Adolescent nicotine administration changes the responses to nicotine given subsequently in adulthood: adenylyl cyclase cell signaling in brain regions during nicotine administration and withdrawal, and lasting effects.
Neurodevelopmental vulnerability to nicotine extends into adolescence, the stage at which most smokers begin using tobacco. The "sensitization-homeostasis" model postulates that nicotine treatment permanently reprogrammes neural communication, so that underlying functional changes remain present despite the apparent restoration of behavioral normality. We administered nicotine to adolescent rats (postnatal days PN30-47) or adults (postnatal days PN90-107), using regimens that reproduce plasma levels in smokers, and assessed effects on the adenylyl cyclase (AC) signaling cascade, which is involved in nicotine dependence and withdrawal but also mediates numerous other neurotransmitter responses. Evaluations were made in the cerebral cortex, brainstem and cerebellum on PN105, PN110, PN120, PN130 and PN180. Adolescent nicotine exposure elicited persistent suppression of basal AC activity and eventual compromise of responses to beta-adrenergic receptor stimulation, with effects emerging in late adulthood; maximal AC activity as monitored with forskolin was elevated and in general, all the effects were more notable in males. Nicotine treatment in adulthood produced an immediate increase in AC activity in males that disappeared upon withdrawal; there were late-emerging deficits similar to, but smaller in magnitude than those seen with adolescent nicotine exposure. Adolescent treatment greatly exacerbated the response to subsequent nicotine administration in adulthood, producing profound AC deficits during withdrawal that persisted through at least 6 months of age. Our results reinforce the concept that adolescence is a critical developmental period in which nicotine disrupts neural cell signaling in a lasting manner, and provide a mechanistic framework for understanding the biological substrates that determine the relationship between adolescent nicotine exposure and life-long susceptibility to nicotine addiction.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Theodore A
TA
Slotkin
Ian T
IT
Ryde
Emiko A
EA
Mackillop
Bethany E
BE
Bodwell
Frederic J
FJ
Seidler
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000328:Adult; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D005576:Colforsin / Q000378:metabolism; D005260:Female; D006801:Humans; D007545:Isoproterenol; D008297:Male; D009538:Nicotine / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012907:Smoking
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D009538:Nicotine; D000262:Adenylyl Cyclases; D007545:Isoproterenol