Stimulation of 5-HT1A receptors in the dorsal hippocampus impairs acquisition and performance of a spatial task in a water maze

doi:10.1016/0006-8993(92)91451-J

Brain Research

Volume 595, Issue 1, 6 November 1992, Pages 50-56

https://doi.org/10.1016/0006-8993(92)91451-J Get rights and content

Abstract

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a potent 5-HT_1A receptor agonist, was infused in the dorsal hippocampus of rats and its effect on acquisition and performance of a 2-platform spatial discrimination task was studied using a water maze. The infusion (0.5 μl/min) of 2 but not 0.4 μg 8-OH-DPAT in the CA1 region of the dorsal hippocampus impaired rats' accuracy with no effect on latency (except day 3). At 5 μg 8-OH-DPAT impaired rats' accuracy and significantly increased choice latencies from day 2 to day 5 of the training period. The dose of 2 μg significantly increased the errors of omissions on the first day of training and animals which had received 5 μg 8-OH-DPAT made significantly more errors of omission on the first and second days of training. Intrahippocampal administration of 1 μg spiroxatrine, a 5-HT_1A receptor antagonist, antagonized the effect of 5 μg 8-OH-DPAT on accuracy and choice latency with no significant effect on the errors of omission on days 1 and 2 of training. Infusion of 2 and 5 μg 8-OH-DPAT in the dorsal hippocampus also impaired accuracy in well-trained rats. The results suggest that stimulation of 5-HT_1A receptors in the CA1 region of the dorsal hippocampus causes an impairment of spatial discrimination in rats.

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Serotonergic regulation of hippocampal rhythmical activity
2020, Handbook of Behavioral Neuroscience
Citation Excerpt :
The authors speculated that a 5-HT1A-elicited suppression of gamma may alter “many hippocampal-dependent cognitive processes such as spatial navigation, memory consolidation or pattern separation” which is consistent with the findings that 5-HT1A receptor activation profoundly disrupts cognitive functions (for review, Ogren et al., 2008). For instance, it has been shown that stimulation of 5-HT1A receptors produces severe learning and memory deficits, whereas 5-HT1A antagonists enhance cognitive functions (Carli, Lazarova, Tatarczynska, & Samanin, 1992; Carli & Samanin, 1992; McNaughton. & Morris, 1992; Warburton, Harrison, Robbins, & Everitt, 1997). It remains to be determined whether (or to what extent) 5-HT1A effects on memory involve 5-HT1A actions on gamma oscillations.
The dorsal (DR) and median raphe (MR) nuclei are major serotonin-containing nuclei of the brainstem with extensive projections to the forebrain. With a few exceptions, DR and MR give rise to separate, nonoverlapping, projections to the forebrain. The MR is a midline/paramidline system with fibers mainly distributing to medial parts of the hypothalamus and thalamus, the medial basal forebrain, the septum, and the hippocampus. By contrast, DR is a “lateral” system distributing to the substantia nigra, the lateral hypothalamus, amygdala, lateral basal forebrain, and cortex. The DR and MR essentially only send common projections to the midline and intralaminar thalamus. These differential projections undoubtedly reflect functional differences of the two systems. Recent examinations of inputs and outputs of serotonergic DR and MR cells, using viral-based techniques, has largely confirmed, but also extended, previous descriptions of DR/MR systems using conventional tracers. Serotonergic DR/MR fibers distribute heavily, and largely selectively, to “limbic-related” sites of the forebrain. This is exemplified by the distribution of serotonin (5-HT) fibers to the thalamus and cortex; that is, pronounced 5-HT (SERT+) fiber labeling in the anterior, midline, and intralaminar nuclei of thalamus compared to sparse labeling of principal thalamic nuclei, and dense 5-HT labeling of limbic cortices as opposed to sensorimotor cortices. Serotonergic MR fibers strongly target the hippocampus (HF) and weakly the neocortex, whereas the 5-HT DR fibers distribute heavily to the neocortex and minimally to the HF. Serotonergic MR fibers to the HF serve a prominent role in the modulation of the hippocampal theta rhythm, as this is the only input to the HF that serves to desynchronize the hippocampal EEG—or block the theta rhythm. In an analogous manner, serotonin acting at various 5-HT-receptor sites in the HF also strongly suppresses gamma oscillations and ripple activity in the hippocampus. In effect, the serotonergic MR system serves to suppress the three major oscillations of the hippocampus (theta, gamma, ripples)—and as a corollary, inhibition of the MR triggers each of these rhythms. The dual serotonergic MR actions on hippocampal oscillations has opposite effects on learning and memory; that is, the suppression of hippocampal oscillations severely disrupts memory, whereas releasing rhythmical activity (via inhibition of MR) enhances memory. It has been suggested that median raphe nucleus is an important part of a system of connections that blocks or temporarily suspends memory in the hippocampus and by so doing may direct the hippocampus to essentially disregard insignificant environmental events.
Time of day but not aging regulates 5-HT<inf>7</inf> receptor binding sites in the hamster hippocampus
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Activation of 5-HT₇ receptors influences memory as well as circadian rhythms and other processes. This study investigated the regulation of the 5-HT₇ receptors in the hippocampus, a likely substrate for the effects of 5-HT₇ receptor compounds on memory. Because endogenous serotonin release is higher during the active phase, and chronic treatment with a serotonin-selective reuptake inhibitor down-regulates 5-HT₇ receptors, we hypothesized that 5-HT₇ receptors exhibit 24-h variations. We also hypothesized that aging decreases 5-HT₇ receptors in the hippocampus, as it does in the dorsal raphe nucleus, a brain site for serotonergic resetting of circadian rhythms. Male hamsters (young, 3–5 mos; old, 17–21 mos) exposed to a light:dark cycle were euthanized at 4 times of day (zeitgeber times [ZT]1, 6, 13, & 19; ZT12 = time of lights:off). 5-HT₇ receptor autoradiography was conducted on hippocampal sections using [³H]8-OH-DPAT [2 nM] as the radioligand and SB-269970 [1 μM] to define nonspecific binding. Slide-mounted sections and radioactive standards were apposed to X-ray films; the resultant autoradiograms were assessed by computer-assisted microdensitometry. Specific 5-HT₇ receptor binding was robustly expressed in the dentate gyrus (DG) and CA1 but not in the CA2 or CA3. In the CA1 and DG, specific 5-HT₇ receptor binding exhibited 24-h rhythms with troughs at night (P < 0.005; P < 0.05, respectively). Aging did not significantly affect specific 5-HT₇ receptor binding in these regions, nor were significant time and age interactions observed. These findings suggest that the therapeutic effectiveness of 5-HT₇ drugs may vary with time of day of administration but not with the age of the recipient.
Serotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat
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However, however, it does not rule out a possible effect of 5,7-DHT on the serotoninergic fibres of the hippocampus. In contrast, when 5-HT1A-receptor agonist 8-OH-DPAT is infused into the septum [52,9] or the hippocampus [24], or when it is systemically administered [26], the Morris water maze performances and working memory are impaired. Specifically, pre-acquisition intraseptal 8-OH-DPAT agonist infusions prevent learning in the water maze [66].
Theta activity has been related to the processing of spatial information and the formation of hippocampus-dependent memory. The medial septum (MS) plays an important role in the control and coordination of theta activity, as well as in the modulation of learning. It has been established that increased serotonergic activity may desynchronize theta activity, while reduced serotonergic activity produces continuous and persistent theta activity in the hippocampus. We investigate whether serotonin acting on the medial septum could modify spatial learning and the functional relationship between septo-hippocampal and septo-mammillary theta activity. The serotonin was depleted (5HT-D) from the medial septum by the injection of 5,7 DHT (5,7- dihydroxytryptamine). Theta activity was recorded in the dorsal hippocampus, MS and mammillary nuclei (SUM, MM) of Sprague-Dawley male rats during spatial learning in the Morris water maze. Spatial learning was facilitated, and the frequency of the hippocampal theta activity during the first days of training increased (to 8.5 Hz) in the 5HT-D group, unlike the vehicle group. Additionally, the coherence between the MS-hippocampus and the MS-mammillary nuclei was higher during the second day of the test compared to the vehicle group. We demonstrated that septal serotonin depletion facilitates the acquisition of spatial information in association with a higher functional coupling of the medial septum with the hippocampus and mammillary nuclei. Serotonin, acting in the medial septum, modulates hippocampal theta activity and spatial learning.
Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic 5-HT<inf>1A</inf> receptors
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Citation Excerpt :
In hippocampal slices, the 5-HT1A receptor agonist 8-OH-DPAT inhibits long-term potentiation which is thought to represent the molecular basis for learning and memory (Sakai and Tanaka 1993). In vivo, stimulation of 5-HT1A receptors by infusion of 8-OH-DPAT either in the medial septum or the dorsal hippocampus of rats caused an impairment in the water-maze performance as a model to test spatial learning (Bertrand et al. 2000; Carli et al. 1992). In contrast, blocking serotonin receptors by injection of the selective 5-HT1A receptor antagonist NAN-190 in the hippocampus of rats facilitated learning and memory in shuttle-box testing and compensated for loss of hippocampal cholinergic neurotransmission involved in working memory (Belcheva et al. 1997; Ohno and Watanabe 1996).
The antiphospholipid syndrome (APS) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts. In experimental APS (eAPS), a mouse model of APS, behavioral abnormalities develop in the absence of vessel occlusion or infarcts. Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits, we checked for lymphocytic infiltration, activation of glia and macrophages, as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior. Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3, CD4, CD8 and forkhead box P3 (Foxp3), respectively. GFAP, Iba1 and CD68-immunohistochemistry was performed, to check for activation of astrocytes, microglia and macrophages. Ligand binding densities of NMDA, AMPA, GABA_A and 5-HT_1A receptors were analyzed by in vitro receptor autoradiography. No significant inflammatory reaction occurred in eAPS mice. There was neither activation of astrocytes or microglia nor accumulation of macrophages. Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged. However, ligand binding densities of the modulatory serotonergic 5-HT_1A receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed.
The serotonergic system in ageing and Alzheimer's disease
2012, Progress in Neurobiology
Citation Excerpt :
The introduction of the selective 5-HT1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)-tertralin (8-OH-DPAT) has been of major importance in addressing the role of 5-HT1A receptors in cognitive function (Arvidsson et al., 1981; Meneses and Perez-Garcia, 2007). Systemic treatment with 8-OH-DPAT reduces LTP (Edagawa et al., 1998) and also affects water maze performance (Carli et al., 1992a; Carli and Samanin, 1992; Meneses, 1999), object recognition (Pitsikas et al., 2005) and passive avoidance (Carli et al., 1992b; Elvander-Tottie et al., 2009) in rodents. The detrimental effect of 8-OH-DAPT on memory function appears to be mediated by activation of 5-HT1A heteroreceptors in the septum and the hippocampus (Egashira et al., 2006; Elvander-Tottie et al., 2009).
Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.
The effects of selective antagonists of serotonin 5-HT7 and 5-HT1A receptors on MK-801-induced impairment of learning and memory in the passive avoidance and Morris water maze tests in rats: Mechanistic implications for the beneficial effects of the novel atypical antipsychotic lurasidone
2011, Behavioural Brain Research
Citation Excerpt :
Modulation of the 5-HT1A receptor function with selective ligands has also been shown to influence the performance in various tests of learning and memory function in rats. For example, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) facilitated or impaired the performance in the PA test at low or high doses, respectively [9,27], whereas it impaired the water maze performance [6,7,27]. 5-HT1A receptor antagonists such as WAY-100635 and NAD-299, on the other hand, improved the performance in delayed alternation, PA, and radial-arm maze tests [2,27,28,48].
We have previously reported that lurasidone, a novel atypical antipsychotic with potent serotonin 5-HT₇ antagonist and 5-HT_1A partial agonist activities, is superior to other antipsychotics in improving the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801-induced learning and memory impairment in the passive avoidance (PA) and Morris water maze (MWM) tests in rats. In this study, we investigated the effects of selective antagonists of 5-HT₇ and 5-HT_1A receptors (SB-656104-A and WAY-100635, respectively) on MK-801-induced learning and memory impairment in the same tests. In the PA test, either pre-training (3 and 10 mg/kg, p.o.) or post-training (0.3 mg/kg, i.v.) administration of lurasidone significantly reversed the test response impaired by MK-801, consistent with our previous reports. Pre-training administration of either SB-656104-A (10 and 30 mg/kg, i.p.) or WAY-100635 (1 mg/kg, s.c.) also significantly reversed MK-801-induced memory impairment. Furthermore, post-training administration of either SB-656104-A (0.3 mg/kg, i.v.) or WAY-100635 (0.01 mg/kg, i.v.) counteracted the effect of MK-801, which suggested that both 5-HT receptor subtype-selective antagonists could restore the memory consolidation process. In the MWM test, SB-656104-A (3 mg/kg, i.p.) reversed learning impairment induced by MK-801. On the other hand, WAY-100635 (0.3 and 1 mg/kg, i.p.) did not have any effect on the MK-801-induced learning impairment. Taken together, our results showed that 5-HT₇ and 5-HT_1A receptor antagonists mimic the effect of lurasidone in whole or in part, respectively, to reverse MK-801-induced learning and memory impairment, which warrants further investigation of the interaction of lurasidone with these serotonin receptors as a possible mechanism underlying its procognitive effects in these animal models.

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Research reportStimulation of 5-HT1A receptors in the dorsal hippocampus impairs acquisition and performance of a spatial task in a water maze

Abstract

Brain Res.

Eur. J. Pharmacol.

Physiol. Behav.

Pharmacol. Biochem. Behav.

8-Hydroxy-2-(di-n-propylamino)tetralin impairs spatial learning in a water maze: role of postsynaptic 5-HT1A receptors

Br. J. Pharmacol.

Differential modulation of three separate k-conductances in hippocampal CA1 neurons by serotonin

Nature

Research report
Stimulation of 5-HT_1A receptors in the dorsal hippocampus impairs acquisition and performance of a spatial task in a water maze

8-Hydroxy-2-(di-n-propylamino)tetralin impairs spatial learning in a water maze: role of postsynaptic 5-HT_1A receptors