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T A Reader

Publications and source records attributed to T A Reader.

At least 19 recordsLinked to original sources
PubMed2006

Catecholaminergic activation of G-protein coupling in rat spinal cord: further evidence for the existence of dopamine and noradrenaline receptors in spinal grey and white matter.

[35S]GTPgammaS autoradiography of slide-mounted tissue sections was used to examine G-protein coupling in the rat spinal cord, as stimulated by dopamine, the D1 receptor agonist SKF 38393, noradrenaline, and noradrenaline in the presence of the alpha adrenoceptor antagonist, phentolamine. Measurements were obtained from the different laminae of spinal grey and from the dorsal, lateral, and ventral columns of white matter, at cervical, thoracic, and lumbar levels. At every level, there was a relatively strong basal incorporation of GTPgammaS in laminae II-III>lamina IV-X of spinal grey, even in presence of DPCPX to block endogenous activation by adenosine A1 receptors. Dopamine, and to a lesser degree SKF 38393, but not the D2 receptor agonist quinpirole, stimulated G-protein coupling in laminae IV-X. Both dopamine and SKF 38393 also induced a weak but significant activation throughout the white matter. In both grey and white matter, the activation by dopamine was markedly reduced in presence of a selective D1 receptor antagonist. Noradrenaline strongly stimulated coupling throughout the spinal grey at all levels, an effect that was uniformly reduced in the presence of phentolamine. With or without phentolamine, there was also significant stimulation by noradrenaline in the white matter. Under the same experimental conditions, alpha 1, alpha 2, and beta adrenergic receptor agonists failed to activate GTPgammaS incorporation in either grey or white matter. However, in the presence of selective alpha 1 or alpha 2 receptor antagonist, significant reductions of noradrenaline-stimulated GTPgammaS incorporation were observed in both grey and white matter. The beta antagonist propanolol reduced GTPgammaS incorporation in grey matter only. Thus, the results confirmed the existence of D1 dopamine receptors and of alpha 1, alpha 2, and beta adrenergic receptors in the grey matter of rat spinal cord. In white matter, they strongly suggested the presence of dopamine D1, and of alpha 1 and alpha 2 adrenergic receptors on glia and/or microvessels, that might be activated by diffuse transmission in vivo.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2002

Decreased G-protein coupling of serotonin 5-HT(1A) receptors in the brain of 5-HT(1B) knockout mouse.

The firing of central serotonin (5-hydroxytryptamine, 5-HT) neurons and their capacity to release 5-HT are subjected to a receptor-mediated auto-control via 5-HT(1A) and 5-HT(1B) receptors respectively located on the somata/dendrites (5-HT(1A) autoreceptors) and preterminal axon arborizations (5-HT(1B) autoreceptors) of these neurons. To further characterize mutual adaptations of these two receptor subtypes in the absence of one of them, activation of G-protein coupling by agonist was measured and compared to wild-type (WT) in 5-HT(1A) and 5-HT(1B) homozygous knockout (KO) mice. As expected, in WT, the non-selective 5-HT(1A/1B) receptor agonist 5-carboxyamidotryptamine (5-CT) stimulated guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTP(gamma)S) incorporation in many brain regions endowed with one and/or the other receptor. In the respective KOs, no stimulation was measured in regions known to express only or mainly the deleted receptor. In the 5-HT(1A) KOs, the amplitude of G-protein activation in regions endowed with 5-HT(1B) receptors was unchanged by comparison to WT. In the 5-HT(1B) KOs, the magnitude of the 5-CT stimulation was the same as WT in all regions containing 5-HT(1A) receptors, except in the amygdala, where it was significantly lower, even if this region was one of the most strongly activated in the WT. A similar result was obtained in the amygdala of 5-HT(1B) KOs after activation by the selective 5-HT(1A) receptor agonist R-(+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Under these conditions, however, there was in addition a significant lowering of the stimulated (but not basal) [(35)S]GTP(gamma)S incorporation by comparison to WT in all regions endowed with 5-HT(1A) receptors, including the dorsal raphe nucleus. Thus, eventhough agonist radioligand binding to either 5-HT(1A) or 5-HT(1B) receptors is unchanged in the reciprocal KOs, it appears that a compensatory decrease in the efficiency of G-protein coupling to 5-HT(1A) receptors has developed in the 5-HT(1B) mutant. This could represent the first indication of a cross-talk between these two 5-HT receptor subtypes, at least in brain regions where they are co localized in the same neurons.

Animals↗
PubMed2002

Biochemical and autoradiographic studies of the central noradrenergic system in dystonia musculorum mutant mice.

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways leading to ataxia. To determine the consequences of this pathology on the central noradrenergic (NA) system, NA contents were measured by high-performance liquid chromatography (HPLC) in 22 brain regions and spinal cord, while NA transporters, or uptake sites, were evaluated by quantitative ligand binding autoradiography, using [3H]nisoxetine, in wild-type and dt(J)/dt(J) mutant mice. The only significant differences in NA contents between the two genotypes were increased levels in hypothalamus and mesencephalic dopaminergic regions A9/A10 of dt(J)/dt(J) mutants. The dt(J)/dt(J) spinal cord showed a similar result, but its NA content remained unchanged when taking into account its reduced volume. Binding to NA transporters revealed increased densities in sensory nuclei of cranial nerves, granular layer of the cerebellar cortex, as well as in cerebellar-related and basal ganglia structures, such as the lateral cuneate nucleus, pontine nuclei, substantia nigra, pontine reticular formation, median raphe nucleus and superior colliculus. Forebrain regions were relatively unaffected in the dt(J)/dt(J) mutants, although NA transporter densities were higher in piriform cortex, hippocampal subdivisions and ventro-anterior thalamic nucleus. In contrast, densities of NA transporters were decreased in hypothalamic subregions and in two ventrobasal thalamic nuclei. The results are discussed in relation to expression of the dystonin gene in normal brain, cellular defects resulting from the loss of gene transcription in the dt(J)/dt(J) mutation, functional circuits of the central nervous system and some of the phenotypical characteristics of dystonia musculorum mutants.

Animals↗
PubMed2001

Topology of ionotropic glutamate receptors in brains of heterozygous and homozygous weaver mutant mice.

In weaver mice, mutation of a G-protein inwardly rectifying K(+) channel leads to a cerebellar developmental anomaly characterized by granule and Purkinje cell loss and, in addition, degeneration of dopaminergic neurons. To evaluate other deficits, ionotropic glutamate receptors sensitive to N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA) were examined by autoradiography with [(3)H]MK-801, [(3)H]AMPA, and [(3)H]KA. These surveys were carried out in selected areas of cerebral cortex, hippocampus and related limbic regions, basal ganglia, thalamus, hypothalamus, brainstem, and cerebellum from heterozygous (wv/+) and homozygous (wv/wv) weaver mutants, and compared to wild-type (+/+) mice. In wv/+ and wv/wv mutants, NMDA receptor levels were lower in cortical areas, septum, hippocampus, subiculum, neostriatum, nucleus accumbens, superior colliculus, and in the cerebellar granular layer. Densities of KA receptors were lower in cortical areas, hippocampus, limbic system structures, neostriatum, nucleus accumbens, thalamus and hypothalamus, superior and inferior colliculi, and cerebellar cortex of wv/wv mutants. Levels of AMPA receptors in the weaver were higher than in +/+ mice, particularly in somatosensory and piriform cortices and periaqueductal gray of wv/+, and in somatosensory cortex, CA1 field of Ammon's horn and cerebellar granular layer of wv/wv. Abnormal developmental signals, aberrant cellular responses, or a distorted balance between neurotransmitter interactions may underlie such widespread and reciprocal glutamate receptor alterations, while in the case of cerebellar cortex, NMDA receptors are lacking due to a massive disappearance of cerebellar granule cells and some loss of Purkinje neurons.

Animals↗
PubMed2001

Pharmacological aids to locomotor training after spinal injury in the cat.

This Topical Review summarizes some of the work we have done mainly in the cat using agonists and antagonists of various neurotransmitter systems injected intravenously or intrathecally to initiate or modulate the expression of hindlimb locomotion after a spinal lesion at T13. The effects of the same drugs are compared in various preparations: complete spinal, partial spinal or intact cats. This has revealed that there can be major differences in these effects. In turn, this suggests that although the locomotor rhythm might normally be triggered and modulated by the activation of a variety of receptors (noradrenaline, serotonin, glutamate), after spinalization there appears to be a predominance of glutamatergic mechanisms. Recent work also suggests that, in the cat, the integrity of the midlumbar segments is crucial for the expression of spinal locomotion. Taken together, this work raises some hope that a targeted pharmacotherapy with better understood drugs and mode and locus of delivery could become a clinical reality.

2-Amino-5-phosphonovalerate↗
PubMed2001

Effects of chronic antidepressant treatments on 5-HT and NA transporters in rat brain: an autoradiographic study.

Tricyclic antidepressants and serotonin (5-HT) uptake inhibitors rapidly block uptake sites, or transporters; however, their therapeutic effects are only seen after 2-3 weeks of treatment. Thus, direct blockade of 5-HT and noradrenaline (NA) transporters cannot account entirely for their clinical efficacy, and other long-term changes may be involved. Adult Sprague-Dawley rats were treated for 21 days with daily injections of either desipramine, trimipramine, fluoxetine, or venlafaxine; a fifth group that was used as a control, received daily saline injections. Identified cortical areas, hippocampal divisions and nuclei raphe dorsalis, raphe medialis and locus coeruleus were examined by quantitative autoradiography using either [3H]citalopram to label 5-HT transporters, or [3H]nisoxetine for NA uptake sites. Increases in [3H]nisoxetine binding were found in the cingulate, frontal, parietal, agranular insular, entorhinal and perirhinal cortices as well as in the hippocampal divisions CA1, CA3, dentate gyrus and subiculum, and in nucleus raphe dorsalis of trimipramine-treated animals compared to the control rats. Also, densities of NA transporters decreased in temporal cortex, CA2 and nucleus raphe dorsalis in fluoxetine-treated rats as compared to the controls. Also, there was a decrease in NA transporters in the locus coeruleus of the desipramine-treated animals as compared to the densities measured in the control group. Chronic treatment with desipramine or trimipramine, which do not directly inhibit 5-HT uptake, compared to fluoxetine and venlafaxine, lead to increases in 5-HT transporter densities in cingulate, agranular insular and perirhinal cortices. The present study shows differential region-specific effects of antidepressants on 5-HT and NA transporters, leading to distinct consequences in forebrain areas.

Animals↗
PubMed2001

Distribution of serotonin, its metabolites and 5-HT transporters in the neostriatum of Lurcher and weaver mutant mice.

Serotonin (5-HT) uptake sites, or transporters, were measured in the neostriatum (caudate putamen) of wild type (+/+) mice and heterozygous (wv/+) and homozygous (wv/wv) weaver, as well as in heterozygous Lurcher (Lc/+) mutants. These topological surveys were carried out by quantitative ligand binding autoradiography using the uptake site antagonist [3H]-citalopram as a probe of innervation densities in four quadrants of the rostral neostriatum and in two halves of the caudal neostriatum. In addition, tissue concentrations of 5-HT, 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol were measured by high-performance liquid chromatography with electrochemical detection in these neostriatal divisions. In +/+ mice and in Lc/+ mutants there was a dorso-ventral gradient of increasing 5-HT levels, and they exhibited a similar heterogeneity of [3H]-citalopram labeling. In contrast, the gradients of 5-HT concentrations and [3H]-citalopram binding disappeared in the weaver mutants, suggesting a rearrangement of the 5-HT innervation. This reorganization of the 5-HT system in the neostriatum was more obvious in the wv/wv and is compatible with the hypothesis that the postnatal dopaminergic deficiencies that characterize weaver mutants lead to a sprouting of fibers and thus constitute a genetic model of dopaminergic denervation that leads to a 5-HT hyperinnervation.

Animals↗
PubMed2001

Distribution of glutamate receptors of the NMDA subtype in brains of heterozygous and homozygous weaver mutant mice.

In weaver mice, mutation of an G-protein inwardly rectifying K+ channel leads to a cerebellar developmental anomaly characterized by granule and Purkinje cell loss and, in addition, degeneration of dopaminergic neurons. To evaluate other deficits, glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) were examined by autoradiography with [3H]MK-801 in 36 brain regions from heterozygous (wv/+) and homozygous (wv/wv) weaver mutants, and compared to wild type (+/+) mice. In wv/+ and wv/wv mutants labelling decreased in cortical regions, septum, hippocampus, subiculum, neostriatum, nucleus accumbens, superior colliculus and in the cerebellar granular layer. The reductions in [3H]MK-801 binding were particularly specific in the cerebellar granular layer of wv/wv mutants, but an ubiquitous altered NMDA receptor topology was revealed in other brain regions. Abnormal developmental signals, or aberrant cellular responses, may underlie widespread NMDA receptor reductions, while in cerebellar cortex they could be lacking due to the massive loss of cerebellar granule cells.

Animals↗
PubMed2001

Regional changes in density of serotonin transporter in the brain of 5-HT1A and 5-HT1B knockout mice, and of serotonin innervation in the 5-HT1B knockout.

5-HT1A knockout (KO) mice display an anxious-like phenotype, whereas 5-HT1B KOs are over-aggressive. To identify serotoninergic correlates of these altered behaviors, autoradiographic measurements of 5-HT1A and 5-HT1B serotonin (5-HT) receptors and transporter (5-HTT) were obtained using the radioligands [3H]8-OH-DPAT, [125I]cyanopindolol and [3H]citalopram, respectively. By comparison to wild-type, density of 5-HT1B receptors was unchanged throughout brain in 5-HT1A KOs, and that of 5-HT1A receptors in 5-HT1B KOs. In contrast, decreases in density of 5-HTT binding were measured in several brain regions of both genotypes. Moreover, 5-HTT binding density was significantly increased in the amygdalo-hippocampal nucleus and ventral hippocampus of the 5-HT1B KOs. Measurements of 5-HT axon length and number of axon varicosities by quantitative 5-HT immunocytochemistry revealed proportional increases in the density of 5-HT innervation in these two regions of 5-HT1B KOs, whereas none of the decreases in 5-HTT binding sites were associated with any such changes. Several conclusions could be drawn from these results: (i) 5-HT1B receptors do not adapt in 5-HT1A KOs, nor do 5-HT1A receptors in 5-HT1B KOs. (ii) 5-HTT is down-regulated in several brain regions of 5-HT1A and 5-HT1B KO mice. (iii) This down-regulation could contribute to the anxious-like phenotype of the 5-HT1A KOs, by reducing 5-HT clearance in several territories of 5-HT innervation. (iv) The 5-HT hyperinnervation in the amygdalo-hippocampal nucleus and ventral hippocampus of 5-HT1B KOs could play a role in their increased aggressiveness, and might also explain their better performance in some cognitive tests. (v) These increases in density of 5-HT innervation provide the first evidence for a negative control of 5-HT neuron growth mediated by 5-HT1B receptors.

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

Comparison of the effect of intrathecal administration of clonidine and yohimbine on the locomotion of intact and spinal cats.

Several studies have shown that noradrenergic mechanisms are important for locomotion. For instance, L-dihydroxyphenylalanine (L-DOPA) can initiate "fictive" locomotion in immobilized acutely spinalized cats and alpha(2)-noradrenergic agonists, such as 2,6,-dichloro-N-2-imidazolidinylid-enebenzenamine (clonidine), can induce treadmill locomotion soon after spinalization. However, the activation of noradrenergic receptors may be not essential for the basic locomotor rhythmicity because chronic spinal cats can walk with the hindlimbs on a treadmill in the absence of noradrenergic stimulation because the descending pathways are completely severed. This suggests that locomotion, in intact and spinal conditions, is probably expressed and controlled through different neurotransmitter mechanisms. To test this hypothesis, we compared the effect of the alpha(2) agonist, clonidine, and the antagonist (16 alpha, 17 alpha)-17-hydroxy yohimbine-16-carboxylic acid methyl ester hydrochloride (yohimbine), injected intrathecally at L(3)--L(4) before and after spinalization in the same cats chronically implanted with electrodes to record electromyograms (EMGs). In intact cats, clonidine (50-150 microg/100 microl) modulated the locomotor pattern slightly causing a decrease in duration of the step cycle accompanied with some variation of EMG burst amplitude and duration. In the spinal state, clonidine could trigger robust and sustained hind limb locomotion in the first week after the spinalization at a time when the cats were paraplegic. Later, after the spontaneous recovery of a stable locomotor pattern, clonidine prolonged the cycle duration, increased the amplitude and duration of flexor and extensor bursts, and augmented the foot drag at the onset of swing. In intact cats, yohimbine at high doses (800--1600 microg/100 microl) caused major walking difficulties characterized by asymmetric stepping, stumbling with poor lateral stability, and, at smaller doses (400 microg/100 microl), only had slight effects such as abduction of one of the hindlimbs and the turning of the hindquarters to one side. After spinalization, yohimbine had no effect even at the largest doses. These results indicate that, in the intact state, noradrenergic mechanisms probably play an important role in the control of locomotion since blocking the receptors results in a marked disruption of walking. In the spinal state, although the receptors are still present and functional since they can be activated by clonidine, they are seemingly not critical for the spontaneous expression of spinal locomotion since their blockade by yohimbine does not impair spinal locomotion. It is postulated therefore that the expression of spinal locomotion must depend on the activation of other types of receptors, probably related to excitatory amino acids.

Adrenergic alpha-Agonists↗
PubMed2000

Central serotonin system in Dystonia musculorum mutant mice: biochemical, autoradiographic and immunocytochemical data.

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5-HT transporters were quantified by [(3)H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dt(J)/dt mice, and decreases in the ventral tegmental area (-13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice.

5-Hydroxytryptophan↗
PubMed2000

Effects of buspirone on brain indoleamines and catecholamines in wild-type mice and Lurcher mutants.

The effects of a chronic serotoninergic stimulation on brain monoamine levels and metabolism were studied in wild-type (+/+) mice and Lurcher (Lc/+) mutants. Endogenous serotonin, dopamine, noradrenaline and some of their major metabolites were measured in the frontal cortex, neostriatum, thalamus, brainstem, cerebellum and spinal cord. In +/+ mice, buspirone (1 mg/kg; i.p.) treatment during 40 days increased indoleamines, albeit with moderate changes in the ratios between tissue serotonin metabolites and endogenous serotonin, augmented noradrenaline contents in the spinal cord, and caused elevations of dopamine metabolites in most regions. In Lc/+ mutants, the effects of buspirone were attenuated, but higher L-tryptophan and indoleamine levels, suggest a storage of serotonin in a non-releasable compartment. In the hypoplastic Lc/+ cerebellum, indoleamine content was accrued, but with a decreased [serotonin metabolites]/[serotonin] ratio, indicating that the reorganized nerve terminals in Lc/+ mutants although they can synthesize and accumulate serotonin, may not utilize it efficiently in synaptic transmission.

Animals↗
PubMed2000

Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum.

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with L-tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after L-tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, L-tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Dopamine D(1) and D(2) receptors in the forebrain of dystonia musculorum mutant mice: an autoradiographic survey in relation to dopamine contents.

Dystonia musculorum (dt(J)/dt(J)) mutant mice suffer from a degeneration of spinocerebellar tracts as well as a dystrophy of peripheral sensory tracts. This neurological mutant has been proposed as an animal model of human cerebellar ataxia, in particular of the Friedreich's type; thus, it was deemed of interest to examine the endogenous contents of dopamine (DA) and metabolites as well as the distribution of DA receptors of the D(1) and D(2) subtypes, in order to delimit the biochemical characteristics of this pathological disorder, and determine an eventual dopaminergic dysfunction in this mutant. Tissue DA and its major metabolites 3, 4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine were measured by HPLC coupled to electrochemical detection in six cortical regions, in four divisions of rostral neostriatum and two halves of caudal neostriatum, as well as in olfactory bulb, nucleus accumbens, septum, amygdala, hippocampus, thalamus, hypothalamus, brainstem, cerebellum, substantia nigra, and ventral tegmental area. The only significant difference between dt(J)/dt(J) mice and wild-type controls was an increase in hypothalamic DA contents (+47%). Quantitative autoradiography with [(3)H]SCH23390 and [(3)H]raclopride, to label D(1) and D(2) receptors, respectively, revealed only moderate changes in receptor densities in a few localized regions. In dt(J)/dt(J) mutants, D(1) receptor numbers were found to be higher in thalamus (+27%) as well as in the medio-dorsal (+16%) and in the latero-dorsal (+16%) quadrants of rostral neostriatum, while D(2) receptor densities were greater in the medio-ventral (+32%) and the latero-dorsal (+17%) quadrants. The present results indicate an overall conservation of dopaminergic functions, albeit the few localized sites of increased D(1) and D(2) receptor densities, and that are seemingly independent of the DA innervation pattern, as revealed by the tissue measurements of DA and metabolites. They also rule out a major pathology linked to deficits in DA neurotransmission, and validate this mutant as an animal model of human cerebellar ataxia, probably of the Friedreich type.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice.

Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Autoradiography of glutamate receptor binding in adult Lurcher mutant mice.

The mutation Lurcher, resulting from a gain of malfunction of the delta2 glutamate receptor expressed specifically by cerebellar Purkinje cells, causes a primary total loss of these neurons of the cerebellar cortex, as well as the secondary degeneration of cerebellar granule and inferior olive neurons. The distributions of glutamate receptors sensitive to amino-methylisoxazole-propionic acid (AMPA), to kainic acid (KA), and to N-methyl-D-aspartic acid (NMDA) as well as metabotropic sites (MET1 and MET2) were examined in wild type and Lurcher mice by quantitative autoradiography. This study was undertaken to determine the gene effect on the distribution of the various glutamate receptor subtypes, as well as how the cerebellar lesion affects the glutamatergic system in other brain regions. In cerebellum, there were postsynaptic AMPA and metabotropic receptors on Purkinje cells, postsynaptic NMDA receptors on granule cells, as well as KA receptors on granule cells or on parallel fibers. Taking into account surface areas, binding to all receptor subtypes was lower in the cerebellar cortex of Lurcher mutants than in wild type mice, while in the deep cerebellar nuclei only KA receptors were diminished. In other brain regions, the alterations followed always the same pattern characterized by a decrease of NMDA and KA receptors but with an increase of AMPA sites; these reciprocal changes were seen in thalamus. neostriatum, limbic regions, and motor cerebral cortical regions. Comparisons of glutamate receptor distribution in Lurcher mutants and in human autosomal cerebellar ataxia may permit further understanding of the role of glutamate-induced toxicity on neuronal death in these heredo-degenerative diseases.

Animals↗
PubMed1999

Autoradiographic study of alpha1- and alpha2-noradrenergic and serotonin1A receptors in the spinal cord of normal and chronically transected cats.

Serotoninergic and noradrenergic drugs have been shown to initiate and/or modulate locomotion in cats after spinal cord transection and in patients suffering from spinal cord injuries. To establish a firmer basis for locomotor pharmacotherapy, the distribution of alpha1- and alpha2-noradrenergic and serotonin1A (5-HT1A) receptors was examined in the spinal cord of control cats and of from animals with spinal cord transection at T13 some weeks or months previously. In control cats, the highest levels of alpha1-noradrenergic receptors, labeled with [3H]prazosin, were found in laminae II, IX, and X. The alpha2-noradrenergic receptors, labeled with [3H]idazoxan, were found mainly in laminae II, III, and X, with moderate densities in lamina IX. After spinal transection, both receptors did not change in segments above the lesion. At 15 and 30 days after spinal transection, binding significantly increased in laminae II, III, IV, and X for alpha2 and in laminae I, II, III, and IX for alpha1 receptors in lumbar segments. For longer survival times, binding densities returned to near control values. The 5-HT1A receptors, labeled with [3H] 8-hydroxy-dipropylaminotetralin, were found mainly in laminae I-IV and X. After spinal transection, binding significantly increased only in laminae II, III, and X of lumbar segments at 15 and 30 days. Thereafter, binding returned to control values. The pronounced upregulation of different monoaminergic receptors observed in the lumbar region in the first month after spinal transection suggests that these receptors may be important during the period when cats normally recover functions such as locomotion of the hindlimbs.

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