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

Nicotinic acetylcholine receptors (nAChRs) can modulate transmitter release. Striatal [H]dopamine ([H]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 [H]noradrenaline ([H]NA) release from rat hippocampal slices. The nicotinic agonist anatoxin-a (AnTx) evoked monophasic [H]NA release (EC50 1.2 M) that was unaffected by -conotoxin-MII or dihydro-erythroidine, antagonists of 3/ 6 2* and 2* nAChR, respectively. In contrast AnTx-evoked striatal [H]DA release was biphasic (EC50 138.9 nM; 7.1 M) and blocked by these antagonists. At a high AnTx concentration (25 M), 7 nAChR antagonists (methyllycaconitine, -conotoxin-ImI) and glutamate receptor (GluR) antagonists [kynurenic acid, 6,7dinitroquinoxaline-2,3-dione (DNQX)] partially inhibited [H]NA release. The 7 nAChR-selective agonist choline evoked [H]NA release (Emax 33% of that of AnTx) that was blocked by GluR antagonists, supporting a model in which 7 nAChRs trigger glutamate release that subsequently stimulates [H]NA release. A GABAergic component was also revealed: cholineevoked [H]NA release was partially blocked by the GABAA 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 [H]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. Neuronal nicotinic acetylcholine receptors (nAChRs) have a pivotal role in modulating the release of various neurotransmitters from different brain areas, including the hippocampus and the striatum (Wonnacott, 1997; Vizi and Kiss, 1998). The hippocampus is a key structure implicated in memory formation where changes in long term synaptic potentiation are considered to be a cellular mechanism underlying aspects of learning and memory. Nicotinic agonists, through activation of neuronal nAChR, improve cognitive performance in both animals and humans (Levin and Simon, 1998; Newhouse et al., 2004), and hippocampal nAChRs, including 7 nAChRs, influence synaptic plasticity through the facilitation of presynaptic and postsynaptic mechanisms (Ji et al., 2001). Furthermore, patients with Alzheimer’s disease exhibit memory deficits characterized by a marked decline in cholinergic transmission and a decreased number of nAChR binding sites in the cortex and hippocampus (Gotti and Clementi, 2004), and nicotine can ameliorate the cognitive deficit in these patients (Newhouse et al., 2004). Therefore, the modulatory properties of nAChR contribute to both normal and pathological brain functions. The noradrenergic input to the hippocampus largely arises from the ascending dorsal noradrenergic bundle that projects This work was supported by a Research Training Network Award from the Commission of the European Community. Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.105.018184. ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; NA, noradrenaline; DA, dopamine; -CnTxMII, -conotoxin-MII; -CnTxImI, -conotoxin ImI; DH E, dihydro-erythroidine; MLA, methyllycaconitine; Bgt, -bungarotoxin; DNQX, 6,7-dinitroquinoxaline-2,3-dione; AnTx, anatoxin-a; GluR, glutamate receptor; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; KB, Krebs buffer; PMSF, phenylmethylsulfonyl fluoride; ANOVA, analysis of variance; TTX, tetrodotoxin; MK801, 5H-dibenzo[a,d]cyclohepten-5,10-imine; GBR 12909, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; CGP 54626, [S-(R*,R*)]-3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2hydroxypropyl](cyclohexylmethyl) phosphinic acid. 0026-895X/06/6902-618–628$20.00 MOLECULAR PHARMACOLOGY Vol. 69, No. 2 Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics 18184/3078687 Mol Pharmacol 69:618–628, 2006 Printed in U.S.A. 618 at A PE T Jornals on O cber 9, 2017 m oharm .aspeurnals.org D ow nladed from from the locus coeruleus (Ungerstedt, 1971). In vivo, intrahippocampal administration of nicotine evoked noradrenaline (NA) release in a mecamylamine-sensitive manner (Mitchell, 1993). The presence of presynaptic nAChRs on noradrenergic terminals in the hippocampus is consistent with nicotine-evoked [H]noradrenaline ([H]NA) release from hippocampal synaptosomes (Clarke and Reuben, 1996; Luo et al., 1998). Pharmacological studies to characterize the nAChRs mediating [H]NA release from hippocampal synaptosomes and slices provided evidence for nAChR heterogeneity, but the paucity of specific antagonists has limited the resolution of the subtypes of nAChRs involved (Clarke and Reuben, 1996; Sershen et al., 1997; Vizi and Kiss, 1998; Anderson et al., 2000). Luo et al. (1998) demonstrated that -conotoxinAuIB blocked 30% of the NA release elicited by nicotine from hippocampal synaptosomes, consistent with 3 4* nAChR on noradrenergic terminals being responsible for this proportion of the response. It is likely that [H]NA release from slice preparations will reflect additional, indirect contributions of nAChRs present on neighboring neurons. Leslie et al. (2002) suggested an indirect GABAergic component in the modulation of NA release in a hippocampal slice preparation, because [H]NA release evoked by nicotine (100 M) was partially blocked by the GABAA antagonist bicuculline. Functional glutamate heteroreceptors on hippocampal synaptosomes have been reported (Risso et al., 2004), and there is a large body of evidence from electrophysiological recordings from hippocampus that 7 nAChRs regulate both glutamatergic and GABAergic neurotransmission (Gray et al., 1996; McQuiston and Madison, 1999; Alkondon and Albuquerque, 2000a; Buhler and Dunwiddie, 2001). Hence, 7 nAChR is a plausible candidate for an indirect modulation of NA release. In the present work, we examined the role of 7 nAChR in the modulation of [H]NA release from hippocampal slices, which preserves some of the existing neuroanatomical connections, enabling the investigation of neurotransmitter cross-talk. Pharmacological dissection of the response provides evidence for the indirect modulation of [H]NA release by 7 nAChRs via activation of both GABA and glutamate release. This is shown to differ from the nicotinic control of striatal [H]dopamine ([H]DA) release. We have also demonstrated that the indirect 7 nAChR modulation of [H]NA release was selectively up-regulated during nicotine withdrawal. Materials and Methods