DOWN-REGULATION OF MUSCARINIC-MEDIATED AND 5-HT1B-MEDIATED MODULATIONOF [H-3] ACETYLCHOLINE-RELEASE IN HIPPOCAMPAL SLICES OF RATS WITH FIMBRIA-FORNIX LESIONS AND INTRAHIPPOCAMPAL GRAFTS OF SEPTAL ORIGIN

Adult Long-Evans female rats sustained electrolytic fimbria-fornix les ions and, two weeks later, received intrahippocampal suspension grafts of fetal septal tissue. Sham-operated and lesion-only rats served as controls. Between 6.5 and 8 months after grafting, both the [H-3]choli ne accumulation and the electrically evoked [H-3]acetylcholine ([H-3]A Ch) release were assessed in hippocampal slices. The release of [H-3]A Ch was measured in presence of atropine (muscarinic antagonist, 1 mu M ), physostigmine (acetylcholinesterase inhibitor, 0.1 mu M), oxotremor ine (muscarinic agonist, 0.01 mu M-10 mu M), mecamylamine (nicotinic a ntagonist, 10 mu M), methiothepin (mixed 5-HT1/5-HT2 antagonist, 10 mu M), 8-OH-DPAT (5-HT1A agonist, 1 mu M), 2-methyl-serotonin (5-HT, ago nist, 1 mu M) and CP 93129 (5-HT1B agonist, 0.1 mu M-100 mu M), or wit hout any drug application as a control. In lesion-only rats, the speci fic accumulation of [3H]choline was reduced to 46% of normal and the r elease of [H-3]ACh to 32% (nCi) and 43% (% of tissue tritium content). In the grafted rats, these parameters were significantly increased to 63%, 98% and 116% of control, respectively. Physostigmine reduced the evoked [H-3]ACh release and was significantly more effective in graft ed (-70%) than in sham-operated (-56%) or lesion-only (-54%) rats. Whe n physostigmine was superfused throughout, mecamylamine had no effect. Conversely, atropine induced a significant increase of [H-3]ACh relea se in all groups, but this increase was significantly larger in sham-o perated rats (+209%) than in the other groups (lesioned: + 80%; grafte d: + 117%). Oxotremorine dose-dependently decreased the [3H]ACh releas e, but in lesion-only rats, this effect was significantly lower than i n sham-operated rats. Whatever group was considered, 8-OH-DPAT, methio thepin and 2-methyl-serotonin failed to induce any significant effect on [H-3]ACh release. In contrast, CP 93129 dose-dependently decreased [H-3]ACh release. This effect was significantly weaker in grafted rats than in the rats of the two other groups. Our data confirm that choli nergic terminals in the intact hippocampus possess inhibitory muscarin ic autoreceptors and serotonin heteroreceptors of the 5-HT1B subtype. They also show that both types of receptors are still operative in the cholinergic terminals which survived the lesions and in the grafted c holinergic neurons. However, the muscarinic receptors in both lesioned and grafted rats, as well as the 5-HT1B receptors in grafted rats sho w a sensitivity which seems to be downregulated in comparison to that found in sham-operated rats. In the grafted rats, both types of downre gulations might contribute to (or reflect) an increased cholinergic fu nction that results from a reduction of the inhibitory tonus which ACh and serotonin exert at the level of the cholinergic terminal.