Fetal cocaine exposure causes persistent noradrenergic hyperactivity in rat brain regions: effects on neurotransmitter turnover and receptors.
Fetal cocaine exposure has been shown to cause neurobehavioral abnormalities related to ontogeny of catecholaminergic systems. In the current study, pregnant rats received cocaine (30 mg/kg s.c. daily) from gestational days 8 through 20 and markers of presynaptic and postsynaptic noradrenergic function were monitored in the offspring from birth to young adulthood. Animals in the cocaine group had normal body and brain region weights, and norepinephrine levels showed only minor differences from control values. However, fetal cocaine exposure produced marked noradrenergic hyperactivity, as assessed by norepinephrine turnover. The effect was selective for noradrenergic synapses, as dopamine levels and turnover were largely unaffected. The regional hierarchy of effects on norepinephrine turnover corresponded to the timetable of cell replication/differentiation, namely midbrain + brainstem > forebrain > cerebellum; the resemblance of this pattern to that for effects of glucocorticoids and hypoxia on noradrenergic cell differentiation suggests that cocaine alters development of noradrenergic activity by eliciting fetal hypoxia/ischemia and a consequent release of endogenous glucocorticoids. Effects of fetal cocaine exposure on development of adrenergic receptor subtypes (alpha-1, alpha-2 and beta receptors) were separable from those on noradrenergic presynaptic activity, exhibiting a different regional selectivity. Because cocaine exposure caused an increase in receptor binding superimposed on the increase in presynaptic activity, both factors are likely to contribute to a net synaptic hyperactivity and resultant behavioral teratogenesis.
Seidler
F J
FJ
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.
Slotkin
T A
TA
D000367:Age Factors; D000818:Animals; D001835:Body Weight; D001923:Brain Chemistry; D001933:Brain Stem / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D004298:Dopamine / Q000032:analysis; D004837:Epinephrine / Q000032:analysis; D008636:Mesencephalon / Q000187:drug effects; D009638:Norepinephrine / Q000032:analysis; D009929:Organ Size; D016548:Prosencephalon / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects*; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity*
D011941:Receptors, Adrenergic; D017981:Receptors, Neurotransmitter; D013723:Teratogens; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine