Cocaine inhibits central noradrenergic and dopaminergic activity during the critical developmental period in which catecholamines influence cell development.
Cocaine produces neurobehavioral damage in the fetus and neonate both through its ischemic actions and through direct effects mediated by the drug within the developing brain. The replication and differentiation of catecholaminergic target cells are controlled in part by neurotransmitter input and the current study assess whether cocaine modifies the function of these neurons during the critical periods in which target cell programming occurs. Neonatal rats (1, 7, 14 and 21 days old) were given cocaine (30 mg/kg) acutely and the turnover of norepinephrine and dopamine, a measure of synaptic activity, was evaluated in vivo in three different brain regions known to be adversely affected by cocaine. For norepinephrine, cocaine suppressed transmitter turnover in the immediate postnatal period in all regions, reaching a maximal effect within the first 2 postnatal weeks; at subsequent ages, the inhibitory actions were no longer evident. For dopamine, an inhibitory effect also appeared during the first postnatal week, but by 14 to 21 days the effect was replaced by the excitatory response that is characteristic of mature brain; effects on dopamine turnover were restricted to the forebrain. The inhibitory effects of cocaine on immature brain could not be attributed to localized actions at the nerve terminal itself (blockade of reuptake, autoreceptor activation, local anesthesia), but instead are likely to represent reductions in nerve impulse activity. Brain development in the neonatal rat corresponds to fetal stages in man, and thus the transient ability of cocaine to interfere with noradrenergic and dopaminergic activity during the period in which differentiation is being patterned by neurotransmitter input, may be important in the neurobehavioral teratology of cocaine.
Seidler
F J
FJ
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710, USA.
Temple
S W
SW
McCook
E C
EC
Slotkin
T A
TA
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects; D003042:Cocaine / Q000009:adverse effects*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D009474:Neurons / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats
D018492:Dopamine Antagonists; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine