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Indirect Modulation by 7 Nicotinic Acetylcholine Receptors of Noradrenaline Release in Rat Hippocampal Slices: Interaction with Glutamate and GABA Systems and Effect of Nicotine Withdrawal

Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom

Nicotinic acetylcholine receptors (nAChRs) can modulate transmitter release. Striatal [³H]dopamine ([³H]DA) release is regulated by presynaptic nAChR on dopaminergic terminals and 7 nAChR on neighboring glutamatergic afferents. Here, we explored the role of 7 nAChR in the modulation of [³H]noradrenaline ([³H]NA) release from rat hippocampal slices. The nicotinic agonist anatoxin-a (AnTx) evoked monophasic [³H]NA release (EC₅₀ = 1.2 µM) that was unaffected by -conotoxin-MII or dihydro--erythroidine, antagonists of 3/62* and 2* nAChR, respectively. In contrast AnTx-evoked striatal [³H]DA release was biphasic (EC₅₀ = 138.9 nM; 7.1 µM) and blocked by these antagonists. At a high AnTx concentration (25 µM), 7 nAChR antagonists (methyllycaconitine, -conotoxin-ImI) and glutamate receptor (GluR) antagonists [kynurenic acid, 6,7-dinitroquinoxaline-2,3-dione (DNQX)] partially inhibited [³H]NA release. The 7 nAChR-selective agonist choline evoked [³H]NA release (E_max = 33% of that of AnTx) that was blocked by GluR antagonists, supporting a model in which 7 nAChRs trigger glutamate release that subsequently stimulates [³H]NA release. A GABAergic component was also revealed: choline-evoked [³H]NA release was partially blocked by the GABA_A receptor antagonist bicuculline, and coapplication of bicuculline and DNQX fully abolished this response. These findings support 7 nAChR on GABAergic neurons that can promote GABA release which, in turn, leads to [³H]NA release, probably by disinhibition. To investigate the impact of long-term nicotine exposure on this model, rats were exposed for 14 days to nicotine (4 mg/kg/day) with or without 3 or 7 days of withdrawal. 7 nAChR responses were selectively and transiently up-regulated after 3 days of withdrawal. This functional up-regulation could contribute to the withdrawal effects of nicotine.

Address correspondence to: Dr. S. Wonnacott, Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom. E-mail: s.wonnacott{at}bath.ac.uk

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