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Biomedical subjects

L Segu

Publications and source records attributed to L Segu.

At least 19 recordsLinked to original sources
PubMed2004

Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus.

Adenylyl cyclase (AC) subtypes have been implicated in memory processes and synaptic plasticity. In the present study, the effects of aging and learning on Ca2+/calmodulin-stimulable AC1, Ca2+-insensitive AC2 and Ca2+/calcineurin-inhibited AC9 mRNA level were compared in the dorsal hippocampus of young-adult and aged C57BL/6 mice using in situ hybridization. Both AC1 and AC9 mRNA expression were downregulated in aged hippocampus, whereas AC2 mRNA remained unchanged, suggesting differential sensitivities to the aging process. We next examined AC mRNA expression in the hippocampus after spatial learning in the Morris water maze. Acquisition of the spatial task was associated with an increase of AC1 and AC9 mRNA levels in both young-adult and aged groups, suggesting that Ca2+-sensitive ACs are oppositely regulated by aging and learning. However, aged-trained mice had reduced AC1 and AC9, but greater AC2, mRNA levels relative to young-trained mice and age-related learning impairments were correlated with reduced AC1 expression in area CA1. We suggest that reduced levels of hippocampal AC1 mRNA may greatly contribute to age-related defects in spatial memory.

Adenylyl Cyclases↗
PubMed2003

Serotonin 1B knockout mice exhibit a task-dependent selective learning facilitation.

Serotonin 1B knockout (KO) mice exhibit better spatial reference memory performance in the Morris water maze than their wild type (WT) controls. The present study was aimed at dissecting the underlying cognitive bases of this facilitation using a stepwise water maze paradigm. The performance of KO mice did not differ from WT in a single start-goal task, nor when using two opposite starts. However, KO mice exhibited better performance in stages requiring cognitive flexibility or the higher level of spatial navigation planning (standard version). In a short-term memory version of the task, no such genotype effect was observed, confirming our previous findings. These results suggest that the serotonin 1B receptor gene deletion selectively enhances learning performance when the cognitive requirement of the task is elevated.

Animals↗
PubMed2001

Region-specific decrease in 5-HT1A and 5-HT1B binding sites after intra-hippocampal ibotenic acid injections in the rat.

The cellular location of 5-HT1A and 5-HT1B binding sites in the hippocampus was investigated using a stereotaxic unilateral lesion of the CA1 field by ibotenic acid, followed by autoradiography on brain sections with the specific ligands [3H]8-OH-DPAT and S-CM-G[125I]TNH2, respectively. As compared to the contralateral side of the lesion, the ipsilateral side exhibited a decrease in the density of 5-HT1A binding sites in the strata oriens and radiatum of CA1, and of 5-HT1B binding sites in the dorsal subiculum and stratum oriens of CA1. The results demonstrate that 5-HT1A binding sites are located on dendrites whereas 5-HT1B binding sites are located on axon terminals of CA1 pyramidal cells.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Exploration, anxiety, and spatial memory in transgenic anophthalmic mice.

Contradictory results are found in the literature concerning the role of vision in the perception of space or in spatial navigation, in part because of the lack of murine models of total blindness used so far. The authors evaluated the spatial abilities of anophthalmic transgenic mice. These mice did not differ qualitatively from their wild-type littermates in general locomotor activity, spontaneous alternation, object exploration, or anxiety, but their level of exploratory activity was generally lower. In the spatial version of the water maze, they displayed persistent thigmotaxic behavior and showed severe spatial learning impairments. However, their performances improved with training, suggesting that they may have acquired a rough representation of the platform position. These results suggest that modalities other than vision enable some degree of spatial processing in proximal and structured spaces but that vision is critical for accurate spatial navigation.

Animals↗
PubMed2000

Role of serotonin in memory impairment.

As a result of its presence in various structures of the central nervous system serotonin (5-HT) plays a role in a great variety of behaviours such as food intake, activity rythms, sexual behaviour and emotional states. Despite this lack of functional specialization, the serotonergic system plays a significant role in learning and memory, in particular by interacting with the cholinergic, glutamatergic, dopaminergic or GABAergic systems. Its action is mediated via specific receptors located in crucial brain structures involved in these functions, primarily the septo-hippocampal complex and the nucleus basalis magnocellularis (NBM)-frontal cortex. Converging evidence suggests that the administration of 5-HT2A/2C or 5-HT4 receptor agonists or 5-HT1A or 5-HT3 and 5-HT1B receptor antagonists prevents memory impairment and facilitates learning in situations involving a high cognitive demand. In contrast, antagonists for 5-HT2A/2C and 5-HT4, or agonists for 5-HT1A or 5-HT3 and 5-HT1B generally have opposite effects. A better understanding of the role played by these and other serotonin receptor subtypes in learning and memory is likely to result from the recent availability of highly specific ligands, such as 5-HT1A, 5-HT1B, 5-HT2A receptor antagonists, and new molecular tools, such as gene knock-out mice, especially inducible mice in which a specific genetic alteration can be restricted both temporally and anatomically.

Aging↗
PubMed1999

5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze.

In an attempt to characterize the contribution of the 5-HT1B receptor to behavior, 5-HT1B knock-out (KO) mice were subjected to a battery of behavioral paradigms aimed at differentiating various components of cognitive and emotional behaviors. In an object exploration task, wild-type (WT) and 5-HT1B KO mice did not differ in locomotor activity. 5-HT1B KO mice, however, displayed lower thigmotaxis (an index of anxiety) associated with a higher level of object exploratory activity, but no genotype differences were observed in the elevated plus maze. 5-HT1B KO mice also displayed a lack of exploratory habituation. In the spatial version of the Morris water maze, 5-HT1B KO mice showed higher performances in acquisition and transfer test, which was not observed in the visual version of the task. No genotype differences were found in contextual fear conditioning, because both WT and 5-HT1B KO mice were able to remember the context where they had received the aversive stimulus. The deletion of the 5-HT1B receptor, associated with appropriate behavioral paradigms, thus allowed us to dissociate anxiety from response to novelty, and perseverative behavior (lack of habituation) from adaptive behavioral inhibition underlying cognitive flexibility (transfer stage in the water maze). The deletion of the 5-HT1B receptor did not result in significant developmental plasticities for other major 5-HT receptor types but may have influenced other neurotransmission systems. The 5-HT1B receptor may be a key target for serotonin in the modulation of cognitive behavior, particularly in situations involving a high cognitive demand.

Analysis of Variance↗
PubMed1999

Serotonin receptors and cognitive behaviour--an update.

The serotonergic system appears to play a role in behaviors that involve a high cognitive demand and in memory improvement or recovery from an impaired cognitive performance. This is made evident after administration of 5-HT(2A/2C), and 5-HT4 receptor agonists, or 5-HT1A, 5-HT3 and probably 5-HT1B receptor antagonists. These serotonin receptor subtypes are localized on 'cognitive' pathways, with the hippocampus and frontal cortex as the main target structures. A better understanding of the role played in cognition by these and other serotonin receptor subtypes is likely to result from the recent availability of highly specific ligands such as 5-HT1A, 5-HT1B, and 5-HT2A receptor antagonists, and new molecular tools such as gene knock-out mice, especially inducible mice for which the genetic alteration can be restricted both temporally and anatomically.

Journal Article↗
PubMed1998

Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence.

The serotonin (5-HT) transporter (5-HTT) is known to play a role in depression and many 5-HT related diseases, and is the target site for drugs of abuse, such as cocaine, MDMA, and methamphetamine. The major role of the 5-HTT has long been considered to be to inactivate serotonin transmission through the elimination of serotonin at release sites. However, immunocytochemistry using an antibody against the N-terminal of the 5-HTT at the light microscopic (LM) level indicates that the 5-HTT is associated not only with 5-HT varicosities but also with axons. Electron microscopy (EM) reveals that the majority of the 5-HTTs exist on the axolemma outside the synaptic junctions. In studying whether axonal 5-HTTs are involved in the uptake of 5-HT, we found with autoradiography that [3H]citalopram bound to all major 5-HT fibers, not only in the terminal regions, but also in 5-HT axonal bundles such as the cingulum bundle and medial forebrain bundle. Furthermore, voltammetry recordings indicated that serotonin axonal bundles were actively engaged in high affinity serotonin uptake. The evidence indicates that 5-HTTs on 5-HT axons away from the synapse are likely to be functional in a manner similar to the terminal 5-HTT for serotonin uptake. It also suggests that the role of the 5-HTT may not only be for the termination of synaptic transmission, but also for the regulation of 5-HT through extrasynaptic (volume) transmission. Our findings may also impact the understanding of the sites of action of selective serotonin reuptake inhibitors and drug entry into serotonin neurons via the numerous axonal sites.

Animals↗
PubMed1998

Differential effects of serotonin (5-HT) lesions and synthesis blockade on neuropeptide-Y immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C receptor binding sites in the rat cerebral cortex.

The present study was aimed at comparing the effects of serotonin (5-HT) synthesis blockade using chronic administration of p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine injections of variable volume (3 vs. 6 microl) on the density of NPY immunoreactive (Ir) neurons and binding of [3H]8-OH-DPAT, S-CM-G[125I]TNH2 and [125I]DOI to 5-HT1A, 5-HT1B/1D, and 5-HT2A/2C receptors in rat cortical regions. Three weeks after large but partial (89% depletion in 5-HT tissue concentration) lesions of 5-HT neurons no changes in neither NPY immunoreactivity nor 5-HT receptor binding were detected. The complete 5,7-DHT lesions produced increases in the number of NPY-Ir neurons in the upper regions of the cingular (134%), frontal (140%) and parietal cortex (48%) and corresponding decreases in 5-HT2A/2C binding (16-26%). No changes in 5-HT1A and 5-HT1B/1D binding were observed after lesions of this kind. After PCPA treatment, decreases in NPY-Ir neurons density (22-40%) and increases in 5-HT1A and 5-HT1B/1D receptor binding sites (20-50%) were distributed in both upper and deeper cortical regions. The lack of effect of the partial lesion suggests that spared 5-HT neurons may exert compensatory mechanisms up to a large extent. The changes in NPY immunoreactivity and 5-HT2A/2C binding detected in the upper regions of the cortex after complete 5-HT lesions probably result from local cellular rearrangements, whereas blocking 5-HT synthesis has more widespread influence on NPY neurons and on 5-HT1A and 5-HT1B/1D receptor subtypes. Moreover, decreases in DOPAC concentrations detected only after complete lesions suggest that the involvement of catecholaminergic transmission may also differentiate 5,7-DHT and PCPA treatments. Altogether, these data suggest that different receptor subtypes might be involved in 5-HT-NPY relationships.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Selective increases in serotonin 5-HT1B/1D and 5-HT2A/2C binding sites in adult rat basal ganglia following lesions of serotonergic neurons.

Quantitative autoradiography was used to examine possible adaptive changes in serotonin 5-HT1B/1D and 5-HT2A/2C receptor binding sites in adult rat basal ganglia, after partial or severe lesions of serotonergic neurons produced by intraraphe injections of variable amounts of 5,7-dihydroxytryptamine. In controls, the 5-HT1B/1D sites labeled with S-CM-G[125I]TNH2 were evenly distributed in the core and the shell of the nucleus accumbens. The density of 5-HT1B/1D sites was higher in the ventral than dorsal part of the striatum and no regional differences were detected along the rostrocaudal axis of the structure. The 5-HT2A/2C sites labeled with [125I]DOI were preferentially distributed in the mediodorsal striatum and higher densities were detected in the shell than core of the nucleus accumbens. Following 5,7-dihydroxytryptamine injections, there were no changes in binding of either receptor subtype after partial lesions entailing 80-90% 5-HT depletions. After severe 5-HT depletions (over 95%), large increases in 5-HT1B/1D binding were observed in the substantia nigra (78%), but no changes took place in the globus pallidus. Increases in 5-HT1B/1D binding were also detected in the shell of the nucleus accumbens (27%). Similar sized increases in 5-HT2A/2C binding (22%) were restricted to the medial striatum. The present results suggest a preferential association between 5-HT1B/1D receptors and the striatonigral neurons containing substance P, as indicated by the striatal distribution of these receptors and their selective increases in the substantia nigra after severe 5-HT deprivation. We recently proposed a similar relationship between the 5-HT4 receptors and the striatopallidal neurons containing met-enkephalin. Moreover, the increases in 5-HT1B/1D binding in the substantia nigra and in the shell of the nucleus accumbens reinforce the view of an implication of this receptor subtype in motor functions. In contrast, the prominent increases in 5-HT2A/2C binding after severe 5-HT deprivation as restricted to the medial region of the striatum and suggest up-regulation of most probably 5-HT2C receptors in a region implicated in cognitive functions.

5,7-Dihydroxytryptamine↗
PubMed1997

5-Hydroxytryptamine1B receptors modulate the effect of cocaine on c-fos expression: converging evidence using 5-hydroxytryptamine1B knockout mice and the 5-hydroxytryptamine1B/1D antagonist GR127935.

Serotonergic transmission has been suggested to modulate the effects of cocaine. However, the specific receptors and brain structures underlying this phenomenon have not been identified. To test the possible contribution of the 5-hydroxytryptamine1B (5-HT1B) receptor, we studied the induction of the immediate-early gene c-fos elicited by cocaine in knockout mice lacking this receptor. 5-HT1B knockout mice display a markedly reduced effect of cocaine on c-fos induction in different brain structures, most notably in the striatum. In addition, the administration to wild-type mice of the 5-HT1B receptor agonist RU24969 results in a striatal induction of c-fos expression very similar to that induced by cocaine in its time course, cellular and anatomical distribution, and pharmacology. Here, we also report the ability of a 5-HT1D receptor antagonist, GR127935, to antagonize 5-HT1B receptors in vivo. Finally, when administered to wild-type mice, GR127935 reduces the increase in striatal c-fos expression elicited by cocaine. These converging lines of evidence obtained with the knockout mice and 5-HT(1B/1D) antagonist indicate that cocaine acts as an indirect agonist of 5-HT1B receptors in vivo and demonstrate that activation of 5-HT1B receptors contributes to the cellular responses elicited by cocaine.

Animals↗
PubMed1996

Subcellular localization of 5-HT1B binding sites in the stratum griseum superficiale of the rat superior colliculus: An electron microscopic quantitative autoradiographic study.

Previous works have shown the potential location of 5-HT1B binding sites on the retinal afferents to the superior colliculus in the rat. In order to confirm this hypothesis, the distribution of 5-HT1B binding sites, labelled by S-CM-G[125I]TNH2, was analysed by quantitative autoradiography at both light and electron microscopic levels in the upper stratum griseum superficiale (SGS) of the superior colliculus, 5 days after unilateral eye ablation. At the light microscopic level, no 5-HT1B sites were found to be associated with capillaries, glial, or neuronal cell bodies, but the fine neuropile was specifically labelled. At the electron microscopic level, the quantitative analysis performed with 50% probability circles showed that classical dendritic processes, presynaptic dendritic processes, and processes containing flat synaptic vesicles were not labelled. In the SGS ipsilateral to the eye ablation, silver grains were specifically associated with processes containing round and pleomorphic vesicles and with non-synaptic contacts between those processes and dendritic or other non identified neuronal processes. In the deafferented contralateral SGS, 5-HT1B receptors were associated with degenerating retinal terminals, with processes containing round vesicles and with non-synaptic contacts between those two tissue compartments. This is the first direct demonstration of the existence of 5-HT1B receptors in non-synaptic contacts and in non-serotonergic terminals. The existence of 5-HT1B terminal heteroreceptors localised on primary visual afferents shows that serotonin might modulate the transmission of visual messages to the superior colliculus.

Animals↗
PubMed1996

5-HT1B receptor knock out--behavioral consequences.

Serotonin is a neuromodulator that is involved in a number of mood disorders such as depression, anxiety and impulsive violence. In an attempt to dissect the contribution of individual 5-HT receptor subtypes to behavior, we have generated by homologous recombination, mutant mice lacking the 5-HT1B receptor. These mice did not exhibit any obvious developmental or behavioral defect. However, the hyperlocomotor effect of the 5-HT1A/1B agonist, RU 24969 was completely absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, isolated mutant mice attacked the intruder faster and more intensely than wild-type mice, suggesting an involvement of 5-HT1B receptors in the modulation of aggressive behavior. These data might be related to the fact that a class of 5-HT1 agonists, termed serenics, have anti-aggressive properties, and with the findings that certain impulsive aggressive behaviors are associated with deficits in central serotonin.

Aggression↗
PubMed1995

Distractibility and locomotor activity in rat following intra-collicular injection of a serotonin 1B-1D agonist.

The superior colliculus (SC) is thought to be the decision center for reactions to novel and/or moving stimuli in the peripheral visual field. Serotonin 1B (5-HT1B) receptors were previously demonstrated to be located on collicular axon terminals of retinal ganglion cells and their activation might depress afferent inputs from the retina. The effects of intra-collicular injections of 5-HT1 drugs on distractibility were studied in hooded rats trained to run toward illuminated targets for a food reward in a 2-choice runway. 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT), a 5-HT1A receptor agonist, RU 24969, a mixed 5-HT1A and 5-HT1B agonist, serotonin-O-carboxymethylglycyltyrosinamide (S-CM-GTNH2), a mixed 5-HT1B and 5-HT1D receptor agonist and saline (control) were alternately injected. Following the S-CM-GTNH2 treatment alone, animals exhibited an erratic running style, involving side-to-side movements of the head, without change in the overall accuracy of their locomotor trajectories, but with substantial decrease in their running speed. When distracting peripheral lights were introduced at the mid-points of the animals' run, in the weaker distracting condition (unilateral distractor) only, distraction indexes were found lower following the S-CM-GTNH2 treatment than following the other drug or saline treatments. It is concluded that serotonin, via 5-HT1B-1D receptors, may induce an elevation of the visual distractibility threshold by modulating directly the transmission of the primary visual signal.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Serotonin 1B receptor regulation after dorsal subiculum deafferentation.

The subiculum may be the key structure in the transfer of relevant processed information from the hippocampal formation to cortical areas. We investigated the location of the serotonin 1B receptor (5-HT1B) in the hippocampus with the specific ligand serotonin-O-carboxymethyl-glycyl[125I]tyrosinamide in rat brain sections using in vitro autoradiography. A high density of 5-HT1B binding sites was found in the dorsal subiculum (DS), in the lacunosum moleculare, and in the most dorsal layer of the stratum oriens of the CA1 field. CA1 pyramidal neurons that contain 5-HT1B mRNA project primarily to the DS. We interrupted the pyramidal CA1 axons unilaterally by a stereotaxic knife cut. Histological analysis showed that the lesion was restricted to a trial of cells lost between CA1 and DS. Specific 5-HT1B binding site density was decreased in the DS on the ipsilateral side of the lesion compared to the contralateral side. We conclude that 5-HT1B receptors are located on CA1 pyramidal axon terminals in the DS. Serotonin, acting on these receptors, should inhibit CA1 neurotransmitter release and, in this way, modulate subicular functions.

Animals↗
PubMed1994

Impairment of serotoninergic transmission is followed by adaptive changes in 5HT1B binding sites in the rat suprachiasmatic nucleus.

Serotonin1B (5-HT1B) receptor binding in the suprachiasmatic nucleus (SCN) following impairment of serotoninergic transmission was studied by quantitative autoradiography. Serotonin (5-HT) denervation with 5,7-dihydroxytryptamine (5,7-DHT) caused a significant increase in the density of 5-HT1B receptors in both the ventral (62%) and dorsal (53%) parts of the SCN as early as 3 days after axotomy. The magnitude of this increase did not differ 3, 15 or 21 days post-lesion. An up-regulation of 5-HT1B receptors with similar magnitude was obtained in the two parts of the SCN after inhibition of 5-HT synthesis by chronic parachlorophenylalanine treatment. In this case, up-regulation was shown to be reversible after restoration of 5-HT synthesis with L-5-hydroxytryptophan. These results indicate that 5-HT1B receptor density in the SCN was inversely correlated with 5-HT levels. These plastic properties exhibited by 5-HT1B receptors in the SCN are discussed in relation to the mode of 5-HT transmission and possible localization of the receptors onto the main chemically defined cell populations of the nucleus.

5,7-Dihydroxytryptamine↗
PubMed1994

Enhanced aggressive behavior in mice lacking 5-HT1B receptor.

The neuromodulator serotonin (5-hydroxytryptamine, 5-HT) has been associated with mood disorders such as depression, anxiety, and impulsive violence. To define the contribution of 5-HT receptor subtypes to behavior, mutant mice lacking the 5-HT1B receptor were generated by homologous recombination. These mice did not exhibit any obvious developmental or behavioral defects. However, the hyperlocomotor effect of the 5-HT1A/1B agonist RU24969 was absent in mutant mice, indicating that this effect is mediated by 5-HT1B receptors. Moreover, when confronted with an intruder, mutant mice attacked the intruder faster and more intensely than did wild-type mice, suggesting the participation of 5-HT1B receptors in aggressive behavior.

Aggression↗