Receptores de la serotonina que inhiben el tono simpático vasopresor en la rata descerebrada y desmedulada / Role of serotonin receptors in vascular tone in the pithed rat

Serotonin (5-hydroxytryptamine; 5-HT) has been shown to produce vascular sympatho-inhibition in a wide variety of isolated blood vessels by activation of prejunctional 5-HT1 receptors. After considering the mechanisms involved in modulating neuroeffector transmission, the present review analyzes the experimental findings identifying the pharmacological profile of the 5-HT receptors that inhibit the sympathetically-induced vasopressor responses in pithed rats. Thus, 5-HT-induced sympatho-inhibition has been shown to be: (i) unaffected by physiological saline or by the selective antagonists ritanserin (5-HT2), MDL72222 (5-HT3) or tropisetron (5-HT3/4); (ii) blocked by methysergide, a non-selective 5-HT1/2 receptor antagonist; and (iii) potently mimicked by 5-carboxamidotryptamine (5-CT), a non-selective 5-HT1 receptor agonist, as well as by the selective agonists 8-OH-DPAT (5-HT1A), indorenate (5-HT1A), CP93,129 (5-HT1B), and sumatriptan (5-HT1B/1D). These findings show the involvement of prejunctional 5-HT1 receptors. With the use of selective antagonists, it has been shown subsequently that the sympatho-inhibition induced by indorenate, CP93, 129, and sumatriptan was selectively antagonized by WAY100635 (5-HT1A), cyanopindolol (5-HT1A/1B), and GR127935 (5-HT1B/1D), respectively. These results demonstrate that the 5-HT1 receptors mediating sympatho-inhibition on the systemic vasculature of pithed rats resemble the pharmacological profile of the 5-HT1A, 5-HT1B, and 5-HT1D subtypes.

Increase in serotonin-1A receptor responsiveness following haloperidol, withrawal

In view of a role of 5-hydroxtryptamine [serotonin; 5-HT]-1A receptors in the elicitation of extrapyramidal symptoms [EPS], The present study was designed to monitor pre- and postsynaptic responses to a selective 5 HT-1A ligand, 8-hydroxy-2- [di-n-propylamino] tetralin [8-OH-DPAT] following single and repeated [two times a day for 9 days] administration of haloperidol [5 mg/kg] in rats. The intensity of 5 H-T syndrome elicited by 8-OH-DPAT [0.5 mg/kg] was taken as measure of postsynaptic response. 8-OH-DPAT induced decreases of 5-HT metabolism in the striatum and brain were taken as a measure of postsynaptic response. 8-OH-DPAT induced forepaw treading and hyperlocomotion were smaller in haloperidol than saline injected rats. The decreases were not observed following withdrawal from repeated administration of haloperidol. Flat body posture not altered by single injection of haloperidol was enhanced following withdrawal from repeated administration of haloperidol. Haloperidol plus 8OH-DPAT injected animals exhibited comparable levels of 5-HT metabolism in the striatum as well as in the brain. Administration of 8-OH-DPAT significantly decreased 5-HT metabolism in brain but not in striatum of repeated saline injected animals. Conversely, same dose of 8-OH-DPAT injected to haloperidol-injected animals did not decrease 5-HT metabolism in the brain but decreased it in the striatum. The results show an increase in the responsiveness of pre-and postsynaptic 5-HT-responsiveness of post and presynaptic 5-HT-1A receptors may be involved in the greater incidence of EPS in patients treated with neuroleptics such as haloperidol

Evaluation of the role of melatonin in formalin-induced pain response in mice.

BACKGROUND: Melatonin, the major secretory product of pineal gland has been suggested to play a regulatory role in the circadian rhythm of body activities including the pain sensitivity. Three subtypes of melatonin receptors, i.e. ML1, ML2 and ML3 have been identified. AIM: To investigate the antinociceptive activity of melatonin and to unravel the underlying receptor mechanisms involved in this action. MATERIAL AND METHODS: Effect of melatonin (25-100 mg/kg, ip) and its interaction with putative melatonin receptor antagonists and opioidergic and serotoninergic agents have been studied in formalin test, a model of tonic continuous pain. Formalin (0.1 ml of 1% solution) was injected under the plantar surface of right hind paw of mice and the time an animal spent in licking the injected paw was measured. STATISTICAL ANALYSIS: The data were analysed by one-way ANOVA followed by Tukey's test for multiple comparisons. RESULTS: Injection of formalin produced two phases of intense licking, an early phase (0-5 min) and a late phase (20-25 min). Melatonin dose-dependently decreased the licking response in both the phases, effect being more marked in the late phase. Luzindole, a ML1 receptor antagonist did not block but rather enhanced the antinociceptive activity of melatonin. However, prazosin, a ML2 receptor antagonist in the low dose (0.5 mg/kg) significantly attenuated but in higher dose (1 mg/kg) enhanced the analgesic effect of melatonin. Naloxone, an opioid receptor antagonist did not reverse but morphine, an opioid agonist enhanced the antinociceptive activity of melatonin. Both mianserin and ondansetron the 5HT2 and 5HT3 receptor antagonists, respectively increased the analgesic effect of melatonin. CONCLUSION: The present results suggest the involvement of ML2 receptors in mediating the antinociceptive activity of melatonin in formalin-induced pain response. Further an interplay between melatonin, alpha-1 adrenergic and 5HT2 and 5HT3 serotoninergic receptors may also be participating in this action.

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.

Effect of the 5-HT3 receptor antagonist ondansetron on amphetamine-induced hyperactivity and stereotypy in rats.

The effects of different doses of ondansetron (0.1, 0.5, 1, 2 mg/kg) administered intra-peritoneally were studied on amphetamine-induced hyperactivity and stereotypy in wistar rats. Ondansetron was administered 30 minutes prior to d-amphetamine (3 mg/kg, i.p.). Ondansetron in doses of 0.5 and 1 mg/kg significantly decreased the mean number of head dippings and crossings in the hole board test and in doses of 0.1 and 0.5 mg/kg significantly decreased the average stereotypic score. Since the hyperactivity and stereotypy are dopamine mediated, the effect of ondansetron to reduce these states suggests a potential role for ondansetron in conditions with dopamine excess.

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

Involvement of dopamine D2 and 5-HT1A receptors in roxindole-induced antinociception.

Roxindole, a DA D2 receptor agonist (2-16 mg/kg) produced dose-dependent increase in percentage antinociception. The effect which was blocked by DA D2 antagonist (-)sulpiride (50 mg/kg) and 5-HT1A receptor antagonist (-) pindolol (5 mg/kg). Roxindole (4 and 8 mg/kg) reversed both naloxone (20 mg/kg)-induced hyperalgesia and reserpine (2 mg/kg)-induced hyperalgesia. This reversal was sensitive to blockade by both (-)sulpiride (50 mg/kg) and (-) pindolol (5 mg/kg). The present study suggests that roxindole-induced antinociception is mediated by postsynaptic DA D2 and 5-HT1A receptors.

5-HT2 receptor blockade by ICI 170.809 does not affect the inhibitory effect of the 5-HT1a receptor ligand gepirone on neuroleptic induced catalepsy

Considerable experimental evidence suggests that central dopaminergic (DA) transmission is under serotonergic (5-HTergic) modulation. For instance, neuroleptic-induced catalepsy (NIC) in rodents, a behavior mainly due to blockade of DA receptors in the striatum, can be affected by 5-HTergic manipulation. It has been shown that ligands of 5-HT1A receptors (e.g. buspirone, gepirone) reduce NIC, while 5-HT2 receptor antagonists (e.g. ritanserin) do not affect this phenomenon. However, the role of 5-HT2 receptors in the modulation of NIC is still controversial and there is evidence from behavioral models other than NIC suggesting the existence of functional interaction between the two subtypes of 5-HT receptors. The present study was designed to evaluate the effect of ICI 170,809 (a selective 5-HT2 receptor antagonist) on NIC and to test the possible effect of this drug on the anticataleptic effect of gepirone (GP). Male Wistar rats weighing 300-350 g were used, and each animal (7 per group, 4 groups) was used only once. Catalepsy was induced with haloperiodol (H; 1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Animals received either ICI 170,809 (3 mg/kg, ip) or 0.9 percent saline(SL; 0.8 ml, ip) 30 min before H. At 110 min after H, the rats received GP (1 mg/kg, ip) or SL (0.8 ml, ip). GP significantly attenuated NIC (e.g. 739 + or - 106 s vs 1009 + or - 85 s for controls, at 150 min after H), while ICI 170,809 did not significantly affect the phenomenon (e.g. 978 + or - 89 s vs 1009 + or - s for controls, at 150 min after H). Pretreatment with ICI 170,809 did not significantly modify the anticataleptic effect of GP (e.g. 617 + or - 90 s vs 739 + or - 106 s for SL-pretreated animals, at 150 min after H). These results confirm reports of the anticataleptic effect of GP and the lack of effect of 5-HT2 receptor antagonists on NIC. Moreover, these data also suggest the absence of functional interactions between central 5-HT1A and 5-HT2 receptors in this model of DA transmission

Estrogenic actions of norethisterone and its A-Ring reduced metabolites: induction of in vitro uterine sensitivity to serotonin

The estrogen-like effects of norethisterone (NET) seem to be mediated by the interaction of 3ß5alpha- and 3alpha-5alpha-tetrahydronorethisterone (3ß5alpha- and 3alpha5alpha-NET, respectively) with the estrogen receptor. Considering that the in vitro uterine contractile response to sertonin (5-HT) is specifically dependent on estrogen, the aim of the present study was to investigate whether NET and its A-ring reduced metabolites administered in vivo to ovariectomized rats induce uterine sentivity to 5-HT in vitro. The administration of 3ßNET in vivo, wich is the NET metabolite with the highes affinity for the estrogen receptor, induced a maximal contractile response to serotonin similar to that of 17ß-estradiol treatment. The other metabolites induced less uterine activity. According to the effective dose 50, the order of estrogenic potency was 17ß-estradiol>3ß5alphaNET>3alpha5alphaNET>NET>5alphaNET. The estrogenic effect of 3ß5alpha- and 3alpha5alphaNET may be exerted throug their interaction with the estrogen receptor, whereas NET and 5alphaNET, which do not bind to the estrogen receptor and display a minor estrogenic activity, require prior bioconversion to 3ß5alpha NET. The A-ring reduced metabolites of NET, mainly the 3ß5alphaNET, may be exerting estrogenic responses and modulation uterine activity when administered in vivo

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

Triptofano y su uso en medicina / Medical uses of tryptophan

Ha habido importantes avances en el conocimiento del metabolismo del triptofano, la síntesis de serotonina y los receptores serotoninérgicos encefálicos. Se ha determinado la efectividad terapéutica del 5-hidroxitriptofano en la depresión, insomnio, dolor crónico, mioclonías, etc. Eso sí, ha surgido inquietud al establecerse, como efecto adverso del tratamiento con L-triptofano, la producción del síndrome de mialgia-eosinofilia con compromiso importante de las fuerzas debido a una polineuropatía

Serotonergic modulation of spinal cord sympathetic preganglionic neurone activity in cardiovascular regulation.

The present study demonstrates the effect of activation of spinal serotonergic receptors on heart rate, blood pressure and cardiac arrhythmia induced by coronary artery ligation in cervical spinal cord transected and bilaterally vagotomized dogs. Intrathecal injection of serotonin (5-HT) evoked a fall in blood pressure (mean decrease, 16 +/- 3) and a decrease in heart rate (mean change, 24 +/- 6) and these effects were blocked by intrathecal pretreatment with methysergide. The magnitude of ventricular ectopics evoked by coronary artery ligation was decreased by serotonin (mean decrease, 31 +/- 5%), and this effect of serotonin was blocked by methysergide pretreatment intrathecally (mean change, 7 +/- 5%). Methysergide per se, increased the magnitude of ventricular ectopics (mean increase, 24 +/- 5%). The serotonergic receptors of the spinal cord appear to have an inhibitory influence on the cardiovascular functions.

Participation of the median raphe nucleus and central serotoninergic pathways in the control of water electrolyte excretion

1. The role of the median raphe nucleus (MRN) and of increased central serotonin (5HT) synthesis/release in the mediation of Na+ excretion (UNaV) and K+ excretion (UKV) and or urine output (UV) was evaluated for 120 min. 2. Male Wistar rats weighing 220-280g were used in each group of 12-13 animals. The rats implanted with a cannula in the MRN were injected with saline (0.5 µl) or with 5.0 and 15.0 ng/0.5 µl kainic acid (KA), an excitatory amino (EAA). Another group of rats was injected ip with 200 mg/Kg saline or tryptophan, the initial precursor of 5HT synthesis. 3. Injection of both kainic acid and tryptophan led to increased Na+ excretion, but the magnitude and time course were different for each treatment. Both KA doses were effective in increasing UNaV (0.061 ñ 0.08, mean ñ SEM, and 0.95 ñ 0.19 -Eq/min, respectively, vs 0.27 ñ 0.04 µEq/min for saline at 60 min). The effect on UKV was statistically significant with the 15.0 ng dose (0.44 ñ 0.05 µEq/min vs 0.25 ñ0.03 µEq/min for saline) at 20 min. 5. Tryptophan adminsitration caused an initial gradual increase in UNaV which became steady and significant after 60 min (1.02 ñ 0.15 µEq/min vs 0.36 ñ 0.06 µEq/min for saline), as well as an increase in UKV (0.58 ñ 0.06 µEq/min vs 0.26 ñ 0.04 µEq/min for saline) at 60 min and throught the remainder of the observation period. 6. KA-induced MRN stimulation and systemic tryptophan overload significantly increased UV at 60, 80 and 100 min (30 to 97% above control values). 7. These data show that kanic acid-mediated transmission at the MRN lellvel may play a modulatory role in hydromineral metabolism. The effects obtained after increased central availability of tryptophan suggest that the excretory response is associated with an increase in 5HT synthesis/release and with an increase in central transmission. 8. We conclude that the data obtained from CA-induced MRN stimulation and systemic tryptophan overload may possibly reflect an increased 5HT synaptic transmission at sites and efferent mechanisms that remain to be elucidated

Effects of ipsapirone and BAY R 1531 on learned helplessness

The effects of the 5-hydroxytryptamine-1A (5-HT1A) receptor agonists on the learned helplessness test were investigated. Rats were submited to a single session of 60 uncontrollable shocks (10-s duration, 1.0 mA, every 60 + or - 40 s) and then treated twice daily with ip ijections of either ipsapirone (13 mg/kg daily) or BAY R 1531 (0.375 mg/kg daily) for four consecutive days. On the last day, the animals were submitted to an escap test. The results showed that both drug treatments blocked the deficit in the escape learning (helplessness effect). These data suggest that drugs which stimulate 5-HT1A receptors have an antidepressant-like activity in this animal model of depression

Excitatory and inhibitory behavioral responses to the pharmacological stimulation of serotonergic function in dorsalis raphe lesioned rats

La lesion de neuronas 5-HT median te neurotoxinas induce supersensibilidad de receptores 5-HT1 sin afectar el "binding" de receptores 5-HT2. Este modelo fue utilizado en el presente trabajo para analizar el papel de ambos subtipos de receptores 5-HT en el mecanismo de control de las respuestas comportamentales excitatorias e inhibitorias provocadas por la estimulación farmacológica del sistema 5-HT. Las lesiones del rafe dorsales (RD) fueron hechas mediante inyección estereotáxica de ác. kaínico. Treinta días después las ratas RD y sus controles mostraron una actividad basal similar en "testes" de "hole board". Tres días después las ratas RD y sus controles fueron inyectadas ip con fluoxetina (5 y 10 mg/Kg) y 30 m después con 50HTP (15 y 30 mg/Kg). Imediatamente antes y después de cada inyección ip la respuesta excitatoria (síndrome mioclónico) fue evaluada. Las ratas RD y sus controles mostraron similares valores de mioclonías en respuesta a fluoxetina-5-HTP. La respuesta inhibitoria fue investigada en sesiones de "holeboard" a los 30 m de la segunda inyección ip. La lesión del RD potenció el efecto depresor de fluoxetina-5-HTP sobre el comportamiento. En concordancia con la literatura, la lesión del RD produjo una caída del 74.9% de la 5-HT del cerebro anterior y un incremento del 75% en el "bilding" de 3H-5HT en membranas corticales. En conclusión, los componentes de la respuesta excitatoria, que no se modificó por la lesión del RD, estarían relacionados principalmente con receptores 5-HT2. El aumento de la respuesta inhibitoria a la estimulación 5-HT observado en las rata lesionadas en RD estaría vinculado a la supersensibilidad de receptores 5-HT1

Fisiopatologia da síndrome do pânico / Physiopathology of panic syndrome

Qualquer pessoa pode ter um ataque de pânico, dependendo das condiçöes e circunstâncias do momento. Entretanto, a repetiçäo de ataques de pânico resulta em um conjunto de sintomas, emoçöes e alteraçöes de comportamento, denominado síndrome do pânico. Sintomas semelhantes aos dos ataques de pânico ocorrem em diversas doenças e síndromes médicas. Essas porém näo têm papel etiopatogênico nestes quadros. A fisiopatologia do pânico é concebida como uma ativaçäo intermitente, ictal, dos sistemas de reaçäo e defesa do sistema nervoso central, resultando em alerta central e autonômico generalizado. As principais hipóteses sobre a patogenia destes quadros (catecolaminas circulantes, sistema GABA/benzodiazepínicos, hiperatividade noradrenérgica central, lacto/"reddox" intraneuronal e supersensibilidade 5-HT) säo analisadas criticamente. A síndrome do pânico parece decorrer de uma baixa de limiar para esses ataques. Fatores emocionais, ambientais e "situacionais", provavelmente interagindo com uma disfunçäo biológica básica, determinam o momento da eclosäo das crises e sua progressäo para a síndrome do pânico