Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

Sertraline inhibits formalin-induced nociception and cardiovascular responses

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8/per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg-1·day-1, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5 percent (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7 percent), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9 percent, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.

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.

The role of magnesium sulfate in prevention of seizures induced by pentylenetetrazole in rats / O papel do sulfato de magnésio na prevenção de crises induzidas por pentilenotetrazol em ratos

Magnesium sulfate (MgSO4) has been used to prevent seizures in eclampsia. This study examined the central effects of MgSO4 on different types of pentylenetetrazole (PTZ)-induced seizures. Male Wistar rats were submitted to intracerebroventricular (ICV) administration of MgSO4 at different doses followed by intraperitoneal administration of PTZ. The latency to the onset of the first seizure induced by PTZ was significantly increased by ICV administration of MgSO4 at a dose of 100 µg compared to the control treatment. In addition, the total period during which animals presented with seizures was significantly reduced at this dose of MgSO4. Furthermore, the latency to the onset of the first partial complex seizure was significantly increased by the lowest dose of MgSO4. However, a high dose of MgSO4 had no effect or even potentiated the effect of PTZ. These results suggest that, depending on the dose, MgSO4 may be important in prevention of epileptic seizures.

Sulfato de magnésio (MgSO4) é utilizado para prevenir crises epilépticas na eclampsia. Este estudo examina os efeitos do MgSO4 em diferentes tipos de crise induzidas por pentilenotetrazol (PTZ). Ratos Wistar foram submetidos à administração intracerebroventricular (ICV) de diferentes doses de MgSO4 seguida de administração intraperitoneal de PTZ. A latência para o início da primeira crise induzida por PTZ foi aumentada pela administração ICV de MgSO4 na dose de 100 µg quando comparada ao tratamento controle. Além disso, o período durante o qual os animais apresentaram crises foi reduzido com a mesma dose de MgSO4. A latência para o início da primeira crise parcial complexa também foi aumentada com a dose menor de MgSO4 (32 µg). No entanto, a maior dose (320 µg) de MgSO4 não foi efetiva ou até potencializou os efeitos do PTZ. Esses resultados sugerem que, dependendo da dose, o MgSO4 pode ser útil na prevenção de crises epilépticas.

Role of the caudal pressor area in the regulation of sympathetic vasomotor tone

It is well known that the ventrolateral medulla contains neurons involved in the tonic and reflex control of the cardiovascular system. Two regions within the ventrolateral medulla were initially identified: the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Activation of the RVLM raises arterial blood pressure and sympathetic nerve activity, and activation of the CVLM causes opposite effects. The RVLM premotor neurons project directly to sympathetic preganglionic neurons and are involved in the maintenance of resting sympathetic vasomotor tone. A significant proportion of tonic activity in the RVLM sympathetic premotor neurons is driven by neurons located in a third region of the ventrolateral medulla denominated caudal pressor area (CPA). The CPA is a pressor region located at the extreme caudal part of the ventrolateral medulla that appears to have an important role controlling the activity of RVLM neurons. In this brief review, we will address the importance of the ventrolateral medulla neurons for the generation of resting sympathetic tone related to arterial blood pressure control focusing on two regions, the RVLM and the CPA.

Acute effects of selective serotonin reuptake inhibitors on neuroleptic-induced catalepsy in mice

Depression found in Parkinson disease (PD) usually responds to selective serotonin reuptake inhibitors (SSRIs). Drugs that modify experimental neuroleptic catalepsy (NC) might affect extrapyramidal symptoms in PD. Therefore, the effects of SSRIs on NC were tested in mice, 26-36 g, separated by sex. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals using a bar test. An SSRI (sertraline, ST; paroxetine, PX; fluoxetine) or vehicle (C) was injected ip 30 min before H. Dunnett's test was used for comparison of means. ST (1-5 mg/kg) or PX (1-5 mg/kg) attenuated NC, with a similar inhibition found in both sexes (5 mg/kg, 180 min: ST - males: 124 ± 10 vs 714 ± 15 s in C; females: 116 ± 10 vs 718 ± 6 s in C; PX - males: 106 ± 10 vs 714 ± 14 s in C; females: 102 ± 10 vs 715 ± 14 s in C). At 0.3 mg/kg, neither of these drugs affected NC. Fluoxetine (1-25 mg/kg) also inhibited catalepsy, although the effect was not dose-dependent; no differences were observed between males and females (5 mg/kg, 180 min: males, 185 ± 14 vs 712 ± 14 s in C; females, 169 ± 10 vs 710 ± 19 s in C). For these SSRIs, maximal inhibition of NC was obtained with 5 mg/kg, 180 min after H. These results are consistent with the hypothesis that serotonergic mechanisms modulate nigrostriatal transmission, and suggest that SSRIs are possibly safe in depressive PD patients.

Functional mapping of the cardiorespiratory effects of dorsal and median raphe nuclei in the rat

The dorsal (DRN) and median (MRN) raphe nuclei are important sources of serotonergic innervation to the forebrain, projecting to sites involved in cardiovascular regulation. These nuclei have been mapped using electrical stimulation, which has the limitation of stimulating fibers of passage. The present study maps these areas with chemical stimulation, investigating their influence on cardiorespiratory parameters. Urethane-anesthetized (1.2 g/kg, iv) male Wistar rats (280-300 g) were instrumented for pulsatile and mean blood pressure (MBP), heart rate, renal nerve activity, and respiratory frequency recordings. Microinjections of L-glutamate (0.18 M, 50-100 nl with 1 percent Pontamine Sky Blue) were performed within the DRN or the MRN with glass micropipettes. At the end of the experiments the sites of microinjection were identified. The majority of sites within the MRN (86.1 percent) and DRN (85.4 percent) evoked pressor responses when stimulated (DRN: deltaMBP = +14.7 ± 1.2; MRN: deltaMBP = +13.6 ± 1.3 mmHg). The changes in renal nerve activity and respiratory rate caused by L-glutamate were +45 ± 11 and +42 ± 9 percent (DRN; P < 0.05 percent), +40 ± 10 and +29 ± 7 percent (MRN, P < 0.05), respectively. No significant changes were observed in saline-microinjected animals. This study shows that: a) the blood pressure increases previously observed by electrical stimulation within the raphe are due to activation of local neurons, b) this pressor effect is due to sympathoexcitation because the stimulation increased renal sympathetic activity but did not produce tachycardia, and c) the stimulation of cell bodies in these nuclei also increases the respiratory rate.

Gender-related differences in the effects of nitric oxide donors on neuroleptic-induced catalepsy in mice

It has been suggested that nigrostriatal dopaminergic transmission is modulated by nitric oxide (NO). Since there is evidence that gonadal hormones can affect extrapyramidal motor behavior in mammals, we investigated the effects of isosorbide dinitrate (ISD), linsidomine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP), three pharmacologically different NO donors, on neuroleptic-induced catalepsy in 60- to 80-day-old male and female albino mice. Catalepsy was induced with haloperidol (1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Drugs (or appropriate vehicle) were injected ip 30 min before haloperidol, with each animal being used only once. ISD (5, 20 and 50 mg/kg) caused a dose-dependent inhibition of catalepsy in male mice (maximal effect 120 min after haloperidol: 64 percent inhibition). In the females only at the highest dose of ISD was an attenuation of catalepsy observed, which was mild and short lasting. SIN-1 (10 and 50 mg/kg) did not significantly affect catalepsy in female mice, while a significant attenuation was observed in males at the dose of 50 mg/kg (maximal inhibition: 60 percent). SNAP (20 mg/kg) significantly attenuated catalepsy in males 120 min after haloperidol (44 percent inhibition), but had no significant effect on females. These results basically agree with literature data showing that NO facilitates central dopaminergic transmission, although the mechanisms are not fully understood. They also reveal the existence of gender-related differences in this nitrergic modulation in mice, with females being less affected than males

Excitatory amino acid receptor blockade within the caudal pressor area and rostral ventrolateral medulla alters cardiovascular responses to nucleus raphe obscurus stimulation in rats

Pressor responses elicited by stimulation of the nucleus raphe obscurus (NRO) depend on the integrity of the rostral ventrolateral medulla (RVLM). Therefore, to test the participation of excitatory amino acid (EAA) receptors in the cardiovascular responses evoked by NRO stimulation (1 ms, 100 Hz, 40-70 æA, for 10 s), the EAA antagonist kynurenic acid (Kyn) was microinjected at different sites in the ventrolateral medullar surface (2.7 nmol/200 nl) of male Wistar rats (270-320 g, N = 39) and NRO stimulation was repeated. The effects of NRO stimulation were: hypertension (deltaMAP = +43 ± 1 mmHg, P<0.01), bradycardia (deltaHR = -30 ± 7 bpm, P<0.01) and apnea. Bilateral microinjection of Kyn into the RVLM, which did not change baseline parameters, almost abolished the bradycardia induced by NRO stimulation (deltaHR = -61 ± 3 before vs -2 ± 3 bpm after Kyn, P<0.01, N = 7). Unilateral microinjection of Kyn into the CVLM did not change baseline parameters or reduce the pressor response to NRO stimulation (deltaMAP = +46 ± 5 before vs +48 ± 5 mmHg after Kyn, N = 6). Kyn bilaterally microinjected into the caudal pressor area reduced blood pressure and heart rate and almost abolished the pressor response to NRO stimulation (deltaMAP = +46 ± 4 mmHg before vs +4 ± 2 mmHg after Kyn, P<0.01, N = 7). These results indicate that EAA receptors on the medullary ventrolateral surface play a role in the modulation of the cardiovascular responses induced by NRO stimulation, and also suggest that the RVLM participates in the modulation of heart rate responses and that the caudal pressor area modulates the pressor response following NRO stimulation

Cardiovascular and respiratory responses to microinjection of L-glutamate into the caudal pressor area in conscious and anesthetized rats

The role of the caudal pressor area (CPA) in the maintenance of vasomotor tonus in anesthetized and decerebrate animals has been clearly established. In conscious animals, however, the participation of CPA in the cardiovascular control remains to be fully elucidated. In the present study, unilateral L-glutamate (L-Glu) (10 and/or 20 nmol/70 nl) microinjection into CPA, in conscious male Wistar rats (250-280 g) caused a significant increase in mean arterial blood pressure (MAP; control: 112 + or - 1.9 mmHg; after 20 nmol L-Glu: 139 + or - 4.5 mmHg, N = 12, P<0.05) and respiratory rate (control: 81 + or - 3.5 breaths/min; after 10 nmol L-Glu: 92 + or - 3 breaths/min, P<0.05; after 20 nmol L-Glu: 104 + or - 5 breaths/min, N = 6, P<0.05). The subsequent anesthesia with urethane caused a significant increase in basal respiratory frequency (conscious: 81 + or - 3.5 breaths/min; under urethane: 107 + or - 1.3 breaths/min, N = 6, P<0.05). Anesthesia also significantly attenuated L-Glu-evoked pressor (conscious: deltaMAP = +27 mmHg; anesthetized: deltaMAP = +18 mmHg, P<0.05) and respiratory responses. These results suggest that glutamatergic receptors in the CPA are involved in cardiovascular and respiratory modulation in conscious rats

Evidence of interaction between fluoxetine and isosorbide dinitrate on neuroleptic-induced catalepsy in mice

Drugs which influence 5-HTergic mechanisms can modify neuroleptic-induced catalepsy (NC) in rodents, a phenomenon produced by striatal dopamine (DA) receptor blockade. Previous research also suggests a role for endogenous nitric oxide (NO) in the modulation of striatal DAergic neurotransmission; in addition, NO seems to play a role in the 5-HT reuptake mechanism. It is known that clomipramine potentiates NC in mice, but the reported effects of selective 5-HT reuptake inhibitors(SSRIs) in this model are rather contradictory. We then decided to re-address this issue, investigating the effect of fluoxetine (FX), an SSRI, on NC. In view of the ubiquitous role of NO as a central neuromodulator, we also studied the effect of isosorbide dinitrate (ID), a centrally active NO donor, and how both drugs interact to effect the phenomenon of NC. Catalepsy was induced in male albino mice with haloperidol (H; 1 mg/kg, ip) and measured at 30-min interval by means of a bar test. Drugs (FX, ID and FX + ID) or saline (controls) were injected ip 30 min before H, with each animal used only once. FX (5 mg/kg) significantly reduced NC, with maximal attenuation (about 74 percent) occurring at 150 min after H. ID (5 mg/kg) also inhibited NC (150 min: 62 percent attenuation). The combined drugs (FX + ID group), however caused a great potentiation of NC (4.7-fold at its maximum, at 90 min). The effect observed with ID is compatible with the hypothesis that NO increases DA release in the striatum. The attenuation of NC observed with FX may be due to a preferential net effect oon the raphe somatodendritic synapse, where inhibitory 5-HT(1A) autoreceptors are operative. The enhancement of NC caused by combined administration of FX and ID suggests the presence of a pharmacodynamic interaction, whose mechanism, still unclear, may be related to a decrease in striatal DA release.

Pressor effects elicited by stimulation within the medullary raphe nuclei of the guinea pig (Cavia porcellus)

The medullary raphe nuclei are involved in central autonomic regulation. In all species investigated, electrical stimulation of the raphe nuclei causes cardiovascular responses, although, these changes vary between species. The present study was designed to investigate the participation of these nuclei in cardiovascular regulation in the guinea pig. We studied the effect on arterial blood pressure (BP) and heart rate (HR) of electrical stimulation (isolated cathodal square wave pulses for 10 s at 100 Hz, 40-100 muA and 1-ms pulse duration) within the medullary raphe nuclei in urethane-anesthetized (1.2g/kg, i.p.) guinea pigs (400-600g. either sex). Electrical stimulation of the same sites was performed on a group of paralyzed (Flaxedil®, 1 mg/kg, i.v.) and artificially ventilated animals. Stimulation sites were histologically defined and maps of the stimuli were obtained for the effect of electrical stimulation on arterial blood pressure. In another series of experiments, L-glutamate (0.2 M) was microinjected (75 to 150 nl) into the nucleus raphe obscurus. Electrical stimulation of the raphe nuclei produced predominantly pressor responses (delta= +15 to +100 mmHg: 43 percent of the stimulated sites). Hypotension (delta= -10 to -25 mmHg, 24 percent of the stimulated sites), biphasic responses (2 percent) or no change in BP (31 percent) were evoked from fewer stimulation sites. Pressor responses were also predominant in paralyzed animals (delta= +15 to +95 mmHg; 47 percent of the stimulates sites), and after microinjection of L-glutamate into the raphe obscurus (A= +20 to +45 mmHg). The present results demonstrate that in the guinea pig the stimulation of these nuclei evokes mainly pressor responses. These responses are similar to those obtained in the rat and hamster but opposite to those observed in the cat and rabbit.

Effects of losartan on neuroleptic-induced catalepsy in mice

Neuroleptic-induced catalepsy remains a useful method to study central dopaminergic function in rodents. Evidence obtained in several studies indicates that this phenomenon can be modified by cholinergic, histaminergic and serotonergic manipulation. Angiotensin II is a central neurotransmitter acting through AT1 and AT2 receptors. There are few data on the effect of angiotensinergic drugs on dopaminergic transmission. We investigated the effect of losartan, a nonpeptide antagonist of central and peripheral AT1 receptors, on neuroleptic-induced catalepsy. Adult male albino mice, 26-35 g, were used. Catalepsy was induced with haloperidol (H; l mg/kg, ip) and measured at 30-min intervals by means of a bar test. Losartan (10 or 100 ng/kg) or saline (control; 0.13 ml) was injected intraperitoneally 20 min before H, with each animal (7 per group) being used only once. Losartan (10 and 100 ng/kg) significantly (P<0.05) potentiated the cataleptic effect of H in comparison to the control group (e.g. 264 ñ 26 and 299 ñ 68 sec, respectively, vs 89 ñ 24 sec for the control group, 90 min after H). No differences were demonstrable 120, 150 or 180 min after H. Considering the high selectivity and the pharmacokinetic properties of losartan, these data suggest that central angiotensin AT1 receptors play a role in neuroleptic-induced catalepsy. However, further studies are necessary to confirm this hypothesis and to clarify the mechanism(s) involved in this process.

Are 5-HT1A receptors involved in the control of reflex bradycardia induced by intracoronary injection of contrast medium in humans?

Transient vagal bradycardia occuring during coronary arteriography (CA) immediately following intracoronary injection of ionic contrast medium is believed to be a component of the von Bezold-Jarisch reflex (BJ). Data obtained from experimental animals using buspirone (BSP) and other 5-HT1A receptor ligands suggest that these serotonergic receptors modulate the excitability of cardiac vagal motoneurones (CVM). This is a preliminary investigation of the possible effects of BSP in altering the bradycardia of patients submitted to CA for diagnostic purpose. Patients were divided into two age-and racematched groups: control (C:N=45, age 58.6 + 1.6 years, mean arterial blood pressure (MAP) 109 + 2.4 mmHg, heart rate (HR) 79 + 2.9 bpm) and BSP-treated (B:N=14, age 58.9 + 2.1 years, MAP 111 + 4.5 mmHg, HR 76 + 3.4 bpm). The prevalent underlying pathology was coronary artery disease. Patients with acute angina, congestive heart failure, symptomatic arrhythmia and patients requiring atropine were excluded. CA was performed by a standard procedure using diatrizoate (MD-76() as contrast agent. The left and then the right coronary ostia were selectively catheterized and 8 ml of contrast medium was injected (over a period of 3 sec). HR was measured from ECG tracing before and after contrast injection into the left (LC) and right (RC) coronary arteries. Peak bradycardia was measured as the longest R-R interval during the first 15 sec after the injection minus the pre-injection R-R value, and reported as deltaR-R. Group B patients received BSP tablets 48 and 24 h before the examination (30 mg/day po). There was no statistically significant difference (P>0.05) in bradycardia between groups (C:LC=-147 + 23,RC=-155+25; B:LC=-143 + 44,RC=-234 + 56 msec). These results suggest that, in contrast to experimental animals, the central 5-HT1A receptors of humans are not relevant for modulating the excitability of CVM in the BJ reflex. However, since drugs and diseases can affect the responses, further studies are necessary to clarify this issue.

Pressor effects elicited by stimulation within the medullary raphe nuclei of the golden hamster (Mesocricetus auratus)

The medullary raphe nuclei are involved in central autonomic regulation. In all species investigated, electrical stimulation of the raphe nuclei causes cardiovascular responses, although these changes vary between species. The present study was designed to investigate the participation of these nuclei in cardiovascular regulation in the hamster. We studied the effect on arterial blood pressure (BP) and heart rate (HR) of electrical stimulation (isolated cathodal square wave pulses for 10 sec at 100 Hz, 40-100 muA and 1-msec pulse duration) within the medullary raphe nuclei in urethane-anesthetized (1.2 g/kg, iv, after ether induction) golden hamsters (Mesocricetus auratus, 130 to 150 g, either sex). Electrical stimulation of the same sites was performed on a group of paralysed (Flaxedi1(, 1 mg/kg, iv) and artificially ventilated animals. Stimulation sites were histologically defined and maps of the stimuli were obtained for the effect of electrical stimulation on arterial blood pressure. In another series of experiments L-glutamate (0.18 M) was microinjected (75 to 150 nl) into the nucleus raphe obseurus. Electrical stimulation of the raphe nuclei produced predominantly pressor responses (delta =+ 12 to + 100 mmHg; 49.3 per cent of the stimulated sites). Hypotension (delta =-5 to -20 mmHg; 14.6 per cent of the stimulated sites) and no change in BP (35.3 per cent) were evoked from fewer stimulation sites. Pressor responses were also predominant in paralysed animals (delta =+ 15 to + 95 mmHg; 62.5 per cent of the stimulated sites), and after microinjection of L-glutamate into the raphe obscurus (delta = +35 to + 135 mmHg). The present results demonstrate that in the hamster the stimulation of these nuclei evokes mainly pressor responses. These responses are similar to those obtained in the rat and guinea pig but opposite to those observed in the cat and rabbit.

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

A comparison of the effects of eserine sulfate on the activity of medullary raphe neurons in the anesthetized rabbit and rat

1. Medullary raphe neurons are involved in the control of sympathetic activity during desynchronized sleep (DS). Eserine sulfate induces a state with the somatic and visceral signs of DS in decerebrate animals. The rabbit and rat display diverse hemodynamic patterns during DS. 2. To determine whether eserine sulfate provokes different responses in the medullary raphe neuron population of these different species, the drug (100 mg/kg, i.v.) was administered to urethane-anesthetized (1.2 g/kg, i.v.) rabbits (1.5-3.0 kg) and rats (Wistar, 260-310 g). 3. Extracellular activity was recorded from 66 neurons in 30 rats. Cholinergic stimulation provoked an increase in discharge rate (DR) in 45 neurons (68), a decrease in 8 neurons (12) and no change in 13 neurons (20). Recordings were obtained from 30 neurons in 11 rabbits. Stimulation of these cells provoked an increase in DR in 17 neurons (57), a decrease in DR in 7 neurons (23) and no change in 6 neurons (20). Interspike interval and auto-correlation analysis was performed on 28 rat and rabbit neurons. No significant difference was found between the rat and the rabbit with respect to the number of the neurons which were either inhibited or excited by cholinergic stimulation (P > 0.05). Similarly, unit response to eserine was not related to whether the unit displayed regular or irregular DR. 4. Therefore, we suggest that the diverse hemodynamic patterns during DS and the distinct cardiovascular responses to raphe nuclei stimulation are not due to differences in the organization of the raphe nuclei themselves but to differences in their axonal projections or in the postsynaptic receptors activated in the intermediolateral cell column or other postsynaptic targets.

Effects of the 5-HT receptor antagonists cyanopindolol, ICI 169,369, cisapride and granisetron on neuroleptic-induced catalepsy in mice

Typical neuroleptics (e.g. haloperidol) can induce catalepsy in rodents. Selective 5-hydroxytryptamine1A (5-HT1A) receptor antagonists reduce neuroleptic-induced catalepsy (NIC), suggesting that this subtype of serotonin receptor plays a role in the modulation of nigrostriatal dopaminergic transmission. The present study was designed to evaluate the participation of other 5-HT receptor subtypes in NIC. Adult albino mice (both sexes, 26-35 g) were used. Catalepsy was induced with haloperidol (H; 1.5 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Cyanopindolol (a 5-HT1B receptor antagonist), ICI 169,369 (a 5-HT1C/2 receptor antagonist) and granisetron (a 5-HT3 receptor antagonist) were used. Buspirone, a 5-HT1A partial antagonist, cisapride, a 5-HT3/5-HT4 ligand and clomipramine, a 5-HT neuronal uptake blocker, were also employed. These drugs were injected ip, 20 min before H, with each animal (9-10 per group) used only once. Cyanopindolol (0.3 mg/kg) or ICI 169,369 (5 mg/kg) did not significantly affect NIC (375 +/- 39 and 378 +/- 34 s vs 372 +/- 44 s for controls, at 2 h after H). Buspirone (1 mg/kg) reduced, while pretreatments with either granisetron (0.5 mg/kg), cisapride (5 mg/kg) or clomipramine (5 mg/kg) potentiated the cataleptic effect of H (107 +/- 19, 576 +/- 52, 815 +/- 76 and 800 +/- 97 s vs 374 +/- 40 s in the control group, at 2 h after H).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the rostral ventrolateral medulla in the pressor response to stimulation of the nucleus raphe obscurus

1. Electrical stimulation of the nucleus raphe obscurus (NRO) in urethane-anesthetized rats increases arterial blood pressure (BP) between 20 and 95 mmHg (mean, 61.14 +/- 6.57; N = 30). 2. Unilateral electrolytic destruction of the rostral ventrolateral medulla (RVLM) did not reduce BP or heart rate (HR) but significantly reduced the pressor response to NRO stimulation (control, delta 76.0 +/- 5.4 mmHg; after lesion, delta 26.0 +/- 13.9 mmHg; P < 0.01, N = 5). 3. Bilateral destruction of the RVLM reduced basal BP (control, 104.1 +/- 11.4 mmHg; after lesion, 58.0 +/- 5.7 mmHg; P < 0.01) and the pressor response to NRO stimulation (control, delta 71.6 +/- 7.3; after lesion, delta 12.5 +/- 3.8 mmHg; P < 0.01, N = 6). 4. When topically applied to or microinjected into the RVLM, pentobarbital sodium (200 nl/1 microliters, 10 nmol) decreased BP, HR and the pressor response to NRO stimulation (control, delta 56.2 +/- 6.7 mmHg; after pentobarbital, delta 11.2 +/- 3.1 mmHg; P < 0.01, N = 13). Similar effects were obtained when glycine (200 nl, 50 nmol) was microinjected into RVLM (control, delta 40.5 +/- 5.9 mmHg; after glycine, delta 18.1 +/- 4.9 mmHg; P < 0.01, N = 6). 5. We conclude that RVLM is essential for the pressor response to NRO stimulation

Influence of median raphe nucleus lesions on neuroleptic-induced catalepsy and on the anticataleptic effect of buspirone

Catalepsy induced by neuroleptics in rats can be modified by 5-hydroxytryptaminergic (5-HTergic) manipulation. For example, buspirone (BUS) and other central 5-HT1A receptor ligands reduce neuroleptic-induced catalepsy (NIC). The dorsal (DRN) and median (MRN) raphe nuclei are reported to be important sources of 5-HTergic projections to the basal ganglia, the site of action of neuroleptics in producing NIC. A previous study showed that lesion of DRN did not affect NIC or the anticataleptic effect of BUS. The present study was designed to evaluate the participation of MRN in NIC and in the anti-NIC effect of BUS. Twenty-four male Wistar rats (N = 6/group) weighing 220-250 g were used. Electrolytic lesion of MRN was carried out in anesthetized rats along with sham operations (electrode inserted but no current applied). Ten days later, the rats were injected with BUS (5 mg/kg, ip) or saline (1 ml, ip). Catalepsy was induced 20 min later with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. The Costall per cent Naylor method of scoring (range 0-5 points) was used. Saline-injected MRN-lesioned rats displayed significantly lower catalepsy scores than sham-lesioned rats (1.5 +/- 0.2 vs 3.8 +/- 0.3 at 90 min after H). In sham-lesioned rats, BUS significantly reduced the catalepsy scores in comparison with saline-treated animals (1.3 +/- 0.2 vs 3.8 +/- 0.3 at 90 min after H). However, BUS was not able to further reduce NIC in the MRN-lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)