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Cholinergic input plays a critical role in brain development, and nicotine, a cholinergic agonist, can disrupt this normal development (Roy et al. 2002). Interference with this input (excessive or inappropriately timed) can have broad-ranging results both in the brain and the peripheral nervous system. Activation of cholinergic input by nicotine is suspected to cause many of the adverse effects of maternal smoking. This is particularly important since the fetus accumulates relatively high levels of nicotine even in situations where maternal exposure occurs via environmental tobacco smoke. Developmental disruptions to rat brains were seen using continuous nicotine infusion pumps in pregnant dams, a delivery route that avoids hypoxia-ischemia and delivers the same steady-state levels of nicotine as seen in smokers or nicotine patch users (reviewed in: Slotkin et al. 1992; Slotkin 1999).

Nicotine-induced disruptions are mediated by specific nicotinic receptors and include neuronal cell death, specific alterations of neuronal activity, and mispro-gramming of receptor signaling mechanisms. Developmental nicotinic receptor stimulation can lead to either an induction of apoptosis or a change from cell replication to cell differentiation. Contrast studies with adult rats indicate that nicotine exerts protective effects (Janson et al. 1988; Owman et al. 1989). In addition, since nicotinic receptors are located not only at postsynaptic sites but also at presynaptic terminals of a wide variety of neurotransmitter systems, particularly the catecholamines (norepinephrine and dopamine), developmental nicotine exposure can affect all brain regions and neurotransmitters that have cholinergic input resulting in both immediate and delayed defects.

Gestational nicotine exposure has been shown to induce brain disruptions in both noradrenergic tonic activity and noradrenergic responsiveness to cholinergic stimulation (Seidler et al. 1992; Slotkin 1998). Comparable alterations also occur in peripheral autonomic pathways. As expected these disruptions result in a number of neurobehavioral and other peripheral organ alterations and defects. Neuronal effects of nicotine exposure have been seen after developmental exposures from early gestation to adolescence. Gestational nicotine exposure disrupts synaptic function and produces behavioral anomalies in two phases (Roy et al. 2002). The first phase of disruptions (widespread apoptosis and disruption of mitotic organization) occur during the immediate neonatal period. Often these disruptions are repaired and resolved by weaning, but may recur during adolescence to cells located largely in the hippocampus and somatosensory cortex. These cells develop after the gestational nicotine exposure, indicating that these deficits were not due to direct effects on these cells but to early events occurring on progenitor cells or alterations to post-mitotic cell migration or connectivity. Gestational nicotine exposure is thus not a general neuroteratogen but specifically affects certain subregions and cell types, including cells that mature after nicotine exposure. Thus, gestational nicotine exposure may cause misprogramming of neural development in regions that are still maturing during adolescence.

Nicotine infusion in adolescent rats also results in neurological disruptions. The disruptions seen after an adolescent exposure both have similarities and differences from those seen after either a gestational or adult exposure (reviewed in: Slotkin 2002). A 2-week infusion of nicotine in adolescent rats, at a dose that produced plasma nicotine levels resembling those of active human smokers, resulted (as with gestational exposure) in decreases in cell number in the hippocampus, cerebral cortex, and midbrain, with greater effects observed in the female hippocampus. Adolescent nicotine exposure also produced an up-regulation of nicotinic acetyl-choline receptors (nAChR) that persisted for over a month, and the changes were greater in males than in females. These changes differ from both an adult exposure, where receptor changes are short-lived, and from a gestational exposure, where receptor changes were less pronounced and less prolonged. Adolescent nicotine exposure also resulted in significant reductions in choline acetyltransferase (ChAT) (the enzyme that synthesizes acetylcholine and is a marker for cholinergic innervation), in the midbrain, but not in the cerebral cortex or hippocampus. This was also accompanied by an increase in the high-affinity presynaptic choline transporter

(the rate-limiting step in acetylcholine synthesis). This pattern is an indication of cholinergic hyperstimulation at the same time as neuronal damage. These midbrain effects were not seen immediately following gestational exposure, but were seen later at adolescence. Gestational nicotine exposure resulted in changes to cholinergic activity in the cerebral cortex, which was not seen following adolescent exposure. The one change consistent between gestational and adolescent exposure was the prolonged reduction in high-affinity presynaptic choline transporter in the hippocampus. As previously discussed, nAChR also control release of the catecholamines, norepinephrine, and dopamine. After adolescent nicotine exposure, it has been shown that there is persistent subsensitivity to acute cholinergic stimulation in both genders, particularly in the midbrain. Similar effects were seen following gestational exposure.

Immune deficits following developmental nicotine exposure from early gestation to adolescence have also been observed (Basta et al. 2000; Navarro et al. 2001a; Navarro et al.), and are suspected to be a result of a combined altered CNS/peripheral nervous system input. A 2-week gestational exposure to infused nicotine was shown to induce neonatal abnormalities of both T-lymphocyte and B-lymphocyte function (Basta et al. 2000). The pattern of immune deficits was similar to the pattern of neural effects produced by gestational exposure. In both the immune and nervous system, defects were observed during the early neonatal period in the treated animals, which resolved to some extent by weaning but which reemerged during adolescence and persisted into adulthood. Therefore, just as in the brain, immune deficits were maintained well after the cessation of nicotine exposure suggesting, as before, that nicotine-induced actions on the developing immune system permanently affect the "programming" of lymphocyte responses. A likely explanation for this finding is that excessive premature stimulation of cholinergic receptors causes disruptions to the normal development of neuroimmune homeostatic controls, potentially through direct alterations of the ANS in immune organs or secondary alterations to signaling pathways. Consistent with the idea that activation of nicotinic cholinergic receptors is a trigger for these events, we found similar effects from an early developmental exposure to chlorpyrifos (discussed later), a pesticide that enhances endogenous cholinergic activity through acetylcholinesterase inhibition (Navarro et al. 2001b). In addition, developmental nicotine exposure has been shown to result in other nonimmune long-lasting changes in neuronal controls, including deficits in peripheral organ sympathetic neuron activity, lasting alterations of adenylate cyclase responses (i.e., increased nonstimulated or basal activity), and minor transient changes in p-AR numbers (Navarro et al. 1990).

The exposure of adolescent rats to infused nicotine employing the 2.5-week adolescent nicotine exposure model described above for neural toxicity (6 mg/kg/day) also caused immune alterations (Navarro et al. 2001a). This study showed that, just as for gestational exposure, adolescent exposure elicits a long-term deficit in T-lymphocyte function, which persists into adulthood. The immune effects were less dramatic than seen with gestational exposure, since only T-lymphocyte function and not B-lymphocyte function was perturbed. Additional studies have examined the effects of adolescent nicotine exposure in terms of dose dependence, duration effect, and differing methods of nicotine administration (Navarro et al.). It was found that an exposure time, as short as one week, beginning on PN 30 (30 days postnatal) was sufficient to elicit the effects on T-lymphocyte function that occur with the longer infusion period. One month after exposure ended or in young adulthood, 6 mg/kg/day of nicotine resulted in a nearly 50% reduction in the mito-genic response of T-lymphocytes, a result virtually identical to that obtained with a 2.5-week infusion. These results are in contrast to those obtained with nicotine infusions given to adult rats, where adults required a much longer minimum exposure period (4 weeks) to produce any immediate effect on T-cell mitogenic responses despite higher plasma nicotine levels (Geng et al. 1995). Further, adults did not show a delayed reappearance of deficits (Geng et al. 1996). As with gestational exposure, this points to a developmental misprogramming.

This same study (Navarro et al. 2001a), also examined the effects of a lower dose (2 mg/kg/day) of infused nicotine over this short one-week period. This dose resulted in plasma nicotine levels well below those seen in active smokers or nicotine patch users, and is consistent with levels detected in occasional smokers or in individuals exposed to nicotine via environmental tobacco smoke (ETS). This low-level adolescent exposure resulted in significant reductions in T cell function. Interestingly, these T cell deficits were not observed when nicotine was delivered by a different mode (repeated injections) at either the 6 mg/kg or the 2 mg/kg dosage rates. This result supports the postulate that early inappropriate sustained action of nicotine at nicotinic cholinergic receptors can alter programming.

Earlier work with agents acting on other neurotransmitter receptors also indicates that a prolonged action is required to elicit long-term developmental deficits (Zagon and McLaughlin 1984), while episodic stimulation or inhibition of neuroreceptors allows for recovery and adaptation during the intervals between doses. This result indicates that hypoxia-ischemic insults associated with an injection model, which produced significant weight deficits into young adulthood, did not produce the immune deficits seen with infusion, which did cause hypoxia-ischemia. This result strongly suggests that nicotine itself is responsible for the adverse effects, not the secondary effects associated with injection. In summary, an adolescent exposure as short as one week, with doses that achieve plasma nicotine levels well below those in active smokers, was sufficient to elicit long-term deficits in mitogenic responses of T-lymphocytes.

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