Methyllycaconitine (MLA) blocks the nicotine evoked anxiogenic effect and 5-HT release in the dorsal hippocampus: possible role of alpha 7 receptors

Nicotine has bimodal effects on anxiety, with low doses having an anxiolytic effect and high doses having an anxiogenic effect. The dorsal hippocampus is one of the brain areas that mediate the anxiogenic effect of nicotine through enhanced 5-HT release, but the nAChR subtype(s) that mediate these effects are not known. Intrahippocampal administration of a high dose of nicotine (1 mu g, 4.3 mM) had an anxiogenic effect in the social interaction test that was reversed by co-administration of a behaviourally inactive dose (1.9 ng, 4.3 mu M) of methyllycaconitine (MLA), which is an antagonist at alpha 7 and alpha 3 nAChR subunits. At a dose (0.8 ng, 4.3 mu M) at which its actions would be specific to alpha 4 beta 2 and alpha 3 beta 2 nAChRs dihydro-beta- erythroidine (DH beta E) was unable to reverse nicotine's anxiogenic effect. Reversal was obtained with a 10-fold higher, but receptor non-specific concentration of DH beta E (7.8ng, 43 mu M), suggesting that the DH beta E reversal might have been due to action at alpha 7 nAChRs. Exposure of hippocampal slices to MLA (0.25, 05, 1 and 10 mu M) significantly reduced the increase in [H]5-HT release evoked by nicotine (100 mu M). DH beta E (0.1-0.5 mu M) failed to reverse this effect of nicotine on [H]5-HT release, although higher concentrations (1 and 10 mu M), at which alpha 7 subunits would also be affected, were able to do so. Because of the lack of effects of low, receptor specific concentrations of DH beta E, it is more likely that the MLA reversal of both nicotine's anxiogenic effect and its stimulation of [H]5-HT release is due to action at alpha 7 than at alpha 3 units. This is perhaps also more likely because the alpha 7 receptors are highly expressed in the dorsal hippocampus, whereas the alpha 3 subunits are much less abundant. However, what is most important is that, in the dorsal hippocampus, nicotine's anxiogenic effect and induced release of [H]5-HT are mediated by non alpha 4 beta 2 nAChRs, which contrasts with the previously reported anxiolytic effect of a low dose of nicotine which is mediated by alpha 4 beta 2 nAChRs within the dorsal raphe nucleus. Thus the anxiolytic and anxiogenic effects of nicotine can be distinguished both by brain region and by nicotinic receptor subtype.