-133
Despite the basic differences in their underlying biological targets, prena
tal exposure to heroin or phenobarbital produces similar syndromes of neuro
behavioral deficits, involving defects in septohippocampal cholinergic inne
rvation-related behaviors. At the cellular level, these deficits are associ
ated with cholinergic hyperactivity, characterized by increased concentrati
ons of muscarinic receptors and enhanced second messenger activity linked t
o the receptors. In the present study, we determined whether the cellular c
hanges are mechanistically linked to altered behavior, using two different
approaches: neural grafting and correlations between behavior and biochemis
try 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 resu
lted in deficits in behavioral performance tested in the eight-arm radial m
aze, accompanied by increases in hippocampal M-1-muscarinic receptor expres
sion and muscarinic receptor-mediated IP formation. Neural grafting reverse
d both the behavioral deficits and the muscarinic hyperactivity. In the dru
g-exposed offspring, there was a significant correlation between maze perfo
rmance and carbachol-induced inositol phosphate (IP) formation. These studi
es indicate that deficits of cholinergic function underlie the neurobehavio
ral deficits seen in the hippocampus of animals exposed prenatally to heroi
n or phenobarbital, and consequently that the observed cholinergic hyperact
ivity 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 in
sults. (C) 2000 Elsevier Science B.V. All rights reserved.