Electrophysiological evidence for a dopaminergic action of LSD: depression of unit activity in the substantia nigra of the rat.

LSD (25–50 μg/kg, i.v.) significantly decreased the firing rate of 78% of the dopamine-containing neurons in the substantia nigra of chloral hydrate anesthetized rats. In a subgroup of neurons (22%), LSD either had no clear effect or caused a slight excitation. On the other hand, brom-LSD (100 μg/kg, i.v.), a non-hallucinogenic congener of LSD, had no effect on 71% of dopaminergic cells and slightly reduced the firing rate with 29% of the units. Pretreatment with haloperidol (0.1 mg/kg) blocked the inhibitory effects of LSD, and haloperidol injected following LSD reversed its depressive effects. Non-dopaminergic neurons in the region of the substantia nigra typically showed large increases in firing rate in response to LSD administration. The inhibitory effects of LSD on dopamine-containing neurons are probably not attributable to the serotonergic properties of LSD, since 5-methoxy N,N dimethyltryptamine (25–100 μg/kg), which has central serotonergic properties similar to those of LSD, produced exclusively excitatory effects on the firing rate of dopaminergic cells. These electrophysiological results are consistent with recent behavioral and neurochemical data which suggest that LSD can act as a dopamine agonist in the CNS.     

Electrophysiological assessment of putative antagonists of 5-hydroxytryptamine receptors: a single-cell study in the rat dorsal raphe nucleus

The intravenous administration of low doses of lysergic acid diethylamide (LSD) or of the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) depresses the firing activity of dorsal raphe 5-HT-containing neurons, presumably via the activation of 5-HT1A receptors. The present studies were undertaken to determine the effect of different types of 5-HT receptor antagonists on this effect of LSD and 8-OH-DPAT. (-)-Propranolol (2 mg/kg i.v.), methiothepin (2 mg/kg i.p., twice daily for 4 days followed by an additional dose of 2 mg/kg i.p., prior to the experiment), pelanserine (0.5 mg/kg i.v.), and indorenate (125 micrograms/kg i.v.) failed to block the effects of either LSD or 8-OH-DPAT on the firing activity of 5-HT neurons of the dorsal raphe nucleus. However, spiperone (1 mg/kg i.v.) significantly reduced the effect of both LSD and 8-OH-DPAT. These results indicate that, among the five putative 5-HT receptor antagonists tested, only spiperone can antagonize the suppressant effect of 5-HT receptor agonists on the firing of dorsal raphe 5-HT neurons.     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

Dopamine D3 (Auto)receptors Inhibit Dopamine Release in the Frontal Cortex of Freely Moving Rats In Vivo

Abstract: In freely moving rats, the novel, selective dopamine (DA) D₃ receptor agonist PD 128,907 dose-dependently [effective dose (ED₂₅) = 0.07 mg/kg, s.c.] reduced dialysate levels of DA in the frontal cortex, a structure innervated by the ventral tegmental area (VTA). This action of PD 128,907 (0.16 mg/kg, s.c.) was abolished by a selective DA D₃ receptor antagonist S 14297 (1.25 mg/kg, s.c.), which alone did not modify levels of DA. In contrast to S 14297, its inactive distomer, S 17777, did not modify the actions of PD 128,907. In addition, PD 128,907 dose-dependently and potently inhibited the firing rate of VTA-localized neurons in anesthetized rats (ED₅₀ = 0.001 mg/kg, i.v.). S 14297, but not S 17777, completely reversed the actions of PD 128,907 (0.005 mg/kg, i.v.) with a 50% inhibitory dose of 0.03 mg/kg, i.v. and did not itself significantly modify the firing rate. In conclusion, these data provide the first direct evidence that DA D₃ (auto)receptors modulate (inhibit) the release of DA in the frontal cortex.     

Comparison of the discriminative stimulus effects of midazolam after intracranial and peripheral administration in the rat.

Rats were trained in a two-lever drug discrimination paradigm to discriminate midazolam (0.32 mg/kg, i.p. or 1.0 mg/kg, i.p.) from the no-drug condition. After completion of i.p. and s.c. midazolam generalization gradients (0.032-1.0 mg/kg), rats were surgically implanted with unilateral cannulae into the lateral ventricles. Intracerebroventricular (i.c.v.) doses of 1.1-44.2 micrograms midazolam were delivered to unrestrained rats. Midazolam produced dose-dependent increases in drug-appropriate responding by all three routes of administration, but was 2.4- to 4.3-fold more potent when given i.c.v. than when given s.c. or i.p. Midazolam, over the dose range tested, did not produce substantial decreases in response rate by any route of administration. The discriminative-stimulus effect of i.c.v. midazolam was blocked by peripherally administered flumazenil, and such antagonism was surmounted by a 2- to 5-fold increase in the i.c.v. midazolam dose. Taken together, these data suggest that the discriminative-stimulus effects of midazolam are mediated via central benzodiazepine (BZ) receptors.     

Central cardiovascular and thermal effects of prostaglandin F2 alpha in rats.

Administration of PGF2 ALPHA (0.2--6.4 micrograms) into the lateral cerebral ventricle (i.c.v.) induced dose-dependent increases in blood pressure, heart rate and body temperature in urethane-anaesthetised rats, but had no effect on these parameters when the same dose range was administered intravenously. Peripheral pretreatment with sodium meclofenamate (50 mg/kg s.c.) shifted all the dose-response curves for PGF2 alpha (i.c.v.) to the left, but indomethacin (50 mg/kg s.c.) did not significantly affect those changes. Central pretreatment with sodium meclofenamate or indomethacin (1.25 mg per rat i.c.v.) failed to modify significantly the effects of centrally administered PGF2 alpha. The results support previous suggestions that PGF2 alpha may participate in the central control of the cardiovascular and thermoregulatory systems, and also suggest that there may be differences in the sites and/or modes of action between sodium meclofenamate and indomethacin.     

Stress-accentuation of the LSD-induced disaggregation of brain polysomes

The application of three types of stress; restraint, food deprivation or epinephrine injection markedly accentuated the disaggregation of rabbit brain polysomes to monosomes induced by LSD (25 μg/kg) whereas no shift of polysomes to monosomes was found with any of the stress treatments alone. LSD when administered intravenously at a very low dose of 1 μg/kg and combined with the restraint procedure produced a massive brain polysome shift. LSD alone at this dosage did not induce a disaggregation of polysomes. Elevations in plasma corticosteroid levels relative to control were found following LSD administration with or without the stressing procedures. LSD and certain elements of environment and physiological arousal appear to have a synergistic effect on disrupting the protein synthesis apparatus of brain.     

CGS8216 noncompetitively antagonizes the discriminative effects of diazepam in rats

The benzodiazepine antagonist properties of CGS8216 were evaluated in rats trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice, stimulus-shock termination procedure. CGS8216 (0.3 to 100 mg/kg) administered alone, either s.c., p.o. or i.p., occasioned only saline-appropriate responding. When administered concomitantly with a constant 1.0 mg/kg dose of diazepam, CGS8216 produced dose-related decreases in drug-appropriate responding. CGS8216 was most potent by the i.p. route, and approximately tenfold less potent by the oral route. CGS8216 was dermatotoxic after s.c. administration. CGS8216 i.p. had a long duration of action. A dose of 30 mg/kg completely antagonized the discriminative effects of the 1.0 mg/kg training dose of diazepam when the antagonist was administered 8 hr before the start of the test session. In order to determine the type of antagonism by CGS8216, the dose-effect curve for diazepam was redetermined in the presence of varying doses of CGS8216 (0.3 to 3.0 mg/kg, i.p.). CGS8216 produced a dose-related rightward shift in the diazepam dose-effect curve, but also decreased the slope and appeared to decrease the maximal effect. These results are consistent with the interpretation that CGS8216 antagonizes diazepam in a noncompetitive manner. It may do so because either it interacts with a subpopulation of benzodiazepine receptors, it functions as a pseudo-irreversible antagonist due to its high affinity, or because it is an antagonist with agonist properties.     

Effects of long-term pretreatment with isoproterenol on bromocriptine-induced tachycardia in conscious rats

It has been shown that bromocriptine-induced tachycardia, which persisted after adrenalectomy, is (i) mediated by central dopamine D2 receptor activation and (ii) reduced by 5-day isoproterenol pretreatment, supporting therefore the hypothesis that this effect is dependent on sympathetic outflow to the heart. This study was conducted to examine whether prolonged pretreatment with isoproterenol could abolish bromocriptine-induced tachycardia in conscious rats. Isoproterenol pretreatment for 15 days caused cardiac hypertrophy without affecting baseline blood pressure and heart rate. In control rats, intravenous bromocriptine (150 microg/kg) induced significant hypotension and tachycardia. Bromocriptine-induced hypotension was unaffected by isoproterenol pretreatment, while tachycardia was reversed to significant bradycardia, an effect that was partly reduced by i.v. domperidone (0.5 mg/kg). Neither cardiac vagal nor sympathetic tone was altered by isoproterenol pretreatment. In isolated perfused heart preparations from isoproterenol-pretreated rats, the isoproterenol-induced maximal increase in left ventricular systolic pressure was significantly reduced, compared with saline-pretreated rats (the EC50 of the isoproterenol-induced increase in left ventricular systolic pressure was enhanced approximately 22-fold). These results show that 15-day isoproterenol pretreatment not only abolished but reversed bromocriptine-induced tachycardia to bradycardia, an effect that is mainly related to further cardiac beta-adrenoceptor desensitization rather than to impairment of autonomic regulation of the heart. They suggest that, in normal conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at peripheral dopamine D2 receptors.     

Effect of D-Ala-2-Me-Phe-4-Gly-ol-5 enkephalin on epinephrine-induced arrhythmias in the rat and the interrelationship to the parasympathetic nervous system

The purpose of this study was to evaluate the effects of the millimicrons opioid agonist D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) on catecholamine-induced arrhythmias. Arrhythmias were produced, in the rat, by continuous infusion of epinephrine until the development of fatal arrhythmias that were usually ventricular fibrillation. Intracerebroventricular (ICV) administration of DAGO, 3 nmol, significantly (p less than 0.05) shifted to the right the relationship between epinephrine and both the onset of ventricular arrhythmias and the development of fatal arrhythmias. Naloxone, 1 mg/kg i.v., prevented these effects of DAGO. Atropine, 1 mg/kg i.v. or 20 micrograms/kg ICV, prevented the shift in these dose response relationships. Antagonism of DAGO's effects on arrhythmias could not be explained by an alteration of the blood pressure response to epinephrine. However, DAGO significantly increased blood pressure and decreased heart rate in separate experiments in animals that did not receive epinephrine and atropine prevent the heart rate and blood pressure effects of DAGO. These data show that 1) the millimicrons opioid receptor agonist DAGO suppresses epinephrine-induced arrhythmias, 2) the site of action can be within the CNS, 3) there is a role for the central parasympathetic nervous system to mediate the effect of DAGO and 4) endogenous opioids could modulate catecholamine-induced cardiac arrhythmias.     

Inhibition of pituitary bioactive prolactin secretion in the male rat by the glucocorticoid agonist decadron phosphate.

In the present studies, the soluble glucocorticoid agonist, decadron phosphate (DEC), was administered i.v. to intact adult male rats in order to evaluate the effects of glucocorticoid receptor stimulation on circulating levels of immunoreactive (ir-) and bioactive (bio-) prolactin (PRL). In light of reports that glucocorticoid-specific receptors exist within the rat brain, additional experiments investigated the effects of intracerebroventricular (i.c.v.) administration of graded doses of the same drug on pituitary ir- and bioPRL secretion. Concentrations of ir- and bioPRL in samples obtained before and after drug treatments were determined by standard PRL radioimmunoassay and the Nb2 rat node lymphoma bioassay, respectively. Rats injected i.v. with 0.5 mg DEC/kg body weight, but not those treated with a tenfold lesser dose, exhibited decreased plasma irPRL concentrations. However, both doses promoted a decline in circulating levels of bioPRL compared to vehicle-treated controls, along with an overall reduction in the plasma bio/irPRL ratio. The magnitude and duration of this drug-induced decline in biopotency of secreted hormone was dose-dependent. While the plasma bio/irPRL ratio was diminished only transiently in rats injected with 0.05 mg DEC/kg, treatment with the higher dose led to a sustained decrease in the plasma bio/irPRL ratio for the duration of the experiment. The current studies also show that intracerebral administration of DEC resulted in dose-dependent alterations in pituitary PRL release. Circulating levels of ir- and bioPRL were not altered in rats injected i.c.v. with 10 ng of DEC, the lowest dose tested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Topiramate as a neuroprotectant in a rat model of global ischemia-induced neurodegeneration.

The neuroprotective properties of topiramate were evaluated in a rat model of stroke in which neurodegeneration was induced by temporary global ischemia. In this model, the ischemia resulted from 11 min of cardiac arrest during atraumatic chest compression. Resuscitated rats exhibit a characteristic neurological syndrome characterized by sound-induced convulsions, specific motor and behavioral deficits, and death of hippocampal CA1 pyramidal neurons. Topiramate, when administered i.v. 30 min after resuscitation, reduced the degree of motor impairment (P< 0.05 vs control at doses of 10 and 20 mg/kg) and seizure severity (P< 0.05 vs control at a dose of 10 mg/kg on the fifth recovery day). The highest dose of topiramate (20 mg/kg i.v.) eliminated nearly all histologic signs of hippocampal ischemic neuronal injury (P< 0.001). Phenytoin at 20 mg/kg i.v. exhibited neuroprotectant effects similar to those observed for topiramate at 20 mg/kg i.v.. In normal rats, neither topiramate nor phenytoin at 20 mg/kg i.v. induced any apparent neurological impairment; however, at 40 and 60 mg/kg i.v. both induced a mild impairment typical of most anticonvulsants. The results of this study support the concept that topiramate possesses neuroprotective properties.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Respiratory and cardiovascular effects of thyrotropin-releasing hormone as modified by isoflurane, enflurane, pentobarbital and ketamine

Thyrotropin-releasing hormone (TRH) possesses significant arousing and cardio-respiratory stimulant actions. The effects of a 2 mg/kg i.v. bolus dose of TRH on respiration and systemic hemodynamics were compared in conscious, freely-moving rats and during anesthesia with 4 different anesthetics. Fifty-four male Sprague-Dawley rats weighing 285 +/- 4 g (mean +/- S.E.M.) were divided into 5 groups: conscious, enflurane (2%), isoflurane (1.4%), pentobarbital (8 mg/kg/h i.v.), and ketamine (60 mg/kg/h i.v.). Anesthetized rats were intubated and breathed oxygen or anesthetic/oxygen spontaneously. Aortic blood pressure, heart rate, cardiac output, respiratory rate, arterial blood pH, blood gases, lactate and glucose were measured, and data were collected over a 20 min baseline period and for 130 min post-TRH. TRH increased respiratory rate in all groups; concomitant changes in arterial PCO2 indicated increased minute ventilation in the inhalation agent groups but not in the i.v. anesthetic groups or in the awake group. Significant respiratory depression in the enflurane group was rapidly reversed by TRH. The respiratory stimulant and arousing effects of TRH were smallest with ketamine anesthesia. The hemodynamic responses to TRH were consistent with a pattern of sympathoadrenalmedullary activation and were relatively uniform across groups despite anesthetic-induced alterations in baseline values. TRH or its analogues may prove useful as an analeptic in clinical anesthesia.     

Central benzodiazepine involvement in clonidine cardiovascular actions

It is well known that the GABAergic and noradrenergic systems play an important role in blood pressure and heart rate regulation. Benzodiazepines and beta-carbolines, respectively, increase or decrease the probability of chloride-channel opening induced by GABA. The aim of this study was to determine, in conscious rats, the interaction existing between the central alpha2-adrenoceptor stimulation induced by clonidine and the facilitation or impairment of benzodiazepine receptor activity through the administration of either diazepam, a benzodiazepine receptor agonist, or methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse benzodiazepine agonist. Clonidine (5-10 microg, intracerebroventricularly) reduced heart rate and increased mean blood pressure by activation of central alpha2-adrenoceptors. Diazepam (2 mg/kg, intravenously (i.v.)) induced an increase in heart rate, while DMCM (0.3 mg/kg, i.v.) elicited a bradycardic effect. The bradycardic effects induced by both clonidine and DMCM were antagonized by the prior administration of methylatropine (1.5 mg/kg, i.v.). DMCM (0.3 mg/kg, i.v.) prevented the clonidine effects on heart rate and mean blood pressure, while diazepam (2 mg/kg, i.v.) failed to modify these effects. Our results suggest that the bradycardic effects of clonidine are mediated by a vagal stimulation and are related to the activation of a GABAergic pathway.     

Opposite influence of MPEP, an mGluR5 antagonist, on the locomotor hyperactivity induced by PCP and amphetamine.

Potential antipsychotic effects of a selective non-competitive antagonist of metabotropic glutamate receptor 5 (mGluR5), 2-methyl-6-phenylethynylpyridine (MPEP), was examined in two commonly used screening tests: (1) the hyperactivity induced by an NMDA receptor antagonist phencyclidine (PCP), and (2) the hyperactivity induced by an indirect dopamine agonist, D-amphetamine. PCP was administered at a dose of 2.5 mg/kg s.c. and D-amphetamine was given at a dose of 1 mg/kg s.c. MPEP (5 mg/kg i.p.) significantly enhanced the locomotor activity increased by PCP, but inhibited amphetamine-induced hyperactivity. The opposite effect of MPEP in the two above-mentioned models questions significance of the blockade of mGluR5 receptors to antipsychotic effects.     

Cardiac and hemodynamic responses to synthetic atrial natriuretic factor in rats

To determine the hemodynamic effects of a hypotensive dose of atrial natriuretic factor (ANF), a synthetic peptide containing 26 amino acids of endogenous rat ANF (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly -Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr-COOH) was studied in two groups of barbiturate anesthetized rats. In the first experiment, a 20-minute infusion of a hypotensive dose, 95 pmole/min i.v., of the synthetic ANF decreased mean arterial pressure (MAP) by 40 +/- 3 mm Hg from a baseline of 128 +/- 5 mm Hg, and cardiac output (CO) (microsphere method) by 7.8 +/- 1.8 ml/min/100 gm from a baseline of 23.5 +/- 1.3 ml/min/100 gm. Synthetic ANF did not significantly affect the total peripheral resistance (TPR) measured at the end of the 20-minute infusion. Sodium nitroprusside (SNP), infused at an equihypotensive dose of 20 micrograms/kg/min i.v., produced the same hemodynamic profile in seven other animals; in contrast, 0.3 mg/kg i.v. of hydralazine (n = 7) lowered MAP by 56 +/- 6 mm Hg and reduced TPR index by 3.0 +/- 0.6 mm Hg/ml/min/100 gm, but did not change CO. Other than an increase in coronary blood during SNF infusion, there were no significant changes in the distribution of cardiac output. Infusion of the saline vehicle had no significant effects on any of these parameters. The results of the second experiment in anesthetized rats confirmed that hypotensive doses of 40 and 100 pmole/kg/min i.v. lowered CO (dye dilution method) from a baseline of 33 +/- 6 to a minimum of 24 +/- 2 ml/min/100 gm (p less than 0.05) without affecting TPR. In addition, synthetic ANF did not significantly affect heart rate (HR) but it slightly reduced cardiac contractility (dp/dt50). These results suggest that the hypotensive dose of synthetic ANF reduced cardiac output, partially by diminishing stroke volume, and perhaps contractility.     

Central cardiovascular and thermal effects of prostaglandin F2α in rats

Administration of PGF_2α (0.2–6.4 μg) into the lateral cerebral ventricle (i.c.v.) induced dosedependent increases in blood pressure, heart rate and body temperature in urethane-anaesthetised rats, but had no effect on these parameters when the same dose range was administered intravenously. Peripheral pretreatment with sodium meclofenamate (50 mg/kg s.c.) shifted all the dose-response curves for PGF_2α (i.c.v.) to the left, but indomethacin (50 mg/kg s.c.) did not significantly affect those changes. Central pretreatment with sodium meclofenamate or indomethacin (1.25 mg per rat i.c.v.) failed to modify significantly the effects of centrally administered PGF_2α.The results support previous suggestions that PGF_2α may participate in the central control of the cardiovascular and thermoregulatory systems, and also suggest that there may be differences in the sites and/or modes of action between sodium meclofenamate and indomethacin.     

Catecholamine-induced changes in vascular capacitance and sympathetic nerve activity in dogs.

The effects of three catecholamines, dopamine, epinephrine, and dobutamine, on the systemic circulation, especially on systemic vascular capacitance, were studied using cardiopulmonary bypass in dogs anesthetized with pentobarbital. Venous outflow was divided into three compartments: splanchnic, renal, and other; changes in systemic blood volume (SBV) were calculated from the changes in total venous outflow. To examine the contribution of sympathetic discharge to these vascular responses, sympathetic efferent nerve activity (SENA) from the ventral ansa subclavian nerve was recorded simultaneously. Experiments were done under three conditions: control, after baroreceptor deafferentation, and after hexamethonium injection with low and high doses of each catecholamine. During control and after baroreceptor deafferentation, dopamine- and epinephrine-induced changes in SBV were less than those after hexamethonium, and not significant except with low dose epinephrine. After hexamethonium, dopamine (200 micrograms/kg), epinephrine (10 micrograms/kg), and dobutamine (100 micrograms/kg) reduced SBV by 10.6 +/- 3.4, 13.1 +/- 1.7, and 1.9 +/- 0.3 mL/kg, respectively. Splanchnic outflow increased significantly with dopamine and epinephrine after hexamethonium. High dose dopamine and epinephrine significantly suppressed SENA to 38 +/- 9 and 15 +/- 6% of baseline, respectively. Low dose dopamine decreased arterial pressure and SENA. This suppression in SENA was attenuated but still observed after baroreceptor deafferentation. Dobutamine reduced SBV, but had no effect on SENA. These results suggest that dopamine and epinephrine primarily decrease SBV by venoconstriction in the splanchnic region, however, these effects are greatly modified by basal sympathetic discharge and changes in SENA and vascular tone.     

Receptor subtype specific activation of the rat gastric vagal afferent fibers to serotonin

Systemic administration (i.v.) of serotonin (5-HT) evoked a transient vagal afferent nerve discharge, bradycardia, and hypotension in the rat. The half-effective dose of 5-HT for nerve discharge was 13 micro g/kg. The time- and dose-dependent kinetics of the nerve discharge rate were similar to the change of heart rate. The afferent neuronal discharge was mimicked by a selective 5-HT3 receptor agonist, 1-phenylbiguanide hydrochloride (PBA), and inhibited by a selective 5-HT3 antagonist, granisetron. The 5-HT(3/4) agonist, cisapride partially activated the vagus nerve, but the 5-HT4 agonist, RS6733 had no effect on the vagal afferent activity. Intra-gastric perfusion of lidocaine, moreover, abolished the 5-HT-induced vagal activation. These results indicate that the 5-HT transmission signal in the gastric mucosa inputs to the brain stem via 5-HT3 receptor-mediated vagal nerve afferent.