Serotoninergic Modulation of Basal Cardiovascular Responses and Responses Induced by Isotonic Extracellular Volume Expansion in Rats / Modulação Serotoninérgica de Respostas Cardiovasculares Basais e Induzidas pela Expansão Isotônica do Volume Extracelular em Ratos

Abstract Background: Isotonic blood volume expansion (BVE) induced alterations of sympathetic and parasympathetic activity in the heart and blood vessels, which can be modulated by serotonergic pathways. Objective: To evaluate the effect of saline or serotonergic agonist (DOI) administration in the hypothalamic paraventricular nucleus (PVN) on cardiovascular responses after BVE. Methods: We recorded pulsatile blood pressure through the femoral artery to obtain the mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and the sympathetic-vagal ratio (LF/HF) of Wistar rats before and after they received bilateral microinjections of saline or DOI into the PVN, followed by BVE. Results: No significant differences were observed in the values of the studied variables in the different treatments from the control group. However, when animals are treated with DOI followed by BVE there is a significant increase in relation to the BE control group in all the studied variables: MBP (114.42±7.85 vs 101.34±9.17); SBP (147.23±14.31 vs 129.39±10.70); DBP (98.01 ±4.91 vs 87.31±8.61); HR (421.02±43.32 vs 356.35±41.99); and LF/HF ratio (2.32±0.80 vs 0.27±0.32). Discussion: The present study showed that the induction of isotonic BVE did not promote alterations in MAP, HR and LF/HF ratio. On the other hand, the injection of DOI into PVN of the hypothalamus followed by isotonic BVE resulted in a significant increase of all variables. Conclusion: These results suggest that serotonin induced a neuromodulation in the PVN level, which promotes an inhibition of the baroreflex response to BVE. Therefore, the present study suggests the involvement of the serotonergic system in the modulation of vagal reflex response at PVN in the normotensive rats.

Resumo Fundamento: Expansão de volume extracelular (EVEC) promove alterações da atividade simpática e parassimpática no coração e vasos sanguíneos, os quais podem ser moduladas por vias serotoninérgicas. Objetivo: Avaliar o efeito da administração de salina ou agonista serotoninérgico (DOI) nos núcleos paraventriculares hipotalâmico (NPV) sobre respostas cardiovasculares após EVEC. Métodos: Foram obtidos registros da pressão arterial pulsátil, por meio da artéria femoral, para obtenção dos valores da pressão arterial média (PAM), sistólica (PAS), diastólica (PAD), frequência cardíaca (FC) e razão simpático-vagal (LF/HF) de ratos Wistar antes e após receberem microinjeções bilaterais no NPV de salina ou DOI seguida de EVEC. Resultados: Não foram observadas diferenças significativas dos valores das variáveis estudadas nos diferentes tratamentos do grupo controle. Entretanto, quando os animais são tratados com DOI seguida de EVEC ocorre aumento significativo em relação ao grupo controle com EVEC em todas as variáveis estudadas: PAM (114,42±7,85 vs 101,34±9,17), PAS (147,23±14,31 vs 129,39±10,70), PAD (98,01 ±4,91 vs 87,31±8,61), FC (421,02±43,32 vs 356,35±41,99) e LF/HF (2,32±0,80 vs 0,27±0,32). Discussão: O presente estudo mostrou que a indução de EVEC isotônica não promoveu alterações na PAM, PAD, PAS, FC e LF/HF. Por outro lado, os animais que receberam microinjeção de DOI no NPV seguida de EVEC apresentaram aumento significativo de todas as variáveis. Conclusão: Esses resultados sugerem que a serotonina exerce uma neuromodulação em nivel do NPV, e essa promove uma inibição da resposta barorreflexa frente à EVEC. Assim, o presente trabalho sugere o envolvimento serotoninérgico na neuromodulação no nivel do NPV na resposta reflexa vagal em ratos normotensos.

Human umbilical artery smooth muscle exhibits a 2-APB-sensitive capacitative contractile response evoked by vasoactive substances and expresses mRNAs for STIM, Orai and TRPC channels

After depletion of intracellular Ca2+ stores the capacitative response triggers an extracellular Ca2+ influx through store-operated channels (SOCs) which refills these stores. Our objective was to explore if human umbilical artery smooth muscle presented this response and if it was involved in the mechanism of serotonin- and histamine-induced contractions. Intracellular Ca2+ depletion by a Ca2+-free extracellular solution followed by Ca2+ readdition produced a contraction in artery rings which was inhibited by the blocker of Orai and TRPC channels 2-aminoethoxydiphenyl borate (2-APB), suggesting a capacitative response. In presence of 2-APB the magnitude of a second paired contraction by serotonin or histamine was significantly less than a first one, likely because 2-APB inhibited store refilling by capacitative Ca2+ entry. 2-APB inhibition of sarcoplasmic reticulum Ca2+ release was excluded because this blocker did not affect serotonin force development in a Ca2+-free solution. The PCR technique showed the presence of mRNAs for STIM proteins (1 and 2), for Orai proteins (1, 2 and 3) and for TRPC channels (subtypes 1, 3, 4 and 6) in the smooth muscle of the human umbilical artery. Hence, this artery presents a capacitative contractile response triggered by stimulation with physiological vasoconstrictors and expresses mRNAs for proteins and channels previously identified as SOCs.

Central 5-HT2A receptors modulate the vagal bradycardia in response to activation of the von Bezold-Jarisch reflex in anesthetized rats

Activation of 5-hydroxytryptamine (5-HT) 5-HT1A, 5-HT2C, 5-HT3, and 5-HT7 receptors modulates the excitability of cardiac vagal motoneurones, but the precise role of 5-HT2A/2B receptors in these phenomena is unclear. We report here the effects of intracisternal (ic) administration of selective 5-HT2A/2B antagonists on the vagal bradycardia elicited by activation of the von Bezold-Jarisch reflex with phenylbiguanide. The experiments were performed on urethane-anesthetized male Wistar rats (250-270 g, N = 7-9 per group). The animals were placed in a stereotaxic frame and their atlanto-occipital membrane was exposed to allow ic injections. The rats received atenolol (1 mg/kg, iv) to block the sympathetic component of the reflex bradycardia; 20-min later, the cardiopulmonary reflex was induced with phenylbiguanide (15 µg/kg, iv) injected at 15-min intervals until 3 similar bradycardias were obtained. Ten minutes after the last pre-drug bradycardia, R-96544 (a 5-HT2A antagonist; 0.1 µmol/kg), SB-204741 (a 5-HT2B antagonist; 0.1 µmol/kg) or vehicle was injected ic. The subsequent iv injections of phenylbiguanide were administered 5, 20, 35, and 50 min after the ic injection. The selective 5-HT2A receptor antagonism attenuated the vagal bradycardia and hypotension, with maximal effect at 35 min after the antagonist (pre-drug = -200 ± 11 bpm and -42 ± 3 mmHg; at 35 min = -84 ± 10 bpm and -33 ± 2 mmHg; P < 0.05). Neither the 5-HT2B receptor antagonists nor the vehicle changed the reflex. These data suggest that central 5-HT2A receptors modulate the central pathways of the parasympathetic component of the von Bezold-Jarisch reflex.

Hypophagic and hypolocomotive effects of metachloro phenyl piperazine in rats treated with theophylline and caffeine

Long term intake of coffee is known to produce anxiety and suppression of appetite. 5- hydroxytryptamine [5-HT] acting via 5-HT-2C receptors elicits anorexia and anxiety. The present study is design to monitor metachloro phenyl piperazine [m-CPP] at a dose of 3mg/ml/kg, induces hypophagia and hypolocomotion in rats taking a solution of caffeine [a component of coffee and tea] or theophylline [a component of tea] as a sole source of water. We found that hypophagic and hypolocomotive effects of m-CPP were attenuated in theophylline but not in caffeine treated animals suggesting that long term intake of theophylline may, attenuate anorexiogenic and anxiogenic effects of 5-HT. A possible role of 5-HT-2C receptors in the modulation of anxiety and appetite in people drinking coffee or tea discussed

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 ± 2.2 vs 4.4 ± 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Effect of 5-HT1B receptor agonists injected into the prefrontal cortex on maternal aggression in rats

Serotonin (5-HT1B) receptors play an essential role in the inhibition of aggressive behavior in rodents. CP-94,253, a 5-HT1B receptor agonist, can reduce aggression in male mice when administered directly into the ventro-orbitofrontal (VO) prefrontal cortex (PFC). The objective of the current study was to assess the effects of two selective 5-HT1B receptor agonists (CP-94,253 and CP-93,129), microinjected into the VO PFC, on maternal aggressive behavior after social instigation in rats. CP-94,253 (0.56 µg/0.2 µL, N = 8, and 1.0 µg/0.2 µL, N = 8) or CP-93,129 (1.0 µg/0.2 µL, N = 9) was microinjected into the VO PFC of Wistar rats on the 9th day postpartum and 15 min thereafter the aggressive behavior by the resident female against a male intruder was recorded for 10 min. The frequency and duration of aggressive and non-aggressive behaviors were analyzed using ANOVA and post hoc tests. CP-93,129 significantly decreased maternal aggression. The frequency of lateral attacks, bites and pinnings was reduced compared to control, while the non-aggressive behaviors and maternal care were largely unaffected by this treatment. CP-94,253 had no significant effects on aggressive or non-aggressive behaviors when microinjected into the same area of female rats. CP-93,129, a specific 5-HT1B receptor agonist, administered into the VO PFC reduced maternal aggressive behavior, while the CP-94,253 agonist did not significantly affect this behavior after social instigation in female rats. We conclude that only the 5-HT1B receptor agonist CP-93,129 administered into the VO PFC decreased aggression in female rats postpartum after social instigation.

Behavioral and neuropharmacological evidence that serotonin crosses the blood-brain barrier in Coturnix japonica (Galliformes; Aves)

This study was carried out aiming to reach behavioral and neuropharmacological evidence of the permeability of the blood-brain barrier (BBB) to serotonin systemically administered in quails. Serotonin injected by a parenteral route (250-1000 æg.kg-1, sc) elicited a sequence of behavioral events concerned with a sleeping-like state. Sleeping-like behaviors began with feather bristling, rapid oral movements, blinking and finally crouching and closure of the eyes. Previous administration of 5-HT2C antagonist, LY53857 (3 mg.kg-1, sc) reduced the episodes of feather bristling and rapid oral movements significantly but without altering the frequency of blinking and closure of the eyes. Treatment with the 5-HT2A/2C antagonist, ketanserin (3 mg.kg-1, sc) did not affect any of the responses evoked by the serotonin. Quipazine (5 mg.kg-1, sc) a 5-HT2A/2C/3 agonist induced intense hypomotility, long periods of yawning-like and sleeping-like states. Previous ketanserin suppressed gaping responses and reduced hypomotility, rapid oral movements and bristling but was ineffective for remaining responses induced by quipazine. Results showed that unlike mammals, serotonin permeates the BBB and activates hypnogenic mechanisms in quails. Studies using serotoninergic agonist and antagonists have disclosed that among the actions of the serotonin, feather bristling, rapid oral movements and yawning-like state originated from activation of 5-HT2 receptors while blinking and closure of the eyes possibly require other subtypes of receptors.

Este estudo foi desenvolvido objetivando ampliar as evidências comportamentais e neurofarmacológicas da permeabilidade da barreira hematoencefálica (BHE) à serotonina administrada sistemicamente em codornas. A serotonina injetada por via parenteral (250-1000 æg.kg-1, sc) produziu uma seqüência de eventos relacionados com um estado semelhante ao sono. Comportamentos semelhantes ao sono começaram com o eriçamento das penas, movimentos orais rápidos, piscadelas e finalmente agachamento e fechamento dos olhos. A administração prévia do antagonista do receptor 5-HT2C, LY53857 (3 mg.kg-1, sc) reduziu significativamente os episódios de eriçamento das penas e movimentos orais rápidos, mas não alterou a freqüência de piscadelas e fechamento dos olhos. Tratamento com o antagonista do receptor 5-HT2A/2C, quetanserina (3 mg.kg-1, sc) não afetou nenhuma das respostas evocadas pela serotonina. A quipazina (5 mg.kg-1, sc), um agonista dos receptores 5-HT2A/2C/3, induziu intensa hipomotilidade e longos períodos de comportamentos semelhantes ao bocejo e ao sono. O tratamento prévio com quetanserina suprimiu as reações de bocejo e reduziu a hipomotilidade, os movimentos orais rápidos e as piscadelas, mas foi sem efeito para as demais respostas induzidas pela quipazina. Os resultados mostraram que, diferentemente dos mamíferos, a serotonina atravessa a BHE e ativa mecanismos hipnogênicos em codornas. Estudos com agonistas serotoninérgicos e antagonistas revelaram que, entre as ações da serotonina, o eriçamento das penas, os movimentos orais rápidos e o comportamento semelhante ao bocejo foram originados pela ativação de receptores 5-HT2, enquanto o piscar e o fechamento dos olhos possivelmente requereu outros subtipos de receptores.

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.

Influence of serotonergic transmission and postsynaptic 5-HT2C action on the feeding behavior of Coturnix japonica (Galliformes: Aves)

Investigamos nesse estudo o papel dos receptores 5-HT2C e da transmissão serotonérgica no controle do comportamento alimentar em codornas. Em grupo de aves em jejum, a administração do liberador de serotonina, fenfluramina (FEN) e dos agonistas 5-HT2C, mCPP e MK212, nas doses de 1,0 e 3,3 mg/Kg induziu a uma redução significativa da ingestão alimentar (0,71 ± 0,18 g e 0,47 ± 0,2 g; 0,49 ± 0,22 g e 0,48 ± 0,29 g; 0,82 ± 0,13 g e 0,71 ± 0,16 g; respectivamente). A ingestão de alimento nos grupos controles variou de 2,89 ± 0,21 g a 2,97 ± 0,22 g, 60 min após a reapresentação de alimento, P < 0,0001). Resultados similares foram obtidos com as codornas normoalimentadas. Tanto o liberador de serotonina, FEN, quanto os agonistas 5-HT2C, mCPP e MK212 em doses de 3,3 mg/Kg induziram resposta hipofágica (FEN, 0,78 ± 0,08 g; mCPP, 0,89 ± 0,07 g; MK212, 1,25 ± 0,17 g vs. controles, 2,05 ± 0,12 g, 120 min após a oferta de alimento, P < 0.0001 a P < 0.01). A administração prévia do antagonista 5-HT2C, LY53857 (5,0 mg/Kg) bloqueou a resposta hipofágica induzida pelos agonistas 5-HT2C, 60 min após a apresentação de alimento. Os resultados obtidos demonstram o papel modulatório da liberação de serotonina e dos receptores pós-sinápticos 5-HT2C, no controle do comportamento alimentar de codornas.

Influence of 5-HT1A agonist on the feeding behavior of Coturnix japonica (Galliformes: Aves)

Investigamos no presente trabalho o efeito da estimulação de receptor serotonérgico 5-HT1A no comportamento alimentar de codornas (Coturnix japonica). A administração do agonista 5-HT1A, 8-OH-DPAT (0,05 a 5,0 mg/kg), inibiu de modo dose-dependente a ingestão de alimento em codornas normoalimentadas. A inibição mais intensa foi obtida com a dose de 5,0 mg/kg (0,93 ± 0,21 g vs. 5,83 ± 0,25 g, P < 0,05, 2 h após a oferta de alimento). Resposta comparável foi alcançada nas aves previamente submetidas ao jejum alimentar. Ao final de 2 h, a dose maior de 8-OH-DPAT induziu a uma intensa resposta hipofágica (1,59 ± 0,41 g vs. 6,85 ± 1,04 g, P < 0,0001). O tratamento prévio com o antagonista 5-HT1A/b-adrenérgico, propranolol, não bloqueou a ação inibidora do 8-OH-DPAT na ingestão alimentar, ao contrário, intensificou-a (controles, 5,22 ± 1,09 g; 8-OH-DPAT, 1,41 ± 0,19 g; propranolol + 8-OH-DPAT, 0,44 ± 0,25 g, P < 0,01, para todas as comparações). A administração isolada de propranolol evidenciou uma ação hipofágica com a dose maior (controles, 4,5 ± 0,8 g vs. propranolol, 2,0 ± 0,2 g, P < 0,01). Os resultados obtidos evidenciaram um possível papel dos receptores 5-HT1A na modulação do comportamento alimentar em codornas de natureza oposta ao referido para mamíferos. Por outro lado, a potencialização da hipofagia pela prévia administração de propranolol suscita a hipótese de um mecanismo b-adrenérgico excitatório no controle do comportamento alimentar em codornas.

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.

Mechanism of action of the cisapride-induced vasodilatation in renal vasculature of rat.

BACKGROUND & OBJECTIVES: Cisapride is a prokinetic agent with cholinomimetic and 5-HT4 receptor agonistic properties. It has been proposed that cisapride-induced hypotension is partly mediated by cholinergic system. The aim of this study was to investigate the mechanism of cisapride-induced dilatation in the rat isolated perfused kidney. METHODS: Left kidneys of Wistar rats were isolated and perfused via renal artery and the perfusion pressure was recorded. Cisapride given as bolus injections (10(-10)-3x10(-5) mol/l) produced dose-dependent dilatations. Perfusion of antagonists or inhibitors was started 30min before the onset of phenylephrine perfusion. RESULTS: 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; blocker of M1, and M3 muscarinic receptors; 10(-7) mol/l) inhibited the responses to the lower doses of cisapride while, dextran (10(-7) mol/l), glibenclamide (inhibitor of ATP-sensitive potassium channels; 10(-5) mol/l) and capsaicin (for neuromediator depletion; 10(-6) mol/l) inhibited those to the higher doses. Dilatations induced by most of the doses of cisapride were inhibited by atropine (non-selective muscarinic receptor antagonist; 10(-7) mol/l), methylene blue (inhibitor of soluble guanylate cyclase; 10(-5) mol/l), 1H-[1,2,4] oxadiazolo-[4,3-a] Quinoxalin-1-One (ODQ; inhibitor of soluble guanylate cyclase; 10(-5) mol/l), and NG-nitro-L-arginine (L-NOARG; NO synthase inhibitor; 10(-4) mol/l). Inhibition induced by L-NOARG was reversed by L-arginine (10(-3) mol/l). The dilatation induced by cisapride was not affected by GR113808 (5-HT4 receptor antagonist; 10(-7) mol/l) and indomethacin (cyclooxygenase inhibitor; 10(-5) mol/l). INTERPRETATION & CONCLUSION: The findings indicated that cisapride caused vasodilatation through the release of nitric oxide (NO) as a result of the release of a substance acting on muscarinic receptors, in the renal vascular bed of the rat. The role of 5-HT4 receptors and prostanoids seemed unlikely.

Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis in dogs.

The effect of drug acting on 5-HT1A, 5-HT2 and 5-HT3 receptors were studied against cisplatin and apomorphine induced emesis in dogs. Buspirone, 5-HT1A receptor partial agonist significantly reduced the emetic episodes though it had no significant effect on emetic latency. Mianserin, 5-HT2 receptor antagonist exhibited significant reduction in emetic episodes and in latency. Buspirone prevented the apomorphine induced emesis while mianserin had no effect. The antiemetic activity of buspirone may be attributable to its agonistic activity at 5-HT1A receptor and antagonistic activity at dopamine receptors. These findings further confirm the involvement of 5-HT1A and 5-HT2 receptor in cytotoxic drug induced emesis, though the species difference in their antiemetic action can not be ruled out.

Palatal myoclonus: report of two cases

We describe two cases of palatal myoclonus (PM), one essential and another secondary to a stroke. Case 1: a 64 years old female who developed clicking sounds in both ears after a stroke and three years later on noticed a progressive involuntary movement of the throat associated with rhythmic contractions of the soft palate, muscles of tongue and throat. MRI showed an ischemic area in brainstem. The patient had a partial response to the use of sumatriptan 6 mg subcutaneously. Case 2: a 66 years old female who began with ear clicking at left ear that worsed slowly associated with tinnitus and arrhythmic movements of soft palate and an audible click at left ear. Brain MRI was normal; audiometry showed bilateral neurosensory loss. She was prescribed clonazepan 1 mg daily with complete recovery. Primary and secondary palatal myoclonus share the same clinical features but probably have different pathophysiological underlying mechanisms

Phenyldiguanide activates cardiac receptors to produce responses by involving three different efferent pathways in anaesthetized rats.

The present study was undertaken to determine the afferent and efferent pathways involved in the phenyldiguanide (PDG)-induced reflex response in rats. Intravenous (iv) injection of PDG (10 microg/kg), produced hypotension, bradycardia and apnea over a period of time. Bilateral vagotomy abolished the PDG-induced reflex changes. Atropine (2 mg/kg; iv) blocked only the bradycardiac response produced by PDG, while prazosin (0.5 mg/kg; iv) blocked the hypotensive response, and bilateral vagotomy in these animals abolished the apneic response. In separate series of experiments, intrapericardial injection of lignocaine abolished the hypotensive and bradycardiac responses evoked by PDG in artificially ventilated rats. The results reveal that the PDG-induced reflex is mediated through vagal afferents originating from the heart and efferents involve three different pathways. The bradycardiac response was through the muscarinic receptors, the hypotension is mediated through alpha1 adrenoceptors and the apnea presumably through the spinal motoneurones supplying the respiratory muscles.

Sistema serotoninérgico: receptores e respostas funcionais / Brain serotonin system: receptors and functional response

A partir da síntese da serotonina, em 1951, iniciou-se a investigaçäo farmacológica dos receptores serotoninérgicos. A estimulaçäo dos mais variados tipos de receptores gera múltiplas respostas funcionais verificadas em nível de sistema nervoso central, terminaçöes nervosas serotoninérgicos em nível metabólico e fisiopatológico

Electro-oscillographic correlation between dorsal raphe nucleus, neocortex and hippocampus during wakefulness before and after serotoninergic inactivation

Theta rhythm in many brain structures characterizes wakefulness and desynchronized sleep in most subprimate mammalian brains. In close relation to behaviors, theta frequency and voltage undergo a fine modulation which may involve mobilization of dorsal raphe nucleus efferent pathways. In the present study we analyzed frequency modulation (through instantaneous frequency variation) of theta waves occurring in three cortical areas, in hippocampal CA1 and in the dorsal raphe nucleus of Wistar rats during normal wakefulness and after injection of the 5-HT1a receptor agonist 8-OH-DPAT into the dorsal raphe. We demonstrated that in attentive states the variation of theta frequency among the above structures is highly congruent, whereas after 8-OH-DPAT injection, although regular signals are present, the variation is much more complex and shows no relation to behaviors. Such functional uncoupling after blockade demonstrates the influence of dorsal raphe nucleus efferent serotoninergic fibers on the organization of alertness, as evaluated by electro-oscillographic analysis.

Control de estímulos con fármacos: aplicaciones en psicofarmacología / Pharmacological stimuli control: applications in psicopharmacology

Uno de los principales objetivos de la farmacología es identificar nuevos y mejores medicamentos, tratando de determinar el mecanismo y el sitio de acción de los mismos, en el entendimiento de que aparte del beneficio terapéutico, dichos hallazgos amplían nuestro conocimiento acerca de la fisiopatología de los padecimientos. Para cubrir este propósito, se comparan los diferentes fármacos, se determinan los efectos terapéuticos y los efectos colaterales, utilizando diversos modelos experimentales. No obstante, debido al gran número de modelos experimentales disponibles, no siempre es eficiente la comparación entre las moléculas. Sin embargo los modelos conductuales conocidos como discriminación de drogas, o más apropiadamente control de estímulos con fármacos, ofrecen una alternativa eficiente para establecer las similitudes y las diferencias entre éstos. El uso de modelos experimentales ha cobrado cierta popularidad, particularmente en el área de psicofarmacología, por lo cual es conveniente familiarizarse con los principios conceptuales de dichos modelos para evaluar sus bondades y deficiencias. En la discriminación de drogas para comparar a diferentes fármacos entre sí uno de ellos se establece como estímulo discriminativo, lo cual significa que este fármaco adquiere una propiedad especifica que se encarga de controlar la conducta de los organismos por medio de las señales del estímulo que produce. Durante la adecuación del sujeto bajo el efecto de este fármaco, debe aprender a emitir una cierta respuesta la cual está relacionada congruentemente con una consecuencia en particular. Además, al mismo sujeto se le entrena para que emita una respuesta diferente en las ocasiones en las que se le presenta algún otro estímulo farmacológico correlacionado con una consecuencia diferente. Después del entrenamiento, en las pruebas de sustitución, se examina la conducta del sujeto ante estímulos diferentes, con los cuales se pretende determinar la similitud que hay con respecto al estímulo de entrenamiento. La proporción de una u otra de las respuestas del sujeto será una función directa de la similitud que exista entre los fármacos (efecto, dosis, mecanismo de acción, etc.). En este trabajo, esta preparación se ilustra con agonistas parciales del receptor serotonérgico 5-HT 1A, por el gran interés que estos compuestos han despertado por sus posibles aplicaciones en el tratamiento de la depresión, de la ansiedad, de la ingesta de alimento y otras más

Animal models of anxiety an ethological perspective

In the field of anxiety research, animal models are used as screening tools in the search for compounds with therapeutic potential and as simulations for research on mechanisms underlying emotional behaviour. However, a solely pharmacological approach to the validation of such tests has resulted in distinct problems with their applicability to systems other than those involving the benzodiazepine/GABA(A) receptor complex. In this context, recent developments in our understanding of mammalian defensive behaviour have not only prompted the development of new models but also attempts to refine existing ones. The present review focuses on the application of ethological techniques to one of the most widely used animal models of anxiety, the elevated plus-maze paradigm. This fresh approach to an established test has revealed a hitherto unrecognized multidimensionality to plus-maze behaviour and, as it yields comprehensive behavioural profiles, has many advantages over conventional methodology. This assertion is supported by reference to recent work on the effects of diverse manipulations including psychosocial stress, benzodiazepines, GABA receptor ligands, neurosteroids, 5-HT(lA) receptor ligands, and panicolytic/panicogenic agents. On the basis of this review, it is suggested that other models of anxiety may well benefit from greater attention to behavioural detail.