Orientadores: Desanka Dragosavac, Antonio Luis Eiras Falcão, Sebastião Araujo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-03T18:11:32Z (GMT). No. of bitstreams: 1 Gasparotto_AnaPaulaDeviteCardoso_M.pdf: 633497 bytes, checksum: c02e20dc885b6507d1ed4dc92372343f (MD5) Previous issue date: 2002 / Resumo: Introdução - Alterações do sódio plasmático são freqüentemente encontradas no pós-operatório de pacientes submetidos à neurocirurgia e estão associadas à piora do estado neurológico desses pacientes. Essas alterações podem ser explicadas por três diferentes síndromes: Síndrome Perdedora de Sal (SPS), Síndrome da Secreção Inapropriada do Hormônio Antidiurético (SIADH) e Diabetes Insipidus (DI). A SPS e a SIADH apresentam características laboratoriais semelhantes como hiponatremia e natriurese, diferindo apenas quanto à volemia. Evidências recentes têm mostrado que a maioria dos pacientes hiponatrêmicos com doença intracraniana e que eram anteriormente diagnosticado como SIADH, na verdade são hipovolêmicos e apresentam SPS. Considerando que o tratamento adequado da SIADH (restrição volêmica) pode aumentar a incidência de infarto cerebral, piorando o prognóstico de pacientes com SPS (hipovolêmicos), e o tratamento para o DI envolve o uso de desmopressina (hormônio antidiurético sintético), a qual pode piorar a hiponatremia da SIADH e SPS, o correto diagnóstico diferencial entre essas síndromes torna-se essencial para um tratamento adequado. Objetivo - Verificar a incidência de alterações do sódio, correlacionando-as com alterações da AVP plasmática e identificar as síndromes responsáveis por essas alterações em pacientes neurocirúrgicos. Local - Hospital das Clínicas da Universidade Estadual de Campinas. Período - Novembro de 2000 a abril de 2001. Desenho - Estudo prospectivo, aberto, observacional. Metodologia - Foram estudados 30 pacientes submetidos à craniotomia para ressecção de tumor cerebral (grupo A) e clipagem de aneurisma (grupo B) no pré-operatório e durante os primeiros cinco dias de pós-operatório. Foram realizadas dosagens diárias de sódio e osmolaridade séricos e urinários (urina de 12h), além de dosagem da arginina-vasopressina (AVP) plasmática no 1º, 3º e 5º dias pós-operatórios. Resultados - O distúrbio do sódio mais freqüente foi a hiponatremia (sódio sérico < 135mEq/L), encontrada em 63,3% dos pacientes durante o pós-operatório, sendo a maior incidência observada no D1 (40%), estando presente no pré-operatório em 33,3% dos pacientes. A hipernatremia (sódio sérico > 146mEq/L) ocorreu em 3,5% dos pacientes do grupo A no pós-operatório. Natriurese (sódio urinário > 110mEq/12h) foi observada em 93,3% dos pacientes no pós-operatório, tendo sido maior no D1 e D2 e já estando presente no pré-operatório, sem diferença estatisticamente significativa entre os grupos. Poliúria (volume urinário > 30mL/kg/24h) foi observada em 100% dos pacientes, sendo mais freqüente no D2, estando presente também no pré-operatório. A AVP plasmática apresentou níveis elevados (>5,0pg/mL) em 10% e diminuídos (<0,5pg/mL) em 46,7% dos pacientes no pós-operatório, sendo esta mais freqüente no D3 (26,7%), sem diferenças estatisticamente significativas entre os grupos. A SPS foi encontrada em 27/30 pacientes (90%), sendo que 14 (46,7%) apresentaram SPS associada a DI e 13 (43,3%), apenas SPS. A SIADH foi encontrada em 3/30 pacientes (10%). Conclusão - A hiponatremia foi o distúrbio do sódio mais freqüentemente encontrado no pós-operatório de pacientes submetidos a neurocirurgia. A poliúria e a natriurese acompanham a hiponatremia e podem ser encontradas desde o pré-operatório, provavelmente, devido à presença de alterações cerebrais prévias (tumor ou HSA). A SPS foi a síndrome mais freqüente, estando associada com grande freqüência a níveis reduzidos de AVP plasmática. A SIADH foi a menos freqüente, podendo tratar-se apenas de resposta apropriada ao estresse cirúrgico, aumento de pressão intracraniana, dor, medicações ou perda de sangue durante a cirurgia / Abstract: Introduction - Alterations of plasmatic sodium are alterations frequently found in the neurosurgery postoperative period and are associate with the worsening of the these patients¿ neurological state. These alterations can be explained by three different syndromes: Cerebral Salt Wasting Syndrome (CSWS), Syndrome of the Inappropriate Secretion of Antidiuretic Hormone (SIADH) e Diabetes Insipidus (DI). The CSWS and the SIADH present similar laboratorial characteristics as hyponatremia and natriuresis, differing only to the volemy. Recent evidences have shown that the majority of the hyponatremic patients with intracranial disease were firstly diagnoses as SIADH, they are hypovolemic and present CSWS. Considering that the adequate treatment to the SIADH (volemic restriction) can increase the incidence of cerebral infarction, worsening the prognostic of patients with CSWS (hypovolemic) and that the treatment for the DI involves the desmopressin use (synthetic antidiuretic hormone), which can worsen the hyponatremia of the SIADH and CSWS; the differential diagnosis between these syndromes becomes essential for an adequate treatment. Objectives: To verify the occurrence of sodium alterations, correlating them with alterations of the plasmatic AVP and to identify the responsible syndromes for these alterations in neurosurgical patients. Local: Hospital of the Clinics of the State University of Campinas. Period: November of 2000 to April of 2001. Set: prospective, opened, observational study. Methodology: 30 patients submitted to the craniotomy for the cerebral tumor resection (group A) and aneurism correction (group B) were studied in the preoperative period and during the first 5 days of the postoperative period. Daily dosages of sodium and plasmatic and urinary osmolarity were used (12-hour urine); besides the dosage of the plasmatic arginine-vasopressin (AVP) in 1st, 3rd and 5th postoperative days. Results: The most frequent sodium disturbance was the hyponatremia (seric sodium <135meq/l), found in 63,3% patients during the postoperative period, being the major observed incidence in the 1st postoperative day (40%), presented in the preoperative in 33,3% of the patients. The hypernatremia (seric sodium > 146mEq/L) occurred in 3,5% of the group A patients in the postoperative period. Natriuresis (urinary sodium > 110mEq/12h) was observed in 93,3% of the patients in the postoperative day, being higher in the 1st and 2nd postoperative days and has already been presented in the preoperative period, without significant statistically difference between the groups. Poliury (urinary volume > 30ml/Kg/24h) was observed in 100% of the patients, being more frequent in the 2nd postoperative day when all the patients had presented poliury, being also present in the preoperative period. The plasmatic AVP presented high levels (> 5,0pg/ml) in 10% and decreased( <0,5pg/ml) in 46,7% of the postoperative patients, and more frequent in the 3rd postoperative day (26,7%), without significant statistically difference between the groups. The CSWS was found in 27/30 patients (90%), seeing that, 14 (46,7%) related to DI and 13 (43,3%), only CSWS. The SIADH was found in 3/30 patients (10%). Conclusion: Hyponatremia was the most frequently sodium disturbance found in the postoperative period of submitted patients to tumor resection and cerebral artery aneurism correction. The poliury and natriuresis follow the hyponatremia and can be found since the pre-operative period, probably, because of the presence of previous cerebral alterations (tumor or HSA). The CSWS was the most incident syndrome, being associated with high frequency to low plasmatic AVP levels. The SIADH was the least frequent and it could be just an appropriate reply to the surgical stress, increase of intracranial pressure, pain, drugs or loss of blood during the surgery / Mestrado / Pesquisa Experimental / Mestre em Cirurgia

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Fossil based energy resources are dominating the world’s primary energy consumption for the last century. However, with decreasing crude oil reservoirs and the role they play in global warming by emitting greenhouse gases, the focus has been turned towards improved utilization of renewable resources and the need for new, sustainable fuels and chemicals is more urgent than ever. Biomass is a carbon neutral resource that can be used to produce biofuels and other useful chemicals. One such chemical is 1-butanol (or simply butanol), which has great potential as a gasoline substitute because of its favorable fuel properties. Butanol can be produced from acetone, butanol and ethanol (ABE) fermentation using e.g. Clostridium acetobutylicum. However, the concentration of butanol in fermentation in the resulting broth is limited to ca. 20 g/L due to its toxicity for microorganisms. Butyric acid is a precursor to butanol, which is produced prior to butanol in ABE fermentation. Butyric acid is an important industrial chemical, which can be further converted into a number of commercial compounds e.g. acetate butyrate, butyl acetate and butanol. Arginine is a semi-essential amino acid that has vast applications in the field of pharmaceutical and food industry. In addition, arginine can replace inorganic nitrogen as nitrogen source in fertilizers. It can be produced via fermentation of sugars using engineered microorganism like E. Coli, but like butanol its concentration is restricted to approximately 12 g/L. Due to low concentration of these useful chemicals in the resulting fermentation broths recovery of these chemicals remain challenging with today’s options and therefore  novel recovery process should be developed. In this study, zeolite adsorbents were used to recover butanol, butyric acid and arginine from model and real fermentation broths. Zeolite MFI adsorbent efficiently adsorbed butanol from model solutions with a saturation loading of 0.11 g/g- zeolite. On the other hand, adsorption of butyric acid was found to be strongly pH dependent, with high adsorption below and little adsorption above the pKa value of the acid. A structured adsorbent in the form of steel monolith coated with a silicalite-1 film was also used and performance was evaluated by performing breakthrough experiments at room temperature using model ABE fermentation broths and the results were compared with those obtained using traditional adsorbent sin the form of beads. Desorption studies showed that a high quality butanol product with purity up to 95.2% for butanol-water system and 88.5% for the ABE system can be recovered with the structured silicalite-1 adsorbent. Further, zeolite X adsorbents in the form of powder and extrudates was used to recover arginine from a real fermentation broth and also from aqueous model solutions. To the best of our knowledge, this is the first time recovery of arginine from real fermentation broths using any type of adsorbent is reported. Arginine loading of 0.15 g/g was observed at pH 11 using zeolite X powder. The selectivity for arginine over ammonia and alanine from the fermentation broth at pH 11 was 1.9 and 8.3, respectively, for powder and 1.0 and 4.1, respectively, for extrudates. Synthesis gas (CO + H2) can be produced e.g.by gasification of lignocellulose biomass. This synthesis gas can be used to produce methanol, which subsequently may be converted into gasoline using zeolite ZSM-5 catalyst. However, during Methanol to Gasoline (MTG) process, undesirable carbon residue (coke) is formed that gradually reduces the activity of catalyst. It was hypothesized that intracrystalline defects in the zeolite formed during conventional synthesis may accelerate the deactivation rate by coke formation. In this work, a novel ZSM-5 zeolite catalyst essentially free of intracrystalline defects was synthesized and evaluated in the  MTG reaction,. The novel catalyst showed significantly higher resistance towards deactivation by coke formation as compared to a reference catalyst containing defects.

Background: Subarachnoid haemorrhage (SAH) is a severe stroke that in 85% of all cases is caused by the rupture of a cerebral aneurysm. The median age at onset is 50-55 years and the overall mortality is approximately 45%.Sufficient cortisol levels are important for survival. After SAH hypothalamic/pituitary blood flow may be hampered this could result in inadequate secretion of cortisol. SAH is also associated with a substantial inflammatory response. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase, mediates vasoconstriction and increased ADMA levels may be involved in inflammation and endothelial dysfunction. Continuous electroencephalogram (EEG) monitoring can be used to detect non-convulsive seizures, leading to ischemic insults in sedated SAH patients. Elevated ADMA levels are risk factors for vascular diseases. Vascular disease has been linked to stress, inflammation and endothelial dysfunction. SAH possesses all those clinical features and theoretically SAH could thus induce vascular disease. Aims: 1. Assess cortisol levels after SAH, and evaluate associations between cortisol and clinical parameters. 2. Assess ADMA levels and arginine/ADMA ratios after SAH and evaluate associations between ADMA levels and arginine/ADMA ratios with severity of disease, co-morbidities, sex, age and clinical parameters. 3. Investigate occurrence of subclinical seizures in sedated SAH patients. 4. Evaluate if patients that survive a SAH ≥ one year have an increased risk of vascular causes of death compared to a normal population. Results: Continuous infusion of sedative drugs was the strongest predictor for a low (&lt;200 nmol/L) serum cortisol. The odds ratio for a sedated patient to have a serum cortisol &lt; 200 nmol/L was 18.0 times higher compared to an un-sedated patient (p &lt; 0.001). Compared to admission values, 0-48 hours after SAH, CRP increased significantly already in the time-interval 49-72 hours (p&lt;0.05), peaked in the time-interval 97-120 hours after SAH and thereafter decreased. ADMA started to increase in the time-interval 97-120 hours (p&lt;0.05). ADMA and CRP levels were significantly higher, and arginine/ADMA ratios were significantly lower in patients with a more severe condition (p&lt;0.05). Epileptic seizure activity, in sedated SAH patients, was recorded in 2/28 (7.1%) patients during 5/5468 (0.09%) hours of continuous EEG monitoring. Cerebrovascular disease was significantly more common as a cause of death in patients that had survived a SAH ≥ one year, compared to the population from the same area (p&lt;0.0001). Conclusions: Continuous infusion of sedative drugs was associated with low (&lt;200 nmol/L) cortisol levels. ADMA increased significantly after SAH, after CRP had peaked, indicating that endothelial dysfunction, with ADMA as a marker, is induced by a systemic inflammation. Patients with a more severe condition had significantly higher ADMA and CRP levels, and significantly lower arginine/ADMA ratio. Continuous sedation in sedated SAH patients seems to be beneficial in protecting from subclinical seizures. Cerebrovascular causes of death are more common in SAH survivors. / <p>Funding: The Swedish Society of Medicine, the Faculty of Medicine at Umeå University, The Kempe Foundations and The Stroke Foundation of Northern Sweden supported this study financially.</p>

Spinal muscular atrophy is an autosomal recessive genetic disease that results from the loss and/or degeneration of alpha motor neurons in the lower part of the spinal cord. With ~ 1 in 6000 live births per year being affected, this disease is the second leading cause of infant death and is caused by the loss or decrease of the Survival of Motor Neuron protein (SMN). While a lot is known about the role that SMN plays in the cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), it remains a crucial question in the field to gain a better understanding of what specific/distinct function(s) SMN might have in motor neurons. We have identified novel interactions between SMN and two RNA-binding proteins (RBPs) known to be components of axonal RNA granules. More specifically, we demonstrated that SMN interacts with HuD and SERBP1 in a direct fashion in foci-like structures along neurites of motor neuron-derived cells. We have also demonstrated that the SMN/HuD interaction is required for the localization of HuD into RNA granules in neurites of motor neuron-derived cells. Furthermore, I have shown that SERBP1 is down-regulated in the absence of normal levels of SMN and, most importantly, that over-expression of SERBP1 can rescue SMA-like neuronal defects using a cell culture model of the disease. These findings may help shed light on the non-canonical molecular pathway(s) involving SMN and RBPs in motor neurons and underscores the possible therapeutic benefits of targeting these RBPs in the treatment of SMA.

Cyclooxygenases (COXs) and their main renal product, prostaglandin E2 (PGE2), regulate many physiological renal functions and are involved in the pathogenesis of diabetic kidney disease. The PGE2 receptor EP3 has been repeatedly shown to be upregulated during diabetes. Physiologically, EP3 is best recognized to act as a diuretic by antagonizing arginine-vasopressin (AVP)-mediated water reabsorption. Incidentally, the first renal manifestation of diabetes is polyuria, which may trigger a cascade of events leading to DN. We hypothesize that EP3 contributes to polyuria and kidney dysfunction during diabetes. We injected EP3-/- mice with streptozotocin (STZ) and evaluated their renal function 12-weeks post injection. EP3-/- STZ mice exhibit attenuated polyuria while exhibiting increased urine osmolality suggesting enhanced water reabsorption. Western blots reveal that EP3-/- STZ mice have increased expression of aquaporin-1 and aquaporin-2 as well as reduced urinary AVP excretion compared to STZ mice. However, salt transporters were equivalently increased in STZ and EP3-/- STZ mice. In vitro microperfusion shows that EP3 completely abrogates AVP-mediated water reabsorption in STZ cortical collecting ducts. Furthermore, EP3-/- STZ mice showed blunted renal COX-2 expression as well as reduced renal hypertrophy, glomerular hyperfiltration, and albuminuria. Taken together, the data suggests that EP3 contributes to polyuria during diabetes by inhibiting expression of aquaporins. Additionally, EP3 seems to contribute to renal COX-2 induction during diabetes. The lack of an increase in renal COX-2 protein levels in EP3-/- STZ mice may be protective by preventing further renal damage.

Leishmania caracteriza-se por apresentar duas formas morfologicamente distintas em seu ciclo de vida: promastigotas e amastigotas. As formas promastigotas vivem tubo digestório do vetor flebotomíneo, sob as condições de pH 7,0 e temperatura ambiente, ao redor de 25ºC. As formas amastigotas são encontradas no interior dos fagolisossomos de macrófagos infectados onde encontram um ambiente de pH ácido e temperatura ao redor de 34ºC. Leishmania utiliza arginina para a síntese de poliaminas, que desempenham papel fundamental no crescimento, diferenciação celular e sucesso da infecção. A tomada de arginina em L. (L.) amazonensis é feita pela proteína transportadora de aminoácidos - amino acid transporter-like 3 (AAP3), codificada por duas cópias do gene (5.1 aap3 e 4.7 aap3) dispostas em tandem no genoma. Os transcritos de 5.1 aap3 e de 4.7 aap3 apresentam 98% de identidade entre as ORFs, mas diferem nas 5\' e 3\' UTR. O objetivo do presente trabalho foi avaliar se os sinais de temperatura, pH e privação de arginina disparam a regulação da expressão de aap3 em formas promastigotas e amastigotas. Para isso avaliamos o nível dos transcritos e realizamos ensaios de tomada de arginina em células submetidas à privação ou suplementadas com arginina, nas temperaturas de 25°C ou 34°C em pH 7,0 ou 5,0. Constatou-se em formas promastigotas que o transcrito 5.1 aap3 apresentou maior abundância em relação a 4.7 aap3, e que a privação promoveu o aumento da tomada do aminoácido quando os parasitos eram mantidos em pH 7,0 a 25°C, corroborando dados anteriores do nosso grupo. Demonstramos que a mudança de temperatura foi um fator importante para o aumento do número de cópias de 5.1 aap3 em promastigotas privadas, principalmente quando associadas com o pH 5,0. Além disso, o aumento da temperatura favoreceu a tomada de arginina, corroborando com a elevação do número de cópias observada para o transcrito 5.1 aap3. Em amastigotas-like, mantidas a 25°C e pH 7,0 a privação reverteu a expressão de 5.1 aap3 para o mesmo perfil observado para promastigotas. Contudo, não observamos um favorecimento na tomada de arginina. Ainda em amastigotas, o tratamento a 34°C e pH 7,0 favoreceu a tomada de arginina, porém não observamos um aumento correspondente na quantificação do transcrito. O transcrito 4.7 aap3 não apresentou alteração significativa em qualquer tratamento em promastigotas e amastigotas. Os nossos resultados indicam que a variação de temperatura e do pH, além da privação de arginina, podem ser sinais importantes para regulação da expressão diferencial de aap3, principalmente a cópia 5.1 aap3, de forma a assegurar a oferta de arginina em formas promastigotas previamente à entrada no hospedeiro mamífero e em formas amastigotas, na passagem para o vetor, assegurando o sucesso da infecção / Leishmania presents two morphologically distinct forms in its life cycle: promastigote and amastigote. The promastigotes live in the midgut of the sand fly vector under the conditions of pH 7.0 and room temperature, around 25°C. The amastigote forms are found inside the phagolysosomes of infected macrophages where they encounter an environment of acidic pH and temperature around 34°C. Leishmania uses the arginine to synthesize polyamines which play an important role in cell growth, differentiation and in the successful of infection. The arginine uptake in Leishmania (L.) amazonensis is made by an amino acid porter 3-like protein (AAP3), coded by a two copies gene (5.1 aap3 e 4.7 aap3) arranged in tandem in the genome. The transcripts, 5.1 aap3 and 4.7 aap3, present 98% of ORFs identity, but differ in the 5\' and 3\' UTR. The aim of this work was to evaluate if canges in temperature, pH and arginine deprivation represent signals to trigger the regulation expression of aap3 in promastigotes and amastigotes. For this, we evaluated the transcripts level and performed assays of arginine uptake in parasites subjected to arginine starvation or supplemented with arginine, at temperatures of 25°C or 34°C and pH 7.0 or 5.0. In promastigotes we verified that the transcript 5.1 aap3 showed higher abundance in relation to 4.7 aap3, and that the arginine starvation promoted an increase in the amino acid uptake when the parasites were maintained at pH 7.0 and 25°C, confirming previous data from our group. The change of temperature was an important factor to the increase of 5.1 aap3 transcripts - in starved promastigotes, particularly when associated with pH 5.0. In addition, the increase of the temperature led to an increase of the arginine uptake, correlated to the increase of 5.1 aap3 transcript. The amastigotes-like maintained at 25°C and pH 7.0 and submitted to the amino acid starvation reverted 5.1 aap3 expression profile to the same observed for promastigotes. However, those condictions did not favor an increase in arginine uptake. The treatment of amastigotes at 34°C and pH 7.0 facilitated the increased of arginine uptake, but did not correlated with the transcripts level. The 4.7 aap3 transcript did not change significantly in any promastigotes and amastigotes treatments. Our results indicate that variation in temperature and pH, in addition to arginine starvation may be important signals for regulating the aap3 expression, mainly the copy 5.1 aap3, in order to ensure the correct supply of arginine in the previous period in relation to the entry of the promastigotes into the mammalian host or to the amastigotes transition in the vector, ensuring the success of the infection.

Chronic damage to pulmonary vessels leads to pulmonary hypertension (PH). Different forms of PH are quite frequent and are associated with significant morbidity and mortality. The treatment of PH is most successful, if its cause can be identified and removed before irreversible damage to the pulmonary vascular bed occurs. For patients, in whom the elimination of the underlying cause is not possible or where the cause is unknown, the treatment is aimed at reduction of pulmonary vascular resistance and improvement of cardiac and circulatory response to pressure overload of the right ventricle. One option for the PH treatment is modification of metabolism of cyclic guanosine monophosphate (GMP), which is the second messenger of nitric oxide and induces vascular vasodilation. Cyclic GMP is degraded by phosphodiesterases (PDE 5). In the clinical part, we tested the hypothesis that acute inhibition of PDE5 by sildenafil provides more selective pulmonary vasodilation than high doses of prostaglandin E1 (PGE1). The study showed that the vasodilator effects of sildenafil on pulmonary circulation is more pronounced than in the systemic circulation and that sildenafil had a greater ability to detect reversible component precapillary PH due to advanced chronic heart failure than PGE1. The aim of our...

Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with β-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress.

Nitric oxide (NO) is a neurotransmitter which is synthesized on demand from L-arginine by the enzyme nitric-oxide-oxidase, and is implicated in a variety of physiological functions, including release and uptake of dopamine. Amphetamine induces stereotyped behavior via release of dopamine from dopaminergic neurons in the striatum and related structures, while apomorphine induces such behavior via activation of central dopaminergic receptors. Recently we have demonstrated that a NO donors and a NO-synthase inhibitor modify the response of some central dopaminergic receptors to their agonists and antagonists. In the present study we examined the effect of two NO donors and one NO-synthase inhibitor on stereotyped behavior induced in rats by amphetamine and apomorphine, and the sex-selectivity of this effect. A highly significant dose-dependent sexual differentiation was recorded in the stereotyped behavior of amphetamine, as the duration and intensity of this effect was shortened by L-NAME but not by L-arginine and Molsidomine. Differences in the stereotyped behavior between female and male rats administered apomorphine were dose-dependent, but were not affected by any of the three drugs tested. It is concluded that while nitric oxide is involved in the reactivity of central dopamine receptors, the intensity and duration of this effect is drug- and sex-dependent.