In search of a mechanism for receptor-mediated neurobehavioral teratogenesis by nicotine: catecholamine release by nicotine in immature rat brain regions.
Nicotine disrupts central nervous system development through interactions with nicotinic cholinergic receptors found in immature brain, leading to discoordination of target cell replication and differentiation. However, it is unclear whether the net result is achieved by nicotine's actions on its specific target cells, or indirectly through receptor-mediated release of other neurotransmitters, such as catecholamines, that possess neurotrophic properties. In the current study, developing rats (1, 7, 14 and 21 days old) were challenged acutely with nicotine (0.3 mg/kg) and the release of catecholamines was evaluated in vivo (AMPT method) in three brain regions that differ in nicotinic receptor concentrations. Nicotine did not stimulate catecholamine release at birth, but developed the capacity to do so in parallel with the ontogeny of nicotinic cholinergic receptors in the midbrain+brainstem and in the forebrain. In the cerebellum, which remains poor in nicotinic receptors, no response was obtained at any age. Superimposed on this general pattern, changes in sensitivity to nicotine were also seen that corresponded to ontogenetic changes in endogenous cholinergic tone, suggesting that receptor desensitization occurs normally during developmental stages in which neuronal activity is high. The absence of a catecholamine response to nicotine at birth in the rat indicates that neurobehavioral teratology associated with fetal nicotine exposure does not reflect secondary actions mediated through catecholamines. However, because brain development in the neonatal rat corresponds to fetal stages in man, the onset of these mechanisms may be relevant to human fetal exposure.
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
F J
FJ
Seidler
E S
ES
Albright
S E
SE
Lappi
T A
TA
Slotkin
D000375:Aging / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002395:Catecholamines / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D009538:Nicotine / Q000633:toxicity*; D009638:Norepinephrine / Q000378:metabolism; D011247:Pregnancy; D016548:Prosencephalon / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D013723:Teratogens / Q000633:toxicity*
D002395:Catecholamines; D011978:Receptors, Nicotinic; D013723:Teratogens; D009538:Nicotine; D004298:Dopamine; D009638:Norepinephrine