Brain Research 988 (2003) 164–172 www.elsevier.com / locate / brainres Research report Impact of adolescent nicotine exposure on adenylyl cyclase-mediated cell signaling: enzyme induction, neurotransmitter-specific effects, regional selectivities, and the role of withdrawal a,b a a, * Yael Abreu-Villac ¸a , Frederic J. Seidler , Theodore A. Slotkin a Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA b ´ ˜ ˜ ˆ ´ ´ Faculdade de Ciencias Medicas, Fundac ¸ao Educacional Serra dos Orgaos ( FESO), Teresopolis, Rio de Janeiro, Brazil Accepted 21 July 2003 Abstract Recent animal studies indicate that the adolescent brain is especially vulnerable to nicotine-induced alterations in synaptic function, echoing the increased susceptibility to nicotine dependence and withdrawal noted for adolescent smokers. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg / kg / day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined the effects on cell signaling mediated through adenylyl cyclase (AC) and its response to catecholamines. Studies were conducted during nicotine administration (PN45) and in the posttreatment, withdrawal period (PN50, 60, 75). Adolescent nicotine augmented AC activity as evidenced by increased responsiveness to the direct AC stimulants, forskolin and 21 Mn . The effects on AC were equally noted in brain regions enriched (striatum) or sparse (cerebellum) in cholinergic projections, implying that the effects are secondary to activation / repression of neural circuits, rather than representing direct effects on AC mediated by nicotinic cholinergic receptors. AC responses to dopaminergic and noradrenergic stimulants were also enhanced by nicotine exposure. However, in contrast to earlier work with serotonin-mediated responses, the effects on catecholaminergic stimulation were smaller and did not display the sex-dependence noted for serotonin. An alternate administration paradigm that maximizes episodic withdrawal (twice-daily nicotine injections) induced AC more rapidly at lower nicotine doses. Our results indicate that adolescent nicotine exposure elicits lasting alterations in synaptic signaling that intensify and persist during withdrawal. These findings support the concept that the adolescent brain is especially susceptible to persistent nicotine-induced alterations.  2003 Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Drugs of abuse: amphetamine and other stimulants Keywords: Adenylyl cyclase; Adolescence; Cerebellum; Dopamine; Nicotine; Norepinephrine; Striatum 1. Introduction during adolescence and, most importantly, smoking during adolescence is a strong predictor of subsequent higher Adolescence is associated with behavioral traits that daily consumption and inability to quit [9]. Recent studies may contribute to susceptibility to drug abuse, including indicate that nicotine, the neuroactive component of tobac- smoking [3,33]. The onset of tobacco use typically occurs co, has lasting, adverse effects on the adolescent brain, producing cell damage and loss as well as long-term disruption of synaptic activity, even with short-term expo- Abbreviations: AC, adenylyl cyclase; ANCOVA, analysis of covar- sures to low doses [1,2,27,36–39]. Although nicotine iance; ANOVA, analysis of variance; cAMP, cyclic 39,59-adenosine works through nicotinic acetylcholine receptors, the effects monophosphate; ETS, environmental tobacco smoke; PN, postnatal day; of adolescent nicotine treatment extend to a wide variety of 5HT, serotonin neurotransmitter systems [10,20,27,36,37,44,45]. One *Corresponding author. Tel.: 11-919-681-8015; fax: 11-919-684- possibility is that nicotine, through its activation or re- 8197. E-mail address: t.slotkin@duke.edu (T.A. Slotkin). pression of specific neuronal circuits, alters the expression 0006-8993 / 03 / $ – see front matter  2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0006-8993(03)03368-7