Indirect modulation by alpha 7 nicotinic acetylcholine receptors of noradrenaline release in rat hippocampal slices: Interaction with glutamate and GABA systems and effect of nicotine withdrawal

Nicotinic acetylcholine receptors (nAChRs) can modulate transmitter release. Striatal [H-3] dopamine ([H-3]DA) release is regulated by presynaptic nAChR on dopaminergic terminals and alpha 7 nAChR on neighboring glutamatergic afferents. Here, we explored the role of alpha 7 nAChR in the modulation of [H-3] noradrenaline ([H-3] NA) release from rat hippocampal slices. The nicotinic agonist anatoxin-a ( AnTx) evoked monophasic [H-3] NA release (EC50 = 1.2 mu M) that was unaffected by alpha-conotoxin-MII or dihydro-beta-erythroidine, antagonists of alpha 3/alpha 6 beta 2* and beta 2* nAChR, respectively. In contrast AnTx-evoked striatal [H-3] DA release was biphasic (EC50 = 138.9 nM; 7.1 mu M) and blocked by these antagonists. At a high AnTx concentration ( 25 mu M), alpha 7 nAChR antagonists ( methyllycaconitine, alpha-conotoxin-Iml) and glutamate receptor (GluR) antagonists [ kynurenic acid, 6,7-dinitroquinoxaline- 2,3-dione ( DNQX)] partially inhibited [H-3] NA release. The alpha 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 alpha 7 nAChRs trigger glutamate release that subsequently stimulates [H-3] NA release. A GABAergic component was also revealed: choline-evoked [H-3] 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 alpha 7 nAChR on GABAergic neurons that can promote GABA release which, in turn, leads to [H-3] 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. alpha 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.