Developmental shift from local to central control of norepinephrine release in the cardiac-sympathetic axis: effects of cocaine and related drugs.
Developmental exposure to cocaine is associated with cardiovascular abnormalities as well as neurobehavioral disturbances. Because of the profound influence of cocaine on noradrenergic neurotransmission, we examined its acute effects on norepinephrine release from cardiac nerve terminals in the neonatal rat, as assessed by turnover measurements. Cocaine reduced norepinephrine turnover at all ages studied, but with an apparent transition in the mechanism of action related to the development of central control of sympathetic tone. At 1 day of age, before the establishment of functional connections between the central nervous system and sympathetic neurons, cocaine acted primarily through blockade of norepinephrine reuptake and consequent activation of alpha-2 adrenergic autoreceptors that inhibit transmitter release. Accordingly, its effects were shared by the uptake inhibitor, desmethylimipramine and the alpha-2 agonist, clonidine, but not by drugs whose actions depend upon sympathetic activity or high tonic release of transmitter (yohimbine, pargyline or chlorisondamine). By 21 days, when neuronal activity is under dynamic control by the central nervous system, cocaine was still effective in shutting off norepinephrine release, but the effect was no longer dependent upon blockade of reuptake; desmethylimipramine did not reduce turnover at this age, but clonidine, pargyline and chlorisondamine did. Yohimbine evoked a profound increase in turnover by 21 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Nye
H E
HE
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina.
Seidler
F J
FJ
Slotkin
T A
TA
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000375:Aging / Q000502:physiology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000294:innervation* / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000254:growth & development; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D015016:Yohimbine / Q000494:pharmacology
D015016:Yohimbine; D008012:Lidocaine; D003042:Cocaine; D009638:Norepinephrine