Altered development of basal and forskolin-stimulated adenylate cyclase activity in brain regions of rats exposed to nicotine prenatally.
Exposure of the fetus to nicotine is known to affect cellular development, synaptogenesis and synaptic activity of a wide variety of neurotransmitter pathways in the central nervous system. In the current study, pregnant rats received nicotine infusions of 6 mg/kg/day throughout gestation, administered by osmotic minipumps. After birth, offspring of the nicotine infused dams displayed marked alterations in membrane-associated adenylate cyclase activity; the regional selectivity correlated both with nicotinic cholinergic receptor concentration and the maturational timetable of each region. In the midbrain and brainstem, which display relatively high receptor concentrations and earliest cell development, basal adenylate cyclase activity in the nicotine group was elevated in the immediate period postpartum, returned to normal by the end of the first month, but then became subnormal in young adulthood. The initial promotion of basal activity was mirrored by forskolin-stimulated activity, suggesting that in this phase, the alterations were occurring at the level of the adenylate cyclase catalytic unit itself. The lack of effect on forskolin stimulation in the later phase, where basal activity was subnormal in the nicotine group, suggests that some alterations in regulatory subunits are responsible for the maturational switch in nicotine's effects on adenylate cyclase. In the cerebellum, where cell replication occurs primarily after birth and receptor concentrations are low, basal adenylate cyclase showed only a deficit in the nicotine group; again, although forskolin stimulation was significantly affected, the actions on basal activity were much more prominent, suggesting defects at the level of G-proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Slotkin
T A
TA
Department of Pharmacology, Duke University Medical Center, Durham, NC 27710.
McCook
E C
EC
Lappi
S E
SE
Seidler
F J
FJ
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D001933:Brain Stem / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D005260:Female; D008636:Mesencephalon / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D016548:Prosencephalon / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D005576:Colforsin; D009538:Nicotine; D000262:Adenylyl Cyclases