The effect of 5-HT2a/2c receptor agonist microinjected into central amygdaloid nucleus and median preoptic area on maternal aggressive behavior in rats

OBJETIVO: Resultados de muitos estudos sustentam a hipótese de que a serotonina (5-HT) está relacionada com a inibição do comportamento agressivo. Foram examinados os efeitos potenciais pró e anti-agressivos do agonista de receptores 5-HT2A/2C em regiões específicas do cérebro. MÉTODO: Ratas fêmeas Wistar no sétimo dia pós-parto receberam microinjeções do agonista seletivo de receptores 5-HT2A/2C, a-methyl-5-hydroxytryptamine maleate (0,2 a 1,0 µg/0,2 µl), no núcleo central da amígdala e núcleo pré-óptico medial. Para cada área estudada, as freqüências dos comportamentos: locomoção, investigação social, postura de ameaça, ataques (frontal e lateral) e ato de morder um intruso, foram comparadas entre os diferentes tratamentos por uma análise da variância, seguida quando apropriado do teste de Tukey. RESULTADOS: Os resultados mostraram que a microinjeção do agonista seletivo a-methyl-5-hydroxytryptamine maleate no núcleo central da amígdala aumentou a agressividade materna, mas não foram encontrados efeitos estatisticamente significativos no comportamento agressivo após a microinjeção do agonista seletivo de receptores 5-HT2A/2C no núcleo pré-óptico medial nas diferentes diluições estudadas. CONCLUSÕES: Os dados atuais e prévios sobre os efeitos pró e anti-agressivos do agonista dos receptores 5-HT2a/2c quando microinjetado no núcleo pré-óptico medial, em comparação com a microinjeção no núcleo central da amígdala, no septo medial (MS) e substância cinzenta periaqueductal em ratas apontam para populações funcionalmente independentes de receptores na amígdala-septo-hipotálamo e substância cinzenta periaqueductal, que são responsáveis pelo controle do comportamento agressivo. É possível que os receptores 5-HT2a/2c da amígdala possam aumentar o comportamento agressivo das fêmeas lactantes, como resultado de mudanças decorrentes do estado emocional de medo.

The bradycardic and hypotensive responses to serotonin are reduced by activation of GABA A receptors in the nucleus tractus solitarius of awake rats

We investigated the effects of bilateral injections of the GABA receptor agonists muscimol (GABA A) and baclofen (GABA B) into the nucleus tractus solitarius (NTS) on the bradycardia and hypotension induced by iv serotonin injections (5-HT, 2 æg/rat) in awake male Holtzman rats. 5-HT was injected in rats with stainless steel cannulas implanted bilaterally in the NTS, before and 5, 15, and 60 min after bilateral injections of muscimol or baclofen into the NTS. The responses to 5-HT were tested before and after the injection of atropine methyl bromide. Muscimol (50 pmol/50 nl, N = 8) into the NTS increased basal mean arterial pressure (MAP) from 115 ± 4 to 144 ± 6 mmHg, did not change basal heart rate (HR) and reduced the bradycardia (-40 ± 14 and -73 ± 26 bpm at 5 and 15 min, respectively, vs -180 ± 20 bpm for the control) and hypotension (-11 ± 4 and -14 ± 4 mmHg, vs -40 ± 9 mmHg for the control) elicited by 5-HT. Baclofen (12.5 pmol/50 nl, N = 7) into the NTS also increased basal MAP, but did not change basal HR, bradycardia or hypotension in response to 5-HT injections. Atropine methyl bromide (1 mg/kg body weight) injected iv reduced the bradycardic and hypotensive responses to 5-HT injections. The stimulation of GABA A receptors in the NTS of awake rats elicits a significant increase in basal MAP and decreases the cardiac Bezold-Jarisch reflex responses to iv 5-HT injections.

Maternal aggression in Wistar rats: effect of 5-HT2A/2C receptor agonist and antagonist microinjected into the dorsal periaqueductal gray matter and medial septum

The objective of the present study was to assess the role of the 5-HT2A/2C receptor at two specific brain sites, i.e., the dorsal periaqueductal gray matter (DPAG) and the medial septal (MS) area, in maternal aggressive behavior after the microinjection of either a 5-HT2A/2C receptor agonist or antagonist. Female Wistar rats were microinjected on the 7th postpartum day with the selective agonist alpha-methyl-5-hydroxytryptamine maleate (5-HT2A/2C) or the antagonist 5-HT2A/2C, ketanserin. The agonist was injected into the DPAG at 0.2 (N = 9), 0.5 (N = 10), and 1.0 æg/0.2 æl (N = 9), and the antagonist was injected at 1.0 æg/0.2 æl (N = 9). The agonist was injected into the medial septal area (MS) at 0.2 (N = 9), 0.5 (N = 7), and 1.0 æg/0.2 æl (N = 6) and the antagonist was injected at 1.0 æg/0.2 æl (N = 5). For the control, saline was injected into the DPAG (N = 7) and the MS (N = 12). Both areas are related to aggressive behavior and contain a high density of 5-HT receptors. Non-aggressive behaviors such as horizontal locomotion (walking) and social investigation and aggressive behaviors such as lateral threat (aggressive posture), attacks (frontal and lateral), and biting the intruder were analyzed when a male intruder was placed into the female resident's cage. For each brain area studied, the frequency of the behaviors was compared among the various treatments by analysis of variance. The results showed a decrease in maternal aggressive behavior (number of bites directed at the intruder) after microinjection of the agonist at 0.2 and 1.0 æg/0.2 æl (1.6 ± 0.7 and 0.9 ± 0.3) into the DPAG compared to the saline group (5.5 ± 1.1). There was no dose-response relationship with the agonist. The present findings suggest that the 5-HT2A/2C receptor agonist has an inhibitory effect on maternal aggressive behavior when microinjected into the DPAG and no effect when microinjected into the MS. Ketanserin (1.0 æg/0.2 æl) decreased locomotion when microinjected into the DPAG and MS, but did not affect aggressive behavior. We interpret these findings as evidence for a specific role of 5-HT2A/2C receptors in the DPAG in the inhibition of female aggressive behavior, dissociated from those on motor activity.

Effects of injection of serotonin into nucleus caudatus on food and water intake and body weight in albino rats.

Serotonin is known to inhibit food and water intake. However, the effect of its injection into nucleus caudatus on food and water intake is not known. In the present study, serotonin hydrochloride, buspirone (the serotonin 5-HT1A agonist) and ondensetron (the 5HT3 antagonist) were injected into nucleus caudatus through stereotaxically implanted cannulae in three different dosages (1, 2 and 5 microg) and their effects on 24 h food and water intake, and body weight were recorded. The injection of serotonin hydrochloride resulted in a dose- dependent decrease in food intake attaining maximum of 27.3% at 5 microg dose, whereas water intake and body weight were decreased 12% and 4.3% respectively only at the highest does. Buspirone elicited a dose dependent inhibition of food and water intake and body weight (22.3%, 19.8% and 5.1% respectively), whereas ondensetron elicited an increase in food and water intake (37.8% and 36.3% respectively) without significantly altering bodyweight. It was concluded that serotonin hydrochloride injected into nucleus caudatus inhibits food and water intake significantly. These effects are mediated via 5-HT1A and 5HT3 receptors. The effect of injections of 5-HT1A receptor agonist is more pronounced on water intake. The effect of injections of 5HT3 receptor antagonist is also more pronounced on water intake.

Effect of microinjections of 5-hydroxytryptamine and adrenaline in central grey on pain responsiveness during acute food deprivation in conscious rats.

To study the effects of microinjections of 5 hydroxytryptamine and adrenaline in central grey on pain responsiveness during acute food deprivation, experiments were conducted in nine male rats. Microinjections of 5 HT (10 micrograms/microliter) and adrenaline (10 micrograms/microliter) were given in central grey before and at the end of 6, 12, 18 and 24 hr food deprivation and the effects on pain threshold, cardiorespiratory parameters and body temperature were noted. Observations showed that 5 HT increased the pain threshold (antinociception) significantly (P < 0.05) with no change in cardiorespiratory response and body temperature, adrenaline did not alter pain threshold with no change in cardiorespiratory response and body temperature. The observations suggest the possible existence of two types of monoaminergic receptors or pathways in the central grey.

Probable función de las vías serotoninérgicas del tallo cerebral en el trabajo de parto en la rata / Probable function of serotonergic pathways of the brainstem in parturition labor in the ratas

La aplicación de serotonina (5-HT) en el núcleo del tracto solitario (NTS) de la rata grávida a término produjo distocia, la que consistió en la supresión del parto o bien, en el retraso del mismo (7-30 horas). En relación a la salud de los productos, en el primer caso, todos los productos murieron en el útero, mientras que en el segundo, una parte de ellos murió durante el trabajo de parto (30-70 por ciento). En contraste, en las ratas del grupo control el parto ocurrió en la fecha esperada o bien, con un ligero retraso (2-4 horas), pero en ambos casos, los productos nacieron normales. Finalmente, dicha distocia probablemente se debe a la disfunción de los sistemas eferentes ocitocinérgico, tanto el humoral magnocelular, como el neural parvocelular, ya sea por la inhibición que ocurre en el NTS, lo que interrumpe la información proveniente principalmente del cérvix uterino o bien por la activación de la vías serotoninérgicas centrales. Esto probablemente disminuye la actividad eléctrica del núcleo supraquiasmático (NSQ), lo que a su vez, produciría una disfunción del núcleo paraventricular (NPV)

Radioprotective efficacy of HT + AET in encapsulated form.

Entrapment of 5-hydroxyl-L-tryptophan (HT) in erythrocyte ghost prepared by hypotonic method and high voltage electric discharge method are nearly same. Release of HT with beta-aminoethylisothiuronium bromide hydrobromide (HT + AET) in in vitro system is rapid but only a portion of the entrapped amount is released. Release of HT + AET in serum marginally increases at 2 hr. Compared to release in in vitro medium the release in serum is less. Survival studies with Swiss albino mice indicates that compared to HT alone, the combination of HT + AET shows about 9 times percentage survival. The same combination in the encapsulated form show comparable percentage survival though the amount needed is 1/200th times compared to free form.

Central serotonergic and histaminergic modulation of peripheral inflammation and nociception in rats.

Possible central serotonergic and histaminergic modulation of acute peripheral inflammation was investigated in rats, adopting the formaldehyde-induced acute pedal inflammation as an experimental model. Intracerebroventricular (icv) administration of central inhibitory neurotransmitter, serotonin and its precursor, 5-hydroxytryptophan (5-HTP) attenuated the oedema volume and exudate protein content alongwith augmentation in pain threshold. On the contrary, cyproheptadine, a 5-HT-receptor antagonist and selective serotonin synthesis inhibitor, parachlorophenylalanine (PCPA) produced oedema augmenting and pro-nociceptive effects besides elevating the protein content of the exudate. Centrally administered histamine attenuated pedal oedema, nociception as well as protein concentration in oedema fluid. Cimetidine, an H2 histaminergic receptor blocker did not produce any significant effect on inflammation.

Exaggerated Bezold-Jarisch reflex in the hypertension induced by inhibition of nitric oxide synthesis

The present study was designed investigate the role of cardio-pulmonary reflex, more specifically the bezold-Jarisch reflex, in experimental hypertension induced by chronic administration of Nw-nitro-L-arginine methyl ester (L-NAME) (0,5 mg/ml) added to the drinking water for 6 days. The study was perfomed in male Wistar rats (200-350 g), 9 animals per group. L-NAME ingestion caused a significant increase in resting mean arterial pressure (MAP: 182 + or - 4mmHg) and heart rate (HR: 447 = or - 20 bpm) when compared to untreated rats (MAP: 112 = or - 3 mmHg and HR: 355 + or - 10 bpm). Cardiopulmonary receptors were chemically stimulated with bolus injections of 5-hydroxytryptamine (5-HT, 4-10 ug/Kg, iv) followed by measuring the falls in diastolic arterial pressure (DAP) and HR in conscious and freely moving animals. An expected, the responses to intravenous injections of 5-HT consisted of a dose-dependent reduction in HR (from 26 = or - 14 to 175 + or - 25 bpm) and DAP (from 7 + or - 4 to 39 + or - 3 mmHg) in the control rats. Both bradycardia and diastolic hypotension were significantly accentuated in the L-NAME animals (approximately 30 per cent). These data suggest that, in contrast to other models of hypertension, in the present one caused by inhibition of nitric oxide synthesis, the Bezold-Jarisch reflex exaggerated. This neural dysfunction could be related to changes in the cardiac vagal effrent or effector

Comparación de los efectos de la serotonina, 2-(2-aminoetil)-quinolina (D-1997) y sumatriptan sobre el flujo sanguíneo carotídeo externo del perro / D-1997 and external carotid blood flow

La 2-(2-aminoetil)-quinolina (D-1997) es un derivado quinolínico capaz de mimetizar el efecto contráctil de la serotonina (5-hidroxitriptamina; 5HT) en la vena safena y la arteria basilar del perro. Debido a la similitud que parece existir en el tipo de receptor serotónergico presente en estas preparaciones y el que media la vasoconstricción de la cirulación carotídea del perro, el presente estudio analiza el perfil hemodinámico del D-1997 en el lecho arterial carotídeo externo de perros vago simpatectomizados anestesiados con pentobarbital. Los efectos del D-1997 se compararon con aquellos producidos por la 5-HT y el agente antimigrañoso, sumatriptan. Las infusiones intracarotídeas (i.c.), durante 1 min, de D-1997 (10, 30, 100, 300 y 1000 µg/min), 5HT (0.3, 1, 3, 10, 30 y 100 µg/min), y sumatriptan (3, 10, 30 y 100 µg/min), produjeron decrementos del flujo sanguíneo carotídeo externo (FSCE) dependientes de la dosis empleada. Debido a que estos efectos no se vieron acompañados de modificaciones en la presión arterial, los agonistas produjeron incrementos dosis-dependientes de la resitencia carotídea externa (RCE). Las respuestas vasoconstrictoras inducidas por el D-1997 y la 5-HT fueron de corta duración (hasta 10 min), mientras que aquellas producidas por el sumatriptan fueron de larga duración (hasta 40 min). Los cambios hemodinámicos producidos por el D-1997 y la 5-HT y el sumatriptan en la carótida externa no modificaron los valores basales de resitencia en el lecho arterial de la carótida común contralateral, hecho que indica un efecto local. El orden de potencia agonista aparente fue 5-HT>sumatriptan>D-1997, mientras que el orden de eficacia, representada aquí como la respuesta máxima observada, siguió un patrón diferente, es decir, D-1997 ò sumatriptan > 5-HT. La administración repetida o la administración previa de 5-HT y sumatriptan no modificó las respuestas inducidas por este nuevo agonista; en consecuencia, el D-1997 se comportó como un agonista completo sin inducción de taquifilaxia. Los resultados de este estudio indican que, al igual que en la arteria basilar y en la vena safena del perro, el D-1997 es capaz de producir contracción del músculo liso vascular en el lecho arterial carotídeo externo del perro

Pharmacological study of prokinetic property of ondansetron, a novel 5HT3 receptor antagonist

This study was carried out to investigate the prokinetic property to ondansetron, a 5HT3 receptor antagontis, in vitro. The results showed that, ondansetron is potent 5HT3-receptor antagonist as it blocked 5HT induced chronotropic and inotropic effect in isolated rabbit heart whereas, methysergide didn't. Also, it produced a significant rightward shift of 5HT cumulative concentration curve in isolated guinea pig ileum. Prokinetic activity of the studied drug was demonstrated and assessed on the basis of its ability to enhance intestinal contractions which were blocked after atropine in isolated rabbit jejunum. In addition, it produced a significant leftward shift of Ach. concentration response curve in isolated guinea pig ileum. Moreover, it significantly potentiated the contractions evoked by high concentrations of 5HT in isolated guinea pig ileum. A clearcut evidence for the prokinetic property of ondansetron was observed as it stimulated rat fundal strip contractions which were completely abolished by atropine. Furthermore, it produced a significant leftward shift of cumulative 5HT concentration response curve in isolated rat fundus

The sensitivity of the Bezold-Jarisch reflex is increased in rats with sinoaortic deafferentation

The sensitivity of the Bezold-Jarisch reflex was evaluated by the cardiovascular changes in response to intravenous injection of increasing doses of serotonin (5-hydroxytryptamine) in conscious male Wistar (300-350 g) rats 1 and 15 days after sinoaortic deafferentation. The bradycardia and hypotension induced by serotonin (2, 4, 8, 16 and 32 micrograms, iv) were does dependent in sinoaortic deafferentated as well as in sham-operated rats, but the magnitude of the bradycardiac and depressor response to all doses of serotonin was significantly greater in both groups of sinoaortic deafferentated rats [1 (N = 8) and 15 days (N = 8)] than in sham-operated animals [1 (N = 8) and 15 days (N = 8)], indicating an increased sensitivity of the Bezold-Jarisch reflex. These data suggest that the increased sensitivity of the Bezold-Jarisch reflex may have some functional role in cardiovascular regulation after removal of aortic and carotid baroreceptors

Two types of irritable bowel syndrome: pathophysiologic and pharmacological considerations / Dos tipos del síndrome de intestino irritable: consideraciones patofisiológicas and farmacológicas

The investigation performed in 18 diarrheid and 24 spastic patients showed adrenal glands hyperactivity in the former and hypoactivity in the latter. The central noradrenergic system was unresponsive to glucose in both groups: probably due to glucose-insulin failure to rise in diarrheics, whereas a hyperactive parasympathetic system may have been resposible in spactics. Diarrheics had the lowest sigmoidal tone with rectal hyperactivity and the highest plasma catecholamines + cortisol + glucose + insulin values. Spastic patients, in turn, had the highest sigmoidal tone and the lowest catecholamine values. Plasma glucose, insulin, platelet serotocin and sigmoidal tone rose in spactics, after glucose ingestion, but failed to do so in diarrheics. Further, in spactic patients, sigmoidal tone correlated positively with platelet serotonin and negatively with noradrenaline. The clonidine test showed hyperresponsivenes of growth hormone, cortisol and diastolic blood pressure in diarrheics, compared to a normal response in spastics, alpha-adrenergic antagonists suppressed diarrhea and renal hiperactivity. Alpha adrenergic agonists (wich also deplete plattelet-and myentericplexa serotonin) reduced signoidal tone to zero, increased rectal activity and provoked diarrhea. These findings suggest that peripheral sympathetic activity (prevalent in diarrheics) and hyperparasympathetic activity (prevalent in spactics) trigger these physiological disorders by respectively suppressing and reinforcing the serotonin-plexa level functioning

Attenuation of behavioral consequences of immobilization stress by intra-hippocampal microinjection of zimelidine

To investigate the role of hippocampal 5-HT neurotransmission on adaptation to aversive events, individually housed male Wistar rats (200-250 g) were immobilized for 2 h and tested 24 h later in an elevated plus-maze. Immediately after the restraint period they received bilateral microinjections into the dorsal hippocampus of either saline (0.5 microliters) or the nonselective 5-HT1 antagonist dl-propranolol (20 nmol/0.5 microliters). In a second experiment the first microinjection of saline or dl-propranolol was followed by a second microinjection of saline (0.5 microliters) or the 5-HT reuptake blocker zimelidine (20 nmol/0.5 microliters). Although dl-propranolol alone did not change exploration of the elevated plus-maze, it antagonized the increase in the percentage of open arm entries induced by zimelidine (26.0 +/- 4.1 vs 5.64 +/- 3.7 in controls). These results are compatible with the view that post-synaptic 5-HT1a receptors in the hippocampus mediate adaptive or coping responses to aversive events

Avaliaçäo da auto hemostasia, em pacientes com Síndrome de Down, por meio de provas de coagulaçäo, contagem de plaquetas e agregaçäo plaquetária estimulada por agonistas / Evaluation of Down's patients hemostasis by coagulation tests, platelet count and platelet binding stimulated by agonists

Objetivando avaliar a hemostasia em pacientes com Síndrome de Down, a autora apresenta nesta tese uma casuíatica de 21 pacientes, os quais foram submetidos aos seguintes exames pré-operatórios: TTPA, TP, TT, contagem de plaquetas e agregaçäo plaquetária estimulada por agonistas (Adrenalina, ADP, AA, Colágeno, PAF e 5HT). Os resultados apresentaram-se dentro dos limites da normalidade para as provas de coagulaçäo e contagem de plaquetas. Encontramos tendência hipoagregante frente a estimulaçäo por adrenalina, ADP, AA, colágeno e PAF, e näo observamos diferenças significantes para a agregaçäo plaquetária estimulada pelo 5HT, quando comparada com o grupo controle normal

Mouse foot-pad studies with M. leprae--effect of desoxy fructo serotonin (DFS) and related compounds.

Mouse foot-pad experiments were carried out to study the effects of DFS and related compounds on the multiplication of M. leprae. Of the 25 cases clinically suspected Dapsone resistance, 8 were found resistant and 14 sensitive to Dapsone by mouse foot-pad experiments. Six were resistant to DFS and 16 were sensitive. Desoxy fructo 5-hydroxy tryptophane as well as Nutrition Antileprosy (NAL) diet were also found effective in suppressing the growth of M. leprae in mouse foot-pad. Of the two liposoluble derivatives of DFS tested (DFS LS-I and DFS LS-II), DFS LS-II was found more effective in suppressing the growth of M. leprae in foot-pads of mice.