Heroin neuroteratogenicity: delayed-onset deficits in catecholaminergic synaptic activity.
Prenatal heroin exposure evokes neurochemical and behavioral deficits that, in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve primary changes in cell signaling proteins that are shared by other transmitter systems. In the current study, we determined whether heroin also targets noradrenergic and dopaminergic inputs that operate through the same signaling cascades. Mice exposed to prenatal heroin showed significant deficits in norepinephrine and dopamine levels and much more pronounced effects on neurotransmitter turnover, an index of synaptic activity. Adverse effects were not present in the immediate postnatal period but rather emerged just before weaning and worsened subsequently. By young adulthood, the most highly-affected regions (hippocampus, cerebral cortex) displayed almost complete inactivation of noradrenergic and dopaminergic tonic activity. These effects arise after prior deficits in cell signaling are discernible, suggesting that the presynaptic effects are secondary to actions on signal transduction cascades shared by numerous neurotransmitter inputs and targeted by other neuroteratogens. These results may explain why apparently unrelated developmental neurotoxicants may ultimately produce a common set of neurochemical and behavioral anomalies.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Box 3813 DUMC, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
Frederic J
FJ
Yanai
Joseph
J
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D003932:Heroin / Q000633:toxicity*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
D002395:Catecholamines; D003932:Heroin; D004298:Dopamine; D009638:Norepinephrine