Myasthenic Crisis Manifesting as Postoperative Respiratory Failure following Resection of Unsuspected Intrathoracic Thymic T-Cell Lymphoma during Thyroidectomy for an Adjacent Large Retrosternal Goiter.

A middle-aged female with a goiter of 10 years' duration presented with progressive pressure symptoms, nocturnal choking and dyspnea on exertion for 5 months. Physical examination demonstrated a large simple multinodular goiter. Imaging revealed a deep retrosternal goiter extending below the tracheal bifurcation with marked tracheal deviation. Total thyroidectomy was carried out via a cervical approach and a median sternotomy. Extubation was not possible, and the patient had to be kept intubated. She then went into a myasthenic crisis. Initial ventilatory support was followed by intravenous immunoglobulin, steroids and pyridostigmine. The patient had complete remission and was asymptomatic 18 months later. Histopathology showed a T-cell-rich thymoma in addition to a nodular colloid goiter.

Hallux ulceration in diabetic patients.

We undertook a prospective cohort study to assess risk factors associated with hallux ulceration, and to determine the incidence of healing or amputation, in consecutive patients with diabetes mellitus who were treated over the observation period extending from September 2004 to March 2005, at the Jabir Abu Eliz Diabetic Centre, Khartoum City, Sudan. There were 122 diabetic patients in the cohort (92 males and 30 females) with an overall mean age of 58 +/- 9 years. Fifty-three percent of patients had complete healing within 8 weeks and 43% healed within 20 weeks. The overall mean time to healing was 16 +/- 8 weeks. In 32 (26.2%) patients, osteomyelitic bone was removed, leaving a healed and boneless hallux. The hallux was amputated in 17 (13.9%) patients; in 2 (1.6%) patients it was followed by forefoot amputation and in 7 (5.7%) patients by below-the-knee amputation. In 90 (73.8%) patients the initial lesion was a blister. In conclusion, hallux ulceration is common in patients with diabetes mellitus and is usually preceded by a blister. Neuropathy, foot deformity, and wearing new shoes are common causative factors; and ischemia, osteomyelitis, any form of wound infection, and the size of the ulcer are main outcome determinants. Complete healing occurred in 103 (85%) of diabetic patients with a hallux ulcer. Vascular intervention is important relative to limb salvage when ischemia is the main cause of the ulcer.

Ondansetron and fluoxetine reduce sleep apnea in mice lacking monoamine oxidase A.

Prospective clinical trials addressing the role of serotonin (5-HT) in sleep apnea have indicated that the 5-HT uptake inhibitor fluoxetine is beneficial to some patients with obstructive apnea, whereas the 5-HT(3) receptor antagonist ondansetron seems of little value despite its efficacy in rat and dog models of sleep apnea (central and obstructive). Here, we examined the effect of these drugs in transgenic mice lacking monoamine oxidase A (Tg8), which exhibit approximately 3-fold higher rates of central sleep apnea than their wild-type counterparts (C3H), linked to their enhanced 5-HT levels. Acute ondansetron (2 mg kg(-1), intraperitoneal), acute fluoxetine (16 mg kg(-1)) and 13-day chronic fluoxetine (1 or 16 mg kg(-1)) decreased by approximately 80% the total (spontaneous and post-sigh) apnea index in Tg8 mice during non-rapid eye movement sleep, with no statistically significant effect on apnea in C3H mice. Our study shows that both drugs reduce the frequency of apneic episodes attributable to increased monoamine levels in this model of MAOA deficiency, and suggests that both may be effective in some patients with central sleep apneas.

Retrosternal goiter: the need for median sternotomy.

INTRODUCTION: The aim of this study was to analyze the features of patients with goiter who underwent thyroidectomy via a cervical incision and a median sternotomy in Khartoum. METHODS: A total of 267 thyroidectomies were performed in Khartoum Teaching Hospital during the period from January 2002 to December 2003. There were 40 patients with evidence of retrosternal goiter (15%). Of those 40 patients, 13 had clinical and radiologic evidence of deep retrosternal extension of the goiter possibly necessitating sternotomy. Only 9 of the 13 patients actually required sternotomy, which accounted for 3.4% of all thyroidectomies performed (n = 267). The clinical, radiologic, and pathologic findings of those 9 sternotomy patients were analyzed and compared to those of the 258 patients who underwent cervical thyroidecomy. RESULTS: Total thyroidectomy was undertaken in all nine patients. Six of them had retrosternal extension on the right side of the mediastinum, and three had bilateral extension. Seven patients had symptoms of respiratory distress, and two were asymptomatic. The duration of the goiter ranged between 7 and 30 years. The chest radiograph and computed tomography scan revealed that the retrosternal part was below the level of the aortic knuckle at the tracheal bifurcation in all cases. The histopathology revealed a simple multinodular goiter in eight of the nine patients (89%) and in one patient with papillary carcinoma. Five of the nine patients underwent intraoperative prophylactic tracheostomy due to tracheomalacia. CONCLUSIONS: A long-standing goiter with deep (below the aortic knuckle) mediastinal extension and tracheal space compromise can be postulated to increase the likelihood of sternotomy.

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.

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.

[Training and extinction of passive avoidance in mice lacking monoamine oxidase A].

The passive avoidance learning and memory trace retention in mice lacking monoamine oxidase A (MAO A) and control C3H strain were analyzed. It is shown that mice of both strains were well the passive avoidance learners. A delay of the memory trace extinction was found in lacking MAO A mice as compared with control C3H strain. Mice with a genetic MAO A knockout showed decreased amounts of transitions, rearings, looking to a dark compartment and appearing from it. These findings seem to reflect more expressed fear reaction to a dangerous compartment and increased anxiety promoting longer retention of memory trace on a high level of retrieval.

A large giant cell tumor of the sacrum. Advantage of an abdomino-sacral approach.

We report a case of giant cell tumor of the sacrum, presenting with sacral pain, swelling, and change of bowel habits. Rectal examination revealed a huge retrorectal mass fixed to the sacrum but not to the wall of the rectum. Abdominal ultrasonography, computed tomography CT scan, and magnetic resonance imaging MRI showed a huge pelvic mass invading the sacrum. Exploration via posterior sacral approach was not successful due to both, extensive bleeding and difficult accessibility. Re-exploration was carried out 2 days later with the patient in lithotomy position. Using abdomino-sacral approach the mass together with part of the sacrum and the whole coccyx were excised. Histopathology reported giant cell tumor of the sacrum with no evidence of mitosis. The patient was symptomless 12 months after surgery and on follow up.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Behavioral characteristics of mice with genetic knockout of monoamine oxidase type A.

Transgenic mice of line Tg8 were used to study the effects of deletion of the monoamine oxidase type A gene and the absence of the corresponding enzyme on behavior. These experiments showed that Tg8 mice with genetic knockout of monoamine oxidase type A differed from mice of the parental line C3H/HeJ by lower levels of the startle reflex in response to an acoustic signal, while there was no difference in the prestimulus inhibition of the startle response. Tg8 mice showed decreased investigative activity and decreases in the number of sector crossings in the light-dark anxiety test. There were significant increases in aggression as a motivation in male Tg8 mice, which was manifest as an increase in the number of mice demonstrating aggression and a decrease in the latent period of attack. The intensity of aggression changed to a lesser extent - the number of fights even decreased, though longer periods of keeping mice together resulted in increased numbers of deaths among intruder mice. At the same time, there were no significant differences between mice with genetic knockout of monoamine oxidase type A and control mice in terms of the expression of sexual activation: the behavioral responses of Tg8 males to presentation of females was marked and was no different from that of male C3H/HeJ mice. Knockout of the gene had no effect on movement activity on behavior in an elevated cross-shaped maze or in the test for predisposition to catalepsy.

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.

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.