Biomedical subjects

I Seif

Publications and source records attributed to I Seif.

At least 19 recordsLinked to original sources

PubMed2006

Acquisition and extinction of a conditioned passive avoidance reflex in mice with genetic knockout of monoamine oxidase A.

We report here the results obtained from comparative analysis of learning and the dynamics of extinction of a conditioned passive avoidance response in mice with genetic knockout of monoamine oxidase A (MAO A) and the progenitor line C3H. Mice of both lines acquired the conditioned passive avoidance reaction efficiently. Mice with genetic knockout of MAO A were characterized by prolonged retention of reproduction of the memory trace, as compared with rapid extinction in C3H mice. Smaller numbers of transfers, and vertical rearings on days 7-13 and the numbers of glances into and rom the dark sector on days 11-13 of extinction in MAO A-knockout mice appear to reflect their more marked fear reactions when confronted with the "dangerous" sector, along with increased anxiety, these facilitating longer-lasting retention of the memory trace.

Analysis of Variance↗

PubMed2005

Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice.

BACKGROUND: Serotonin (5-hydroxytryptamine; 5-HT) overproduction is responsible for cardiac valvular disease in patients with carcinoid tumors. Reduced 5-HT inactivation is one proposed mechanism of the valvulopathy observed in individuals treated with the appetite suppressants fenfluramine and phentermine. One key protein limiting systemic availability of 5-HT is the 5-HT transporter (5-HTT) expressed by platelets and pulmonary vascular cells; 5-HTT is responsible for 5-HT uptake and subsequent inactivation of the amine passing through the lung. Here we investigated whether 5-HTT-deficient (5-HTT-KO) mice developed structural and/or functional cardiac abnormalities and valvulopathy. METHODS AND RESULTS: Cardiac endothelial cells expressed large amounts of 5-HTT in wild-type mice. 5-HTT deficiency appeared to be associated with marked interstitial, perivascular, and valvular fibrosis as evidenced by staining of cardiac collagen in 5-HTT-KO mice. Histological analysis provided evidence for valvulopathy characterized by valvular hyperplasia and prominent fibrosis at the attachment site and base of the leaflets. Echocardiography revealed an increase in left ventricular lumen diameter and a decrease in left ventricular diameter fractional shortening. Although 5-HT1B receptors mediated the 5-HT-induced collagen secretion by human cardiac myofibroblasts, the contribution of this receptor type to valvulopathy was ruled out because double-KO mice deficient in both 5-HTT and 5-HT1B receptors showed the same cardiac alterations as 5-HTT-KO mice. CONCLUSIONS: The present results establish a link between 5-HTT and the development of cardiac fibrosis and valvulopathy in vivo. 5-HTT-KO mice represent an especially relevant model for studying the mechanisms by which 5-HT induces valvulopathy.

Animals↗

PubMed2003

Monoaminergic control of vasopressin and VIP expression in the mouse suprachiasmatic nucleus.

We studied the effects of serotonin and noradrenaline on the expression of arginine-vasopressin (AVP) and vasoactive intestinal peptide (VIP) in the suprachiasmatic nucleus (SCN). We used transgenic Tg8 mice knockout for the MAO-A (monoamine oxidase A) gene, which are characterized by increased amounts of serotonin and noradrenaline in brain compared to wild-type mice (C3H). The MAO-A deficiency caused an increase in AVP and VIP expression (determined by immunohistochemistry, enzyme immunoassay, and in situ hybridization) compared to C3H mice. The number of peptidergic neurons was also increased. Inhibiting serotonin or noradrenaline synthesis in Tg8 mice by the administration of parachlorophenylalanine or alpha-methylparatyrosine, respectively, the amounts of AVP, VIP and their mRNAs were decreased, but not the number of peptidergic neurons. This study indicates that serotonin and noradrenaline stimulate AVP and VIP expression, and could participate in the differentiation of the neurochemical phenotype in the mouse SCN.

Animals↗

PubMed2003

Influence of monoamines on differentiating gonadotropin-releasing hormone neurones in foetal mice.

This study evaluated the influence of monoamines, serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline, on differentiating gonadotropin-releasing hormone (GnRH)-producing neurones in foetal mice. The differentiation and migration of GnRH neurones were compared in Tg8 mice (the knocked-out gene encoding monoamine oxidase A) with increased levels of 5-HT and noradrenaline and in C3H mice with normal metabolism of monoamines in C3H mice. To achieve this, immunocytochemistry for GnRH combined with quantitative and semiquantitative image analysis were employed. GnRH neurones in foetuses at the 18th embryonic day were detected in the forebrain along the trajectory of their migration from the olfactory bulbs to the hypothalamic retrochiasmatic region. The total number of GnRH neurones in the forebrain in knockout mice was significantly lower compared to C3H mice, suggesting an inhibiting influence of monoamines on the proliferation of precursor cells. The fraction of GnRH neurones in the caudal part of the trajectory of their migration in Tg8 mice exceeded significantly those in C3H foetuses, whereas there was a reverse in the rostral part of the trajectory. These data suggest that an excess of 5-HT and noradrenaline served to accelerate the GnRH neurone migration in Tg8 mice. Moreover, an excess of 5-HT and noradrenaline provided a minor effect on the area and optical density of GnRH neurones (i.e. on GnRH neurone differentiation). Thus, an excess of 5-HT and noradrenaline appears to inhibit the proliferation of the precursor cells of GnRH neurones and stimulates the GnRH neurone migration to the place of their final location in the septo-preoptic region.

Animals↗

PubMed2002

Lack of 5-HT(1B) receptor and of serotonin transporter have different effects on the segregation of retinal axons in the lateral geniculate nucleus compared to the superior colliculus.

We have shown previously that raised levels of serotonin (5-hydroxytryptamine or 5-HT) during development prevent retinal ganglion cell axons from segregating into eye-specific regions in their principal targets: the superior colliculus and the dorsal lateral geniculate nucleus. Possible mediators of 5-HT in this system include its plasma membrane transporter, which is transiently expressed by a sub-population of retinal ganglion cells, and the presynaptic 5-HT(1B) receptor carried on retinal ganglion cell axons. We analysed the retinal projections of 5-HT(1B) knockout (n=15), serotonin transporter knockout (n=14), serotonin transporter/5-HT(1B) double knockout (n=4) and monoamine oxidase A/5-HT(1B) double knockout (n=3) mice. In all four different knockout mice, the ipsilateral retinal projection to the superior colliculus was more diffuse and lost its characteristic patchy distribution. The alterations were most severe in the serotonin transporter knockout mice, where the ipsilateral retinal fibres covered the entire rostrocaudal and mediolateral extent of the superior colliculus, whereas in the 5-HT(1B) and double knockout mice, fibres retracted from the caudal and lateral superior colliculus. Abnormalities in the 5-HT(1B) knockout mice appeared only after postnatal day (P) 4. Treatment with parachlorophenylalanine (at P1-P12) to decrease serotonin levels caused an exuberance of the ipsilateral retinal fibres throughout the superior colliculus (n=9). In the dorsal lateral geniculate nucleus in contrast, the distribution and size of the ipsilateral retinal projection was normal in all four knockout mice. In the serotonin transporter knockout mice however, the contralateral retinal fibres failed to retract from the mediodorsal dorsal lateral geniculate nucleus, an abnormality that was reversed by early treatment with parachlorophenylalanine and in the serotonin transporter/5-HT(1B) double knockout. OUR OBSERVATIONS INDICATE: (1) that the lack of 5-HT transporter and the associated changes in 5-HT levels impair the segregation of retinal axons in both the superior colliculus and the dorsal lateral geniculate nucleus; (2) that 5-HT and 5-HT(1B) receptors are necessary for the normal refinement of the ipsilateral retinal fibres in the superior colliculus, but are not essential for the establishment of eye-specific segregation in the thalamus. Thus, both an excess and a lack of 5-HT affect the refinement of the superior colliculus retinal projection, while the establishment of eye-specific patterns in the dorsal lateral geniculate nucleus appears not to be sensitive to the lack of 5-HT or 5-HT(1B) receptors.

Animals↗

PubMed2002

Effects of genetic depletion of monoamines on somatosensory cortical development.

Raised levels of serotonin cause alterations in the development of the barrelfield of the primary somatosensory cortex (S1) in rodents. We examined the development of S1 in genetic mouse models in which the levels of serotonin and/or dopamine and noradrenaline are drastically reduced. Mice lacking the vesicular monoamine transporter type 2 (VMAT2 KO) are hypomorphic with rare pups surviving until postnatal day (P) 6. Serotonin, dopamine and noradrenaline are almost undetectable in the brain. In S1 we find that the segregation of thalamocortical axons into whisker patterns is delayed by 1 day and that layer IV granular neurons fail to form normal barrels. Moreover, the growth of cortical layers II-IV is reduced. Despite severe malnutrition, we show that these alterations are not caused by increased cell death in the thalamus or S1. Moreover, the maturation of cortical neurons is not altered as reflected by calcium-binding protein immunolabeling. Mice lacking both VMAT2 and monoamine oxidase type A (MAOA) were generated. VMAT2-MAOA DKO mice are hypomorphic but survive until P13. Increased levels of serotonin but profoundly reduced dopamine and noradrenaline levels are found in the brains. In S1, alterations are similar to those observed in MAOA KO mice: thalamocortical axons and granular neurons failed to form barrels. In addition there is a severe reduction in the thickness of the upper cortical layers as in the VMAT2 KO mice. These results show that monoamines have no instructive effect per se on the formation of thalamocortical patterning in S1. However, monoamines appear to be essential for the normal cytoarchitectonic maturation of the granular (IV) and supragranular cortical layers (II-III). Since developmental cell death and chemoarchitectonic differentiation of these neurons are not modified, it is possible that these alterations result from migration defects and/or from altered synaptic maturation.

Animals↗

PubMed2002

Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice.

Genetic deficiency of monoamine oxidase-A (MAO-A) induces major alterations of mood and behaviour in human. Because serotonin (5-HT) is involved in mood regulation, and MAO-A is responsible for the catabolism of 5-HT, we investigated 5-HT mechanisms in knock-out mice (2-month-old) lacking MAO-A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches. Compared to paired wild-type mice, basal extracellular 5-HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO-A mutant mice. Conversely, spontaneous firing rate of 5-HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was approximately 40% lower in mutants. Acute 5-HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5-HT levels (by approximately 4 fold) and decrease in DRN neuronal firing (with a approximately 4.5 fold decrease in the drug's ED50) in MAO-A knock-out mice, which expressed lower levels of the 5-HT transporter throughout the brain (-13 to -34% compared to wild-type levels). The potency of the 5-HT1A agonist 8-OH-DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5-HT1A autoreceptors. This was associated with a decreased autoradiographic labelling of these receptors (-27%) in the DRN. Altogether, these data indicate that, in MAO-A knock-out mice, the enhancement of extracellular 5-HT levels induces a down-regulation of the 5-HT transporter, and a desensitization of 5-HT1A autoreceptors which allows the maintenance of tonic activity of 5-HT neurons in the DRN.

Action Potentials↗

PubMed2001

Modulation of [3H]quinpirole binding at striatal D2 dopamine receptors by a monoamine oxidaseA-like site: evidence from radioligand binding studies and D2 receptor- and MAO(A)-deficient mice.

[3H]Quinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptors. A variety of monoamine oxidase inhibitors (MAOIs) inhibit equilibrium binding of [3H]quinpirole binding in rat striatal membranes suggesting that MAOIs interact with a novel binding site that is labeled by [3H]quinpirole or that allosterically modulates [3H]quinpirole binding. To determine whether the D2 receptor is essential for [3H]quinpirole binding and/or modulation of [3H]quinpirole binding by MAOIs, D2 receptor-deficient mice were studied. [3H]Quinpirole binding was decreased in D2 receptor-deficient mice to 3% of that observed in wild-type controls indicating that [3H]quinpirole binding is associated with the D2 dopamine receptors. Then, in an attempt to label the site mediating the modulation of [3H]quinpirole binding, binding of the MAOI [3H]Ro 41-1049 was characterized in rat striatal membranes. [3H]Ro-41-1049 labeled a single binding site with a pharmacological profile with respect to MAOIs that was similar to both [3H]quinpirole binding (Spearman r=0.976) and MAO(A) activity. To determine whether MAO(A) plays a role in the modulation of [3H]quinpirole binding by MAOIs, MAO(A)-deficient mice were examined. In these mice, [3H]Ro-41-1049 binding was decreased to 7% of wild-type control. [3H]Spiperone binding was unaltered. Spiperone-displaceable [3H]quinpirole binding was decreased to 43% of wild-type control; however, the remaining [3H]quinpirole binding in MAO(A)-deficient animals was inhibited by Ro 41-1049 similar to wild-type. [3H]Ro-41-1049 binding was not decreased in D2 receptor-deficient mice. These data suggest that [3H]Ro-41-1049 labels multiple sites and that MAOIs modulate [3H]quinpirole binding to the D2 receptor via interactions at a novel, non-MAO binding site with MAO(A)-like pharmacology.

Animals↗

PubMed2001

Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B.

The availability of mutant mice that lack either MAO A or MAO B has created unique profiles in the central and peripheral availability of serotonin, norepinephrine, dopamine, and phenylethylamine. This paper summarizes some of the current known phenotypic findings in MAO A knock-out mice and contrast these with those of MAO B knock-out mice. Differences are discussed in relation to the biochemical, behavioral, and physiologic changes investigated to date, as well as the role played by redundancy mechanisms, adaptational responses, and alterations in neurodevelopment.

Animals↗

PubMed2001

Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A.

The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic Tg8 mice on the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) biosynthesis, and on the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain, hypothalamus, hippocampus, striatum, amygdala, and frontal cortex was studied. It was shown that mice with a genetic MAO A knockout differed from mice of the initial C3H/HeJ strain in having a higher level of 5-HT and a lower level of its metabolite, 5-HIAA, in all brain regions but the frontal cortex, where the changes were insignificant. Although the 5-HIAA/5-HT ratio in various brain regions differed considerably, the decrease of the 5-HT oxidative deamination index in Tg8 mice was similar in different brain regions (to 41-45% of control values), with the exception of the frontal cortex, where the decrease of the 5-HIAA/5-HT was somewhat smaller (to 54%). The presence of the remaining 45% +/- 1.9% of the control ratio value indicates rather effective oxidative deamination of 5-HT in MAO A knockout mice and explains the lack of severe behavioral and pathological consequences in MAO A genetic deficiency. An increase of TPH activity in mice lacking MAO A was found in the frontal cortex, hippocampus, and amygdala. No significant changes were found in the striatum, hypothalamus, and midbrain. The data show an effect of the MAO A gene mutation on TPH and indicate a uniform decrease of 5-HT catabolism in different brain regions except for the frontal cortex, which is somewhat more resistant to the lack of MAO A than other brain structures.

Amygdala↗

PubMed2001

Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice.

Deficiency in the monoamine degradation enzyme monoamine oxidase A (MAOA) or prenatal exposure to the monoamine uptake inhibitor cocaine alters behavior in humans and rodents, but the mechanisms are unclear. In MAOA knock-out mice, inhibiting serotonin synthesis during development can prevent abnormal segregation of axons in the retinogeniculate and somatosensory thalamocortical systems. To investigate this effect, we crossed MAOA knock-outs with mice lacking the serotonin transporter 5-HTT or the 5-HT1B receptor, two molecules present in developing sensory projections. Segregation was abnormal in 5-HTT knock-outs and MAOA/5-HTT double knock-outs but was normalized in MAOA/5-HT1B double knock-outs and MAOA/5-HTT/5-HT1B triple knock-outs. This demonstrates that the 5-HT1B receptor is a key factor in abnormal segregation of sensory projections and suggests that serotonergic drugs represent a risk for the development of these projections. We also found that the 5-HT1B receptor has an adverse developmental impact on beam-walking behavior in MAOA knock-outs. Finally, because the 5-HT1B receptor inhibits glutamate release, our results suggest that visual and somatosensory projections must release glutamate for proper segregation.

Animals↗

PubMed2001

Differences in somatosensory processing in S1 barrel cortex between normal and monoamine oxidase A knockout (Tg8) adult mice.

Spatio-temporal processing of whisker information was analysed in vivo for single neurons in D2 barrel columns of S1 cortex in Tg8 mutant mice, which lack barrels. Findings were compared with normal C3H mice of the same genetic background. The topographical organization of functional columns was similar in Tg8 and normal mice. Response magnitudes (RMs) to D2 principal whisker deflections in D2 columns for Tg8 were similar to normals for layers I-III and layer IV cells but short latency responses (>10 ms post-stimulus) were twice the magnitude of normal mice. The surrounding whiskers D1 and D3 yielded smaller RMs in layer IV of mutants than normal mice whereas RMs in layers I-III were equipotent (P>0.5). Modal latencies were shorter in Tg8 mice in all layers. Latency distributions for whisker D2 responses in both laminae were bimodal in normal mice, peaking at 6-8 and 12 ms post-stimulus, but unimodal in Tg8 mice in both laminae, peaking at 6-8 ms. Hence, despite an absence of barrels, segregation of columns is enhanced in layer IV and sensory processing is faster in layers I-IV compared with normal mice. This contrasts with adenylyl cyclase knockout mice where both an absence of barrels and enhanced surrounding whisker responses have been observed. These findings suggest that factors other than barrels and clustering of thalamo-cortical terminals define receptive field geometry.

Animals↗

PubMed2000

Abnormal phrenic motoneuron activity and morphology in neonatal monoamine oxidase A-deficient transgenic mice: possible role of a serotonin excess.

In rodent neonates, the neurotransmitter serotonin (5-HT) modulates the activity of both the medullary respiratory rhythm generator and the cervical phrenic motoneurons. To determine whether 5-HT also contributes to the maturation of the respiratory network, experiments were conducted in vitro on the brainstem-spinal cord preparation of neonatal mice originating from the control strain (C3H) and the monoamine oxidase A-deficient strain, which has a brain perinatal 5-HT excess (Tg8). At birth, the Tg8 respiratory network is unable to generate a respiratory pattern as stable as that produced by the C3H network, and the modulation by 5-HT of the network activity present in C3H neonates is lacking in Tg8 neonates. In addition, the morphology of the phrenic motoneurons is altered in Tg8 neonates; the motoneuron dendritic tree loses the C3H bipolar aspect but exhibits an increased number of spines and varicosities. These abnormalities were prevented in Tg8 neonates by treating pregnant Tg8 dams with the 5-HT synthesis inhibitor p-chlorophenylalanine or a 5-HT(2A) receptor antagonist but were induced in wild-type neonates by treating C3H dams with a 5-HT(2A) receptor agonist. We conclude that 5-HT contributes, probably via 5-HT(2A) receptors, to the normal maturation of the respiratory network but alters it when present in excess. Disorders affecting 5-HT metabolism during gestation may therefore have deleterious effects on newborns.

Animals↗

PubMed2000

Altered behavior and alcohol tolerance in transgenic mice lacking MAO A: a comparison with effects of MAO A inhibitor clorgyline.

The influence of deficiency of monoamine oxidase A (MAO A) gene and the lack of enzyme MAO A on the behavior of transgenic mouse strain (Tg8) was studied. It was shown that MAO-A-lacking mice differed from mice of the wild-type strain C3H/HeJ (C3H) by an attenuated acoustic startle response, prepulse inhibition (PPI) was unchanged. In Tg 8 mice, the exploratory nose-poking in the holeboard test as well as exploratory line crossing in the "light-dark" test were decreased. No effect of MAO A deficiency on locomotor activity was found. No alcohol preference or difference between Tg8 and C3H in ethanol consumption in the free-choice test has been found, although an increase in alcohol tolerance has been demonstrated. Ethanol-induced (0.3 g/100 g ip) sleep latency was longer, duration of sleep was shorter and ethanol hypothermia was reduced in MAO-A-lacking mice. Comparison of effects of MAO A knockout with those of irreversible MAO A inhibitor clorgyline (5 and 10 mg/kg ip) on C3H mice showed a similar reducing effect on ethanol-induced sleep, but potentiated ethanol-induced hypothermia. Clorgyline administration provoked a tendency to decrease of exploratory activity in the nose-poking test and decreased the frequency of exploratory rearings in the light-dark test. Clorgyline (5 and 10 mg/kg) did not affect the acoustic startle response, but a dose of 5 mg/kg diminished PPI. Therefore, Tg8 mice exhibited a decreased startle response and exploratory activity and an increased tolerance to ethanol. A similar increase in tolerance to ethanol-induced sleep and a tendency to decrease exploratory behavior were displayed by clorgyline. Other effects on behavior were different, suggesting the influence of long-lasting action of MAO A knockout and the involvement of a compensatory mechanism in Tg8 mice.

Alcohol Drinking↗

PubMed2000

Regional cerebral cortical activation in monoamine oxidase A-deficient mice: differential effects of chronic versus acute elevations in serotonin and norepinephrine.

Mice deficient in monoamine oxidase A have previously been shown to demonstrate a chronic elevation of serotonin and norepinephrine in the brain. Using the autoradiographic [14C]iodo-antipyrine method, we examined cerebral cortical blood flow in conscious, restrained four- to five-month-old knock-out and wild-type animals following the intraperitoneal administration of either saline or D-fenfluramine. Knock-out animals administered saline, compared to their wild-type counterparts, demonstrated a significantly higher regional cortical blood flow in somatosensory and barrel field neocortex, an area which previous histological studies have shown to be characterized by abnormal serotonergic projection fibers and absent barrel formation. Regional cortical blood flow was significantly lower in knock-out than in wild-type mice in the entorhinal and midline motor cortex, with non-significant decreases noted in the olfactory, piriform and retrosplenial cortices and the amygdala. We compared the above findings to those obtained in response to D-fenfluramine which, in conjunction with its metabolite D-norfenfluramine, results in acute elevations of brain levels of serotonin and norepinephrine. Administration of D-fenfluramine (21. 2mg/kg) resulted in changes in regional cortical perfusion in most brain regions of both knock-out and wild-type mice that were opposite to the genotypic differences seen in perfusion in response to saline. Fenfluramine significantly increased regional cortical blood flow in the allocortex (olfactory, piriform, entorhinal) and the amygdala, and significantly decreased regional cortical blood flow in the somatosensory, barrel field, midline motor and retrosplenial cortices. Changes in regional perfusion in response to fenfluramine were topographically equivalent in knock-out and wild-type mice, although in knock-out mice such changes were of greater magnitude. Our study suggests that the effects on regional cortical blood flow of a lifelong absence of monoamine oxidase A, and the consequent chronic increase in serotonin and norepinephrine, differ from those attributable to acute increases in these neurotransmitters following fenfluramine administration. Such a differential response may reflect neurodevelopmental abnormalities and/or effects of a chronic physiological adaptation on the regulation of cortical activation.

Animals↗

PubMed2000

Differential regulation of adenosine A(1) and A(2A) receptors in serotonin transporter and monoamine oxidase A-deficient mice.

The serotonin (5HT) transporter (5HTT) removes 5HT from the synaptic cleft and is thus critical to the control of serotonergic neurotransmission. Mice with a targeted inactivation of the 5HTT represent a novel and unique tool to study serotonergic system functioning. Because the release of 5HT is regulated by adenosine, we investigated 5HTT-deficient mice for possible adaptive changes of adenosine A(1) and A(2A) receptors. A(1) and A(2A) receptors were studied by means of quantitative autoradiography using the radioligands [3H]8-cyclopentyl-1,3-dipropylxanthine and [3H]CGS 21680, respectively. A comparison of 5HTT knockout versus control mice revealed upregulation of A(1) receptors in the dorsal raphe nucleus (DRN, +21%), but not in any of the serotonergic projection areas, and downregulation of A(2A) receptors in basal ganglia. The adaptive changes of A(1) and A(2A) receptors in 5HTT-deficient mice are likely to represent a compensatory neuroprotective effect mediated by the adenosinergic modulatory system. For comparison, these receptors were also studied in monoamine oxidase A (MAOA) knockout mice and in 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed adaptive changes of adenosine A(1) and A(2A) receptors similar to 5HTT knockout mice, while investigation of MAOA-deficient mice revealed an upregulation of A(2A) receptors, which may relate to a role of both MAOA and adenosine A(2A) receptors in anxiety.

Animals↗

PubMed2000

Ginkgo biloba abolishes aggression in mice lacking MAO A.

Mice deficient in monoamine oxidase A (MAO A) have increased brain levels of serotonin (5-HT) and norepinephrine and show enhanced aggression. We used MAO A knock-out (KO) mice as a model to study the effect of ginkgo biloba (EGb) on aggression. When EGb was administered to MAO A KO mice, their aggressive behavior in resident-intruder confrontations was reduced to levels seen in wild types. EGb did not affect the locomotive behavior of MAO A KO mice, which suggests that its effects on aggression were not due to sedation. EGb caused a significant 16.9% decrease in [3H]ketanserin binding to 5-HT2A receptors in the frontal cortex of MAO A KO mice but did not change the receptor affinity for [3H]ketanserin. This suggests that the antiaggressive effect of EGb may be mediated by 5-HT2A receptors and that EGb may be developed as a novel antiaggressive agent.

Aggression↗

PubMed2000

Analysis of the pharmacological and molecular heterogeneity of I(2)-imidazoline-binding proteins using monoamine oxidase-deficient mouse models.

The I(2) subgroup of imidazoline-binding sites was identified as monoamine oxidases (MAOs), but it is unclear whether there are I(2)-binding sites located on proteins distinct from MAOs. To address this issue, we characterized I(2)-binding proteins in liver and brain of wild-type and MAO A- and MAO B-deficient mice. I(2)-binding sites were identified using [(3)H]idazoxan and the photoaffinity adduct 2-[3-azido-4-[(125)I]iodophenoxyl]methylimidazoline ([(125)I]AZIPI). [(3)H]Idazoxan labeled binding sites with ligand recognition properties typical of I(2) sites in both brain and liver of wild-type mice. High-affinity, specific [(3)H]idazoxan binding were not altered in MAO A knockout (KO) mice. In contrast, [(3)H]idazoxan binding was completely abolished in both liver and brain of MAO B KO mice. In wild-type mice, [(125)I]AZIPI photolabeled three proteins with apparent molecular masses of approximately 28 (liver), approximately 61 (brain), and approximately 55 kDa (liver and brain). The photolabeling of each protein was blocked by the imidazoline cirazoline (10 microM). Photolabeling of the approximately 61- and approximately 55-kDa proteins was not observed in MAO A and B KO mice, respectively. In contrast, photolabeling of the liver approximately 28-kDa protein was still observed in MAO-deficient mice, indicating that this protein is unrelated to MAOs. These data indicate that I(2) imidazoline-binding sites identified by [(3)H]idazoxan reside solely on MAO B. The binding sites on MAO A and the liver approximately 28-kDa protein may represent additional subtypes of the family of the imidazoline-binding sites.

Adrenergic alpha-Antagonists↗