The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG-saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.

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Biochemical studies have confirmed that nicotinic acetylcholine receptor mRNA and protein are expressed early in the development of the fetal central nervous system. Perinatal administration of nicotine produces a broad spectrum of effects on brain development, including inhibition of DNA synthesis, altered ornithine decarboxylase activity, altered neurotransmitter function, and significant alterations in cortical morphogenesis. Catecholamine systems, both in the brain and in the periphery, are particularly sensitive to prenatal nicotine exposure. Acute and chronic nicotine administered to pregnant dams causes alterations in dopamine and its metabolites in male and female rat fetuses. These changes can persist into adulthood. Prenatal nicotine exposure also causes locomotor disturbances in pups, which can have long-lasting effects. The effect of nicotine on developing noradrenergic neurons is less clear. Some effects may include increases in noradrenergic neuronal activity in the pup and aberrant central release of norepinephrine in response to neonatal hypoxia after nicotine exposure in utero. Catecholamine neurons develop early in ontogeny, so nicotine induced alterations have the potential to induce permanent changes. Hence, more research is needed to get a clearer picture of the effect of nicotine on developing catecholamine systems. The affects of nicotine on catecholamine systems in the adult are discussed for comparison.

Acute nicotine administration stimulated [3H1norepinephrine ([3H] NE) release from cultured fetal locus coeruleus (LC) cells. The effect was concentration dependent, with an EC 50 of 0.9 ftM, and was abolished by removal of calcium from, or addition of tetrodotoxin (500 nM)to, the assay buffer. Other nicotinic receptor agonists stimulated [ 3H]NE release, with the rank order of potency being (±)-epibatidine> (-)-nicotine > 1,1-dimethyl-4phenylpiperazinium (DMPP). Whereas (-)-nicotine and (±) -epibatidine exhibited equal maximal responses, DMPP was a partial agonist and (-)-cytisine had no agonist activity. Nicotine-stimulated release of [3H]NE was blocked by nicotinic receptor antagonists, with an order of potency of mecamylamine > lobeline > cytisine > methyllycaconitine > dihydro-/3-erythroidine. The pharmacological profile of this nicotinic receptor is largely consistent with that described previously for an a4~2 subunit combination, although discrepancies in the efficacies of agonists were observed. No additivity in NMDAand nicotine-stimulated [3H]NErelease was observed, suggesting a common signal transduction mechanism. However, the pharmacological characteristics of MK-801 blockade of nicotine-induced responses were not consistent with those of an NMDA receptor. We therefore conclude that nicotine directly releases [3H]NE from LC cells and does not act indirectly via activation of glutamate release. Key Words: Nicotinic acetylcholine receptor-Development.