Neurotransmitter release and its presynaptic modulation in the rat hippocampus after selective damage to cholinergic or/and serotonergic afferents

Male Long-Evans rats sustained injections of 5,7-dihydroxytryptamine (5,7-DHT) into the fimbria-fornix and the cingular bundle or/and intraseptal injections of 192 IgG-saporin to induce serotonergic or/and cholinergic hippocampal denervations; Sham-operated rats served as controls. Four to ten weeks after lesioning, we measured (i) the electrically evoked release of acetylcholine ([H-3]ACh), noradrenaline ([H-3]NA) and serotonin ([H-3]5-HT) in hippocampal slices in the presence of drugs acting on auto- or heteroreceptors, (ii) the nicotine-evoked release of NA and (iii) the choline acetyltransferase (ChAT) activity and the concentration of monoamines in homogenates. Saporin lesions reduced the accumulation of [H-3]choline, the release of [H-3]ACh and the ChAT activity, but increased the concentration of NA and facilitated the release of [H-3]NA evoked by nicotine. 5,7-DHT lesions reduced the accumulation and the release of [H-3]5-HT, the concentration of 5-HT, and also facilitated the release of [H-3]NA evoked by nicotine. Accumulation and electrically evoked release of [H-3]NA were not altered by either lesion. The combination of both toxins resulted in an addition of their particular effects. The 5-HT1B receptor agonist, CP 93,129, and the muscarinic agonist, oxotremorine, reduced the release of [H-3]ACh in control and 5,7-DHT-lesioned rats; in rats injected with saporin, their effects could not be measured reliably. GP 93,129 and the alpha(2)-adrenoceptor agonist, UK 14,304, reduced the release of [H-3]5-HT in all groups by about 65%. In conclusion: (i) selective neurotoxins can be combined to enable controlled and selective damage of hippocampal transmitter systems; (ii) 5-HT exerts an inhibitory influence on the nicotine-evoked release of NA, but partial serotonergic lesions do not influence the release of ACh at a presynaptic level and (iii) presynaptic modulatory mechanisms involving auto- and heteroreceptors may be conserved on fibres spared by the lesions. (C) 2002 Elsevier Science Inc. All rights reserved.