Role of the locus coeruleus in the noradrenergic response to a systemic administration of nicotine

Abstract

Experiments were conducted using in vivo microdialysis to ascertain the role of nicotinic receptors in the terminal, or the cell body area, in the hippocampal noradrenaline response provoked by a systemic administration of nicotine. These experiments combined systemic administration of nicotine with local administration of antagonists into the hippocampus via the microdialysis probe, or close to the LC via a cannula, while continuously monitoring extracellular levels of NA in the hippocampus. Systemic administration of nicotine (0.4 mg/kg, s.c.) produced a rapid and prolonged increase in extracellular levels of noradrenaline in the hippocampus of conscious animals, reaching a maximum in the first 10 min sample. In anaesthetised animals the maximum occurred 20 min after administration, but the subsequent response profile was similar. In both anaesthetised and freely moving animals nicotine increased extracellular levels of dihydroxyphenylacetic acid and homovanillic acid in the hippocampus, but failed to alter levels of dopamine or 5-hydroxyindoleacetic acid. In anaesthetised animals intrahippocampal administration of nicotine (250 μM over 10 min via the dialysis probe) significantly increased extracellular levels of noradrenaline; the response was shortlasting, being evident only in the 10 min sample during exposure to the drug. Local administration of nicotine failed to alter extracellular levels of any other amine or metabolite measured. Mecamylamine (25 μM), a nicotinic channel blocker, administered intrahippocampally 10 min prior to an intrahippocampal administration of nicotine completely blocked the increase in noradrenaline. However, intrahippocampal administration of mecamylamine (25 μM) for 10 min, or for the duration of recording, failed to antagonise the effect of a systemic administration of nicotine (0.4 mg/kg, s.c.) on extracellular levels of noradrenaline, dihydroxyphenylacetic acid or homovanillic acid. In contrast administration of mecamylamine (50 μM) close to the locus coeruleus abolished the increase in noradrenaline levels in the ipsilateral hippocampus following a systemic administration of nicotine (0.4 mg/kg, s.c.), while trimethaphan (50 μM), a nicotinic receptor antagonist, significantly reduced the response. Administration of mecamylamine also attenuated increases in dihydroxyphenylacetic acid and homovanillic acid, suggesting that the response of these metabolites may be associated with the functional metabolism of noradrenergic neurones. Locus coeruleus administration of kynurenic acid (1 mM), a non-specific excitatory amino acid antagonist, was without effect. Finally, application of nicotine (50 μ M) close to the locus coeruleus significantly increased extracellular levels of noradrenaline in the ipsilateral hippocampus. It is concluded that although terminals within the hippocampus are sensitive to nicotine this is not the route by which a systemic administration of nicotine increases extracellular levels of noradrenaline; instead, the majority of the response appears to be mediated by a direct effect at the cell body area, the locus coeruleus.