Original ArticlesModulation of 5-hydroxytryptamine release in hippocampal slices of rats: Effects of fimbria-fornix lesions on 5-HT1b-autoreceptor and α2-heteroreceptor function
Introduction
The release of 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in mammalian brain structures, including the hippocampus, is modulated by presynaptic auto- and heteroreceptors (for reviews see 27, 29, 30, 58, 60, 61). 5-HT autoreceptors have been identified as 5-HT1B receptors in the rat hippocampus ([52], see also [27]), and the α2-autoreceptor (at least in the rat cortex) has been classified as α2D-adrenoceptor (see [61]).
Interestingly, there are also well-documented interactions of these two transmitter systems at the presynaptic level. For instance, it has been shown that serotonergic axon terminals in the central nervous system (CNS) of various species (including human) are endowed with inhibitory α2-adrenoceptors, which are activated by endogenously released NA 21, 22, 23, 24, 28, 46, 51, 55, 59. In the rat cortex, these α2-adrenoceptors belong to the α2D-subtype [64]. In contrast, although 5-HT receptors are thought to be present on noradrenergic neurons in peripheral tissues (see [30]), there are conflicting data for the presence of 5-HT receptors on central noradrenergic axon terminals: enhancement of NA release via presynaptic 5-HT3 receptors has been suggested by one laboratory [53], whereas other groups have shown that facilitatory effects of 5-HT3 agonists are mediated by blockade of α2-autoreceptors on central noradrenergic neurons 2, 56.
Among several other afferents, the hippocampal formation receives prominent projections, both from the locus coeruleus and the raphé nuclei in the brain stem (see [3]). Since these noradrenergic and serotonergic afferents profoundly affect the activity of hippocampal neurons, any change in the release of NA and/or 5-HT from the axon terminals of these afferent fibers may also affect hippocampal function. Therefore, it is the aim of the present study to monitor changes in presynaptic 5-HT1B auto- and α2-heteroreceptor function on serotonergic neurons in the hippocampal formation of rats following an experimentally induced pathophysiological situation, i.e., aspirative lesions of the fimbria fornix.
Partial or extensive lesions of the septohippocampal pathways are considered as one of the possible experimental models of Alzheimer’s disease in animals (e.g., 12, 19, 40, 41). Such lesions are known to induce a series of deficits, including severe and lasting depletions of some hippocampal neurotransmitters and related enzymes or metabolites (e.g., acetylcholine, choline acetyltransferase activity, 5-HT; 9, 10, 18, 20, 40, 42, 43, 62, 63). Whereas the markers of cholinergic and serotonergic innervation show poor recovery over time, those of noradrenergic innervation are normalized within several weeks and even largely overcompensated after a few months (e.g. 14, 39, 50). Part of this overcompensation is due to the phenomenon of nonregenerative sprouting of sympathetic fibers arising from the superior cervical ganglia (SCG). Whereas these sympathetic fibers and their axon terminals are normally confined to cerebral blood vessels, the choroid plexus and the pineal gland 14, 16, 49, they begin to invade the hippocampal parenchyma as a consequence of cholinergic denervation 14, 15, 25, 26 and their protracted ingrowth seems inexhaustible.
Although this sprouting reaction of sympathetic neurons has been well-characterized neuroanatomically [14], there are only a few—sometimes contradictory—behavioral studies (e.g. 4, 13, 17, 33, 36), some reports about electrophysiological approaches 6, 44 and several neuropharmacological investigations 5, 31, 32, 34, 35, 45, 54 of this phenomenon. Interestingly, it has been shown that sympathetic sprouting may also occur in the brains of patients with Alzheimer’s disease [7]. Therefore, the functional consequences of sympathetic fiber ingrowth into the hippocampus may also be of clinical interest and hence, need further characterization, in particular at a more cellular level.
Recently, we studied some aspects of the modulation of the evoked release of acetylcholine (ACh; [11]) and NA (unpublished data) in hippocampal tissue of rats subsequent to septohippocampal denervation. However, as concerns functional changes of 5-HT1B autoreceptors subsequent to (serotonergic) denervation, or of α2-heteroreceptors on serotonergic axon terminals subsequent to lesion-induced sympathetic sprouting, no investigation has been undertaken so far. Therefore, the two main questions of the present investigation are whether changes in the functions (a) of 5-HT autoreceptors and (b) of α2-heteroreceptors on serotonergic neurons can be detected in hippocampal tissue subsequent to fimbria-fornix lesions. Our previous neurochemical studies 10, 39 have shown that following aspirative lesions of the fimbria-fornix, reductions of 5-HT levels, or increases in NA concentrations, were most dramatic in the dorsal and ventral parts of the hippocampus, respectively. Therefore, experiments concerning 5-HT autoreceptor function were performed on slices from the dorsal hippocampus, whereas for those concerning α2-heteroreceptor function, slices of the ventral hippocampus were used.
Section snippets
Chemicals and drugs
Chemicals and drugs were obtained from the following sources: 5-[1,2-3H(N)]hydroxytryptamine creatinine sulfate ([3H]5-HT, 30.0 Ci/mmol) from NEN (Dreieich, Germany); 6-nitroquipazine maleate, methiotepine mesylate (metitepine) from RBI, (Biotrend, Köln, Germany). The following drugs were kindly provided by the producers: 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrollo[3,2-b]pyrid-5-one (CP 93,129) Pfizer, Karlsruhe, Germany; 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline tartrate (UK 14,304) Pfizer
Neurochemical determinations
In order to quantify, at least approximately, the changes in the density of cholinergic, noradrenergic, and serotonergic innervation in hippocampal tissue caused by aspirative fimbria-fornix lesions, several neurochemical markers were measured in the hippocampal slices that were not used for superfusion experiments (Table 1). Approximately 13.5–15 months after the lesion surgery, i.e., at the time of the functional assays described below, we found that there was a 50% and 35% reduction in ChAT
Neurochemical effects of fimbria-fornix lesions
Table 1 shows that fimbria-fornix lesions induced approximately 50% reduction of cholinergic and serotonergic markers in the dorsal hippocampus 14 month after lesion surgery. Remarkably, these changes were smaller than those found in earlier studies 10, 39, and this was also observed as to the increase in NA tissue levels induced by the lesions. Some differences in the preparation of the samples used for neurochemical determinations might account for these differences. In contrast with our
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (Ja 244/4-1).
References (64)
- et al.
Functional significance of sympathohippocampal sproutingChanges in single cell spontaneous activity
Brain Res.
(1984) - et al.
Frequency analysis of catecholamine axonal morphology in human brain. II. Alzheimer’s disease and hippocampal sympathetic ingrowth
J. Neurol. Sci.
(1993) - et al.
Graft-derived cholinergic reinnervation of the hippocampus prevents a lasting increase of hippocampal noradrenaline concentration induced by septohippocampal damage in rats
Neurosci. Lett.
(1992) - et al.
Effects of grafts containing cholinergic and/or serotonergic neurons on cholinergic, serotonergic and noradrenergic markers in the denervated rat hippocampus
Brain Res.
(1993) - et al.
Downregulation of muscarinic- and 5-HT1B-mediated modulation of [3H]acetylcholine release in hippocampal slices of rats with fimbria-fornix lesions and intrahippocampal grafts of septal origin
Brain Res.
(1995) - et al.
The fimbria-fornix/cingular bundle pathwaysA review of neurochemical and behavioral approaches using lesions and transplantation techniques
Prog. Neurobiol.
(1997) Sympathetic sprouting in the central nervous systemA model for studies of axonal growth in the mature mammalian brain
Brain Res. Rev.
(1987)- et al.
Sympathetic noradrenergic sprouting in response to central cholinergic denervation
Trends Neurosci.
(1981) - et al.
Medial septal lesions, radial arm maze performance, and sympathetic sproutingA study of recovery of function
Brain Res.
(1983) - et al.
Normalization of subtype-specific muscarinic receptor binding in the denervated hippocampus by septodiagonal band grafts
Exp. Neurol.
(1989)
Transplantation of fetal cholinergic neurons into the hippocampus attenuates the cognitive and neurochemical deficits induced by AF64A
Brain Res. Bull.
Noradrenaline inhibits depolarization-induced 3H-serotonin release from slices of rat hippocampus
Eur. J. Pharmacol.
Pharmacological characterization of presynaptic α-adrenoceptors modulating [3H]noradrenaline and [3H]5-hydroxytryptamine release from slices of the hippocampus of the rat
Eur. J. Pharmacol.
Noradrenergic, serotonergic, and cholinergic sprouting in the hippocampus that follows partial or complete transection of the septohippocampal pathwayContribution of spared inputs
Exp. Neurol.
Hippocampal phosphoinositide turnover is altered by hippocampal sympathetic ingrowth and cholinergic denervation
Pharmacol. Biochem. Behav.
Sympathetic sprouting and recovery of spatial recovery
Exp. Neurol.
Hippocampal sympathetic ingrowth and cholinergic denervation uniquely alter muscarinic receptor subtypes in the hippocampus
Brain Res.
Regional heterogeneity in the distribution of neurotransmitter markers in the rat hippocampus
Neuroscience
Lesions of supracallosal or infracallosal hippocampal pathways in the ratBehavioural, neurochemical and histochemical effects
Behav. Neural Biol.
The effects of intrahippocampal raphe and/or septal grafts in rats with fimbria-fornix lesions depend on the origin of the grafted tissue and the behavioural task used
Neuroscience
Failure to find a behavioral role for anomalous sympathetic innervation of the hippocampus in male rats
Physiol. Behav.
The effect of hippocampal sympathetic ingrowth and cholinergic denervation on hippocampal M(2) cholinergic receptors
Brain Res.
Protein measurement with the folin reagent
J. Biol. Chem.
Anomalous innervation of the hippocampal formations by peripheral sympathetic axons following mechanical injury
Exp. Neurol.
Sprouting of noradrenergic fibers in the hippocampus after medial septal lesionsContributions of the central and peripheral nervous systems
Exp. Neurol.
Activation of 5-HT3 receptors enhances the electrically evoked release of [3H]noradrenaline in rat brain limbic structures
Eur. J. Pharmacol.
Transmitter release from brain slices elicited by single pulsesA powerful method to study presynaptic mechanisms
Trends Neurosci.
Involvement of α-receptors in clonidine-induced inhibition of transmitter release from central monoamine neurones
Neuropharmacology
Intrahippocampal transplants of septal cholinergic neuronsHigh-affinity choline uptake and spatial memory function
Brain Res.
Presynaptic κ-opioid receptors on noradrenergic nerve terminals couple to G proteins and interact with α2-adrenoceptors
J. Neurochem.
Effects of 5-HT receptor agonists on depolarization-induced [3H]noradrenaline release in rabbit hippocampus and human neocortex
Br. J. Pharmacol.
Hippocampal formation
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