PubMed Health⌕ Search

Biomedical subjects

R J Barrett

Publications and source records attributed to R J Barrett.

At least 109 records · Page 6Linked to original sources
PubMed1984

Effects of dopamine (DA) and SKF 82526, a selective DA1-receptor agonist, on vascular resistances in the canine forelimb.

This study was performed to determine the presence of vascular dopamine (DA1) receptors in the canine forelimb. Local i.a. infusions of DA (2, 4 or 8 micrograms base/min) produced cutaneous and skeletal muscle vasoconstriction in the forelimb comparable to that produced by local i.a. infusions of norepinephrine (0.5, 1 or 4 micrograms base/min). In the cutaneous vasculature, DA produced large artery, small vessel and large vein constrictions. The small vessels and large veins constricted proportionately more than the large arteries. The pattern of constriction produced by DA along the cutaneous vascular tree was similar to that produced by norepinephrine. The forelimb vasoconstriction produced by both DA and norepinephrine was abolished completely by treatment with phentolamine, indicating that both agents produce vasoconstriction mediated by stimulation of alpha adrenoceptors. The failure of DA to produce vasodilation after phentolamine suggests that there are no vascular or DA1-subtype DA receptors in the canine forelimb vasculature. The local i.a. infusion of SKF 82526, a selective DA1-receptor agonist, for 3 min produced cutaneous and skeletal muscle dilation which could be antagonized by either sulpiride or phentolamine. This neurogenic dopaminergic vasodilation produced by SKF 82526 (25, 50 or 100 micrograms base/min) was converted into vasoconstriction after ganglionic blockade. Inasmuch as SKF 82526 does not activate presynaptic or DA2-subtype DA receptors, the neurogenic vasodilation caused by SKF 82526 may be due to a dopaminergic inhibition of ganglionic transmission. Whereas the results of our study fail to provide any evidence for the presence of vascular DA (DA1) receptors in the canine forelimb, they show that SKF 82526, a DA1-receptor agonist, produces neurogenic vasodilation probably by activating ganglionic DA receptors.

Animals↗
PubMed1984

Discriminative stimulus properties of quipazine: mediation by serotonin2 binding sites.

The relative abilities of putative serotonin (5-HT) antagonists to block the quipazine discriminative cue were compared with their relative potencies to compete for the 5-HT1 and 5-HT2 binding sites in the brain. Male Sprague-Dawley rats were trained to discriminate 2.5 mg/kg of quipazine from saline. Once training was complete, antagonists were administered 90 min before a 5-min test with 1 mg/kg of quipazine, a dose which gave 75% responding on the quipazine lever. A dose-response curve was generated for each antagonist and an ID50 value (dose that inhibits responding to 50% on the quipazine lever) was determined by log-logit analysis. The binding of [3H]-5-HT to the 5-HT1 site and of [3H]spiperone to the 5-HT2 site was determined in crude membranes prepared from frontal cortex ( [3H]spiperone) or pons-medulla ( [3H]-5-HT) of naive rats. IC50 values for the antagonists were determined by log-logit analyses of competition binding curves. The ID50 values for the blockade of the quipazine discrimination by the 5-HT antagonists correlated significantly with their affinities for the 5-HT2 binding site (r = 0.87). In contrast, no correlation existed between effects on the behavioral measure and affinities for the 5-HT1 site (r = 0.15). These results suggest that the quipazine cue is mediated by an action at central 5-HT2 sites.

Animals↗
PubMed1983

Central and peripheral dopaminergic mechanisms in the cardiovascular actions of pergolide in neurogenic hypertensive dogs.

The cardiovascular actions of the dopaminergic ergoline, pergolide were examined in pentobarbital-anesthetized dogs. When administered intravenously (i.v.) to dogs made hypertensive by sino-aortic deafferentation, pergolide produced a sustained reduction in blood pressure, dilatation of the hindlimb vasculature and bradycardia. The antihypertensive action of pergolide in neurogenic hypertensive dogs was converted into a pressor action when it was given to dogs pretreated with i.v. sulpiride or hexamethonium plus atropine. Pergolide caused significant impairment of renal vasoconstriction elicited during stimulation of renal sympathetic nerves but not that caused by exogenous norepinephrine. The inhibitory action of pergolide on renal sympathetic nerve function was antagonized by sulpiride suggesting that pergolide activated presynaptic dopamine receptors. Direct administration of pergolide within the central nervous system via the cisterna magna (i.c.) to normotensive dogs also resulted in hypotension, bradycardia and iliac vasodilatation. The central actions of pergolide were prevented by sulpiride (i.c.) but not by yohimbine (i.c.), which indicates that specific activation of central dopamine receptors was responsible for these actions of pergolide. The antihypertensive, bradycardic and iliac vasodilatory actions of i.v. pergolide in neurogenic hypertensive dogs were significantly attenuated by i.c. sulpiride. It was determined that while this dose of sulpiride antagonized central dopamine receptors, it did not antagonize peripheral presynaptic dopamine receptors. These results suggest that pergolide exerts antihypertensive and bradycardic actions via simultaneous stimulation of dopamine receptors in the brain and on postganglionic sympathetic neurons. While presynaptic dopamine receptor activation contributes to the blood pressure lowering action of pergolide, stimulation of central dopamine receptors appears to be the dominant mechanism by which pergolide elicits the observed antihypertensive and bradycardic effects. Pergolide appears to lower blood pressure by a novel mechanism of action and may offer an additional therapeutic approach for the treatment of hypertension.

Animals↗
PubMed1983

Additional evidence that L-5-hydroxytryptophan discrimination models a unique serotonin receptor.

The purpose of the present studies was to investigate further the role of central serotonin (5-HT) in mediating the L-5-hydroxytryptophan (L-5-HTP) discriminative cue. Rats were trained to discriminate the stimulus properties of 35 mg/kg L-5-HTP combined with RO 4-4602, a peripheral decarboxylase inhibitor. Considering that several 5-HT antagonists were unable to block the L-5-HTP discriminative cue in our earlier studies, we extended these studies to include the two other presumed 5-HT antagonists mianserin and BC-105 (pizotyline). Only BC-105 completely blocked the training dose of L-5-HTP. Furthermore, the blockade of the L-5-HTP cue was both graded and surmountable by increasing the dose of L-5-HTP, suggesting a competitive antagonism. In neurochemical studies, the regional brain levels of 5-HT, norepinephrine and dopamine were determined after the injection of the training dose of L-5-HTP. Marked changes in the levels of 5-HT were found, while the levels of the catecholamines were changed only slightly or not at all. Furthermore, dose-response studies of L-5-HTP demonstrated an orderly dose-related increase in the levels of 5-HT in brain and in the percent responding on the L-5-HTP lever, while no such relationship was found for brain catecholamines. These results agree with previous pharmacological studies and suggest that the L-5-HTP discrimination is mediated by a central 5-HT receptor that has pharmacological properties distinct from those receptors identified in previous behavioral models of 5-HT receptor stimulation.

5-Hydroxytryptophan↗
PubMed1983

Strain specific cholinergic changes in response to stress: analysis of a time-dependent avoidance variation.

Investigators have established that the performance of an incompletely learned avoidance task is a U shaped function of the time since the original partial acquisition. Thus rats perform more poorly when retested at intermediate time intervals (1-8 hr) after training than they do when tested at longer post-acquisition intervals (24-48 hr). Studies have suggested that such time-dependent deficits are not related to changes in learning ability, but rather result from shock-induced motor suppression which interferes with active avoidance responding. Pharmacological studies utilizing drugs which effect cholinergic function have indicated that an inhibitory cholinergic system may be involved in mediating post-shock motor suppression. To obtain direct biochemical evidence for possible cholinergic mediation of post-shock motor suppression, measurements of high affinity choline uptake and acetylcholine turnover were made at varying time intervals following partial active avoidance training in F-344 rats. An increase in cholinergic function was found in the dorsal, but not the ventral hippocampus 30 min, 1 hr and 4 hr following acquisition training. These biochemical alterations were temporally correlated with deficits in active avoidance responding. We have reported that the immediate behavioral suppression observed in another rat strain (Sprague-Dawley, Zivic Miller Laboratories), which exhibits inferior active avoidance performance, is similarly correlated with cholinergic activation in the dorsal hippocampus [17]. These data support the hypothesis that the dorsal-hippocampal cholinergic system is involved in the mediation of stress-induced behavioral suppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1983

Drug discrimination in rats: evidence for amphetamine-like cue state following chronic haloperidol.

Two groups of male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 sec schedule of reinforcement on the basis of whether they were injected intraperitoneally with d-amphetamine (0.50 mg/kg or 1.50 mg/kg) or saline 15 min prior to daily 30 min training sessions. Following acquisition of the discrimination, dose-response functions were generated for both training-dose groups during 5 min test sessions. All subjects were then injected with 1.0 mg/kg of haloperidol for ten consecutive days and retested on either saline or intermediate doses of amphetamine on days 1, 2, 4 and 7 following the final haloperidol injection. The results indicated that chronic haloperidol enhanced the discriminative stimulus properties of amphetamine in both training groups. More importantly, when tested on saline, subjects in both training groups made significantly more responses on the d-amphetamine lever than observed prior to chronic haloperidol. On the basis of linear regression analysis of the dose-response curves it was shown that rats in both groups responded as though they had been injected with 0.18 mg/kg of d-amphetamine. In a second experiment this increase in amphetamine-lever responding when animals were tested with saline following chronic haloperidol was replicated and in addition it was observed that chronic amphetamine had the opposite effect on this measure.

Amphetamines↗
PubMed1983

Pregnancy following urinary diversion.

Five pregnancies were cared for in four patients who had undergone ureterosigmoid anastomosis or ileal conduit urinary diversions. The most common complication of pregnancy was urinary tract infection, ranging from asymptomatic bacteriuria to pyelonephritis. Significant obstruction of the diverted urinary tract failed to occur during gestation or delivery. Laboratory and radiographic studies demonstrated maintenance of baseline renal function. Offspring delivered showed appropriate growth for gestational age without associated anomalies. The authors' data and a review of the literature suggest that vaginal delivery is safe, and cesarean section may be reserved for obstetric indications. Pregnancy is not contraindicated after urinary diversion.

Bacteriuria↗
PubMed1982

Evaluation of peripheral dopamine receptor and alpha-adrenoceptor blocking activity of sulpiride.

The effect of sulpiride, a dopamine receptor antagonist, on peripheral alpha-adrenoceptors and dopamine receptors was determined. Positive chronotropic responses to cardioaccelerator nerve stimulation in pentobarbital-anesthetized dogs were potentiated by 1.0 and 2.0 mg/kg but not by 0.5 mg/kg intravenous sulpiride. This effect persisted after neuronal uptake blockade with desipramine, but was prevented by alpha 2-adrenoceptor blockade with yohimbine. Positive chronotropic effects of intravenous norepinephrine were unchanged by sulpiride, suggesting that sympathetic nerve function was facilitated via a presynaptic mechanism. Since yohimbine prevented the facilitatory action of sulpiride, an analysis of the ability of sulpiride to antagonize alpha-adrenoceptors was made. The reduction in stimulus-induced tachycardia caused by the alpha 2-adrenoceptor agonist tramazoline was significantly antagonized by sulpiride. Furthermore, while sulpiride did not antagonize the pressor effect of the alpha-adrenoceptor agonist phenylephrine, it significantly attenuated the increases in blood pressure produced by tramazoline. The alpha 2-adrenoceptor blocking action of sulpiride lasted for approximately 15 min at 1.0 mg/kg adn for 90 min at 2.0 mg/kg. In additional experiments, it was determined that the dopamine receptor-mediated bradycardic and hypotensive effects of N,N-di-n-propyldopamine were antagonized for at least 2 h by 0.1, 0.5, and 1.0 mg/kg sulpiride. These studies establish that peripheral neuronal and vascular dopamine receptors may be antagonized by sulpiride without affecting alpha-adrenergic mechanisms. However, at doses of 1.0 mg/kg and higher, sulpiride facilitates sympathetic nerve function via a preferential antagonism of alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1982

Dopaminergic inhibition of cardiac sympathetic nerve function by pergolide.

The effect of pergolide, a dopaminergic ergoline, on cardiac sympathetic neurotransmission was examined in pentobarbital-anesthetized dogs. Positive chronotropic responses to right postganglionic cardioaccelerator nerve stimulation were significantly reduced following infusion of pergolide, 1.25 microgram/kg per min for 10 min, whereas positive chronotropic responses to exogenous norepinephrine were unchanged. Pretreatment with sulpiride but not with yohimbine completely antagonized the inhibitory effect of pergolide. These results demonstrate that pergolide inhibits sympathetic neurotransmission to the heart by a specific activation of presynaptic dopamine receptors.

Animals↗
PubMed1982

Discriminative stimulus properties of L-5-hydroxytryptophan: behavioral evidence for multiple serotonin receptors.

Rats were trained to discriminate the stimulus properties of L-5-hydroxytryptophan (L-5-HTP) (30 mg/kg SC), the immediate precursor of serotonin (5-HT). The peripheral decarboxylase inhibitor R04-4602, administered prior to L-5-HTP, greatly attenuated the disruptive effects observed on responding when L-5-HTP alone was injected. Following acquisition, the discrimination was dose-dependent and generalized to fenfluramine, a 5-HT-releasing drug, but not to amphetamine, a catecholamine-releasing agent. Further evidence for the involvement of 5-HT receptor stimulation in mediating the discrimination was that pretreatment with fluoxetine, a highly specific 5-HT uptake inhibitor, markedly potentiated the cue. Nevertheless, the classical 5-HT antagonists methysergide, cyproheptadine, metergoline, and methiothepin did not block the L-5-HTP-related discriminative stimulus. This finding suggested that the cue properties of L-5-HTP might be mediated by a population of 5-HT receptors previously identified electrophysiologically in limbic structures. As in the present experiment, the putative 5-HT antagonists did not block the synaptic effects of 5-HT in these structures.

5-Hydroxytryptophan↗
PubMed1982

Cardiovascular dopamine receptors: physiological, pharmacological and therapeutic implications.

Dopamine receptor activation can lead to pronounced changes in cardiovascular function. The myriad of effects produced by dopamine receptor agonists results from the activation of dopamine receptors located at different anatomical sites in the cardiovascular system. Further basic research is required to better characterize these dopamine receptors so as to allow the development of more specific dopamine receptor agonists. Endogenous dopamine may be involved in the physiological control of fluid and electrolyte balance and continuing research efforts in this area should provide for a better understanding of the role of cardiovascular dopamine receptors in the maintenance of overall circulatory homeostasis. Cardiovascular dopamine receptor stimulation represents an important and promising approach for the development of novel therapeutic agents for the treatment of hypertension, angina pectoris, congestive heart failure and acute renal failure.

Acute Kidney Injury↗
PubMed1981

The effects of electroconvulsive shock on the discriminative stimulus properties of d-amphetamine and apomorphine: evidence for dopamine receptor alteration subsequent ECS.

Sprague-Dawley male rats responding for sweetened milk on a variable interval 20 s schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with 1.0 mg/kg of d-amphetamine or saline prior to daily training sessions. Following acquisition of the discrimination a dose-response generalization function was determined by testing animals on 0.10, 0.15, 0.25, 0.35, 0.50 and 0.75 mg/kg of amphetamine. Subjects then received either three electroconvulsive shock (ECS) treatments of sham-ECS forty-eight hours after the final treatment all subjects were injected with 0.25 mg/kg of amphetamine and retested. ECS was found to enhance the ability of the animals to discriminate amphetamine. In a second experiment it was found that ECS also facilitated the ability of animals to discriminate the cue properties of apomorphine, a direct dopamine receptor agonist. These results suggest that dopamine receptor sensitivity is altered by electroconvulsive shock.

Animals↗
PubMed1981

Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate.

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.

Amphetamine↗
PubMed1981

Circulatory and vestibular implications of central angiotensin mechanisms in physiological adaptation to weightlessness.

The discovery of an iso-renin angiotensin (AII) system within the central nervous system (CNS) led investigators to theorize a physiological and/or pathological role for the central actions of AII. Activation of central AII receptors in specific brain regions elicits antidiuretic, dipsogenic and pressor responses subsequently producing net body fluid retention. Removal of hydrostatic forces during weightlessness causes a massive translocation of body fluids to the thoraco-abdominal region; physiological adaptation to such a change is manifested as adipsia and net body fluid loss. It is suggested that these events may result from a decrease in the CNS-mediated effects of AII due to suppression of circulating AII levels. Depressed AII activity in the area postrema (AP) may also be responsible for the atypical nausea characteristic of space sickness.

Adaptation, Physiological↗
PubMed1981

Presynaptic dopamine receptor stimulation in the cardiovascular actions of lergotrile.

The involvement of dopamine receptors present at different sites in the hypotensive and bradycardic actions of lergotrile was investigated. Intravenous administration of lergotrile to pentobarbital-anesthetized dogs decreased blood pressure, heart rate and renal vascular resistance and increased renal blood flow. These effects were prevented by prior treatment with sulpiride or with hexamethonium plus atropine. When administered to phentolamine-treated animals, lergotrile failed to alter either blood pressure or renal blood flow, but exerted and an enhanced bradycardic effect. Lergotrile significantly inhibited the positive chronotropic and renal vasoconstrictor effects elicited by cardiac and renal sympathetic nerve stimulation, which could be prevented by prior treatment with sulpiride, suggesting that stimulation of presynaptic dopamine receptors was responsible for the inhibition of sympathetic nerve function caused by lergotrile. Administration of lergotrile into the vertebral artery did not produce any cardiovascular changes, whereas i.c.v. lergotrile caused a transient tachycardia followed by a bradycardia of greater magnitude and duration than that seen after i.v. administration. These studies suggest that lergotrile exerts its hypotensive and bradycardiac effects via stimulation of presynaptic dopamine receptors resulting in subsequent inhibition of sympathetic nerve function. Dopamine receptors present in the brain may contribute to the bradycardia, but vascular dopamine receptors do not appear to be involved in the cardiovascular actions of lergotrile.

Animals↗