5,7‐dihydroxytryptamine lesions enhance and serotonergic grafts normalize the evoked overflow of acetylcholine in rat hippocampal slices

Abstract

Adult rats were subjected to intracerebroventricular injections of 5,7-dihydroxytryptamine (5,7-DHT; 150 micro g) and, 15 days later, to intrahippocampal grafts of fetal raphe cell suspensions. About 11 months later, we assessed baseline and electrically evoked release of tritium ([3H]) in hippocampal slices, preloaded with tritiated ([3H])choline or [3H]serotonin (5-HT), in the presence or absence of the 5-HT1B receptor agonist CP-93,129 and the 5-HT receptor antagonist methiothepine. HPLC determinations of monoamine concentrations were also performed. The lesions reduced the concentration of 5-HT (-90%) and the accumulation (-80%) as well as the evoked release (-90%) of [3H]5-HT. They also decreased the inhibitory effects of CP-93,129 on the evoked release of [3H]5-HT. Most interestingly, they facilitated the evoked release of [3H]acetylcholine (+20%). In slices from rats subjected to lesions and grafts, the responsiveness of the serotonergic autoreceptors (presumably located on the terminals of the grafted neurons) and the release of acetylcholine were close to normal. These results confirm that grafts rich in serotonergic neurons may partially compensate for the dramatic effects of 5,7-DHT lesions on serotonergic hippocampal functions. The lesion-induced reduction of the 5-HT1B autoreceptor-mediated inhibition of evoked 5-HT release may be an adaptation enhancing serotonergic transmission in the (few) remaining terminals. The facilitated release of acetylcholine is probably caused by a reduced serotonergic tone on the inhibitory 5-HT1B heteroreceptors of the cholinergic terminals. When related to data in the literature, this facilitation may be of particular interest in terms of transmitter-based strategies developed to tackle cognitive symptoms related to neurodegenerative diseases.

The Serotonin1AReceptor Partial Agonist S15535 [4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine] Enhances Cholinergic Transmission and Cognitive Function in Rodents: A Combined Neurochemical and Behavioral Analysis

“…Rather than blockade of hippocampal 5-HT 1A sites, S15535 and WAY100,635 may, in fact, enhance hippocampal ACh release by blocking tonically active, inhibitory 5-HT 1A sites on cholinergic cell bodies. This would be consistent with findings that lesions of serotonergic neurons increase extracellular levels of ACh in the DH (Steckler and Sahgal, 1995;Birthelmer et al, 2002).…”

5-HT Receptor Regulation of Neurotransmitter Release

“…Recent studies on hippocampal slices from rats whose serotoninergic neurons were lesioned by intracerebroventricular injection of 5,7-DHT confirmed the data of Vizi et al (1981) in that increased ACh release was found (Birthelmer et al, 2002(Birthelmer et al, , 2003a. This could be ascribed to the attenuated activation of the inhibitory presynaptic 5-HT heteroreceptors on cholinergic projection terminals in the hippocampus.…”

Modulation of cholinergic functions by serotonin and possible implications in memory: General data and focus on 5-HT1A receptors of the medial septum

“…Interestingly, we could also establish that following serotonergic denervation of the hippocampus (by 5,7-DHT lesions), the electrically evoked release of acetylcholine was facilitated in hippocampal slices. Even more interesting was the observation that this facilitation was counterbalanced by intrahippocampal grafts rich in serotonergic neurons [18]. These results suggest that the reduction of the serotonergic tone in the hippocampus may compensate for some dysfunctions subsequent to a loss of cholinergic hippocampal inputs.…”

“…Under the condition of a systemic activation, this release can be facilitated via the activation of 5-HT 1A as well as 5-HT 3 receptors, or inhibited via the activation of 5-HT 1B (5-HT 1D in the guinea-pig) and 5-HT 4 receptors [19,43,73,104]. There is also evidence that a serotonergic denervation of the hippocampus is able to facilitate the evoked release of acetylcholine in hippocampal slices [18]. In the cortex, the release of acetylcholine may be locally controlled by 5-HT 1B and 5-HT 3 inhibitory receptors [42,123], whereas systemic activation of 5-HT 1A and 5-HT 4 receptors induces facilitatory effects [5].…”