bluuebunny/crossref_metadata_2025 huggingface dataset:
GABAergic neurons in the rat pontomesencephalic tegmentum: Codistribution with cholinergic and other tegmental neurons projecting to the posterior lateral hypothalamus
Authors: Ford Blair , Holmes Colin J. , Mainville Lynda , Jones Barbara E.
Published: January 2005

The present study was undertaken to determine the frequency and distribution of GABAergic neurons within the rat pontomesencephalic tegmentum and the relationship of GABAergic cells to cholinergic and other tegmental neurons projecting to the hypothalamus. In sections immunostained for glutamic acid decarboxylase (GAD), large numbers of small GAD‐positive neurons (∼50,000 cells) were distributed through the tegmentum and associated with a high density of GAD‐positive varicosities surrounding both GAD‐positive and GAD‐negative cells. Through the reticular formation, ventral tegmentum, raphe nuclei, and dorsal tegineritum, GAD‐positive cells were codistributed with larger cells, which included neurons immunostained on adjacent sections for glutamate, tyrosine hydroxylase (TH), serotonin, or choline acetyltransferase (ChAT). In sections dual‐immunostained for GAD and ChAT, GABAergic neurons were seen to be intermingled with less numerous cholinergic cells (∼2,600 GAD+ to ∼ 1,400 ChAT+ cells in the laterodorsal tegmental nucleus, LDTg).

Retrograde transport of cholera toxin (CT) was examined from the posterior lateral hypothalamus, where a major population of cortically projecting neurons are located. A small number of GABAergic cells were retrogradely labeled, representing a small percentage of all the GABAergic neurons (∼1%) and of all the hypothalamically projecting neurons (∼6%) in the tegmentum. The double‐labeled GAD+/CT+ cells were commonly found ipsilaterally within (1) the deep mesencephalic reticular field, codistributed with putative glutamatergic projection neurons; (2) the ventral tegmental area, substantia nigra coinpacta, and retrorubral field, codistributed with dopaminergic projection neurons; (3) dorsal raphe, codistributed with serotonergic projection neurons; and (4) laterodorsal and pedunculopontine tegmental nuclei, codistributed with and in similar proportion to cholinergic projection cells (20–30% in LDTg). Acting as both projection and local neurons, the pontomesencephalic GABAergic cells would have the capacity to modulate the influence of the “ascending reticular activating system” and its chemically specific constituents upon cortical activation. © 1995 Wiley‐Liss, Inc.
Axotomy induces a different modulation of both low‐affinity nerve growth factor receptor and choline acetyltransferase between adult rat spinal and brainstem motoneurons
Authors: Rende Mario , Giambanco Ileana , Buratta Marina , Tonali Pietro
Published: January 2005

Adult rat spinal and brainstem motoneurons reexpress low‐affinity nerve growth factor receptor (p75) after their axotomy. We have previously reported and quantified the time course of this reexpression in spinal motoneurons following several types of injuries of the sciatic nerve. Other studies reported the reexpression of p75 in axotomized brainstem motoneurons. Results of these previous studies differed regarding the type of the most effective triggering injury for p75 reexpression, the relative duration of this reexpression and the decrease of choline acetyltransferase (ChAT) immunoreactivity (‐IR) following a permanent axotomy of spinal or brainatem motoneurons. These differences suggest that these two populations of motoneurons respond to axotomy with a different modulation of p75 and ChAT expression. The aim of the present study was to determine whether differential modulation exists. We have analyzed and quantified the presence of p75‐ and ChAT‐IR motoneurone in the hypoglossal nucleus following the same types of injury and the same time course we previously used for sciatic motoneurons. The results show that a nerve crush is the most effective triggering injury for p75 and that it induces similar temporal patterns of p75 and ChAT expression for sciatic and hypoglossal motoneurons. In contrast, a cut injury of the sciatic and hypoglossal nerves resulted in distinct temporal courses of both p75 and ChAT expression between these two populations of motoneurons. In fact, a permanent axotomy of the hypoglossal motoneurons induced (i) a much longer maintenance phase for p75 than in aciatic motoneurons and (ii) a progressive loss of ChAT‐IR with a successive return to normal values in contrast to the modest decrease in the sciatic motoneurons. This evidence indicates that spinal and brainstem motoneurons respond to a permanent axotomy with a different modulation of p75 and ChAT expression. Altogether, the present data and the reported evidence of a differential post‐ axotomy cell death support the hypothesis that these two populations of motoneurons undergo different dynamic changes after axotomy. © 1995 Wiley‐Liss, Inc.
In situ labeling of apoptotic cell death in the cerebral cortex and thalamus of rats during development
Authors: Spreafico Roberto , Frassoni Carolina , Arcelli Paola , Selvaggio Mariateresa , De Biasi Silvia
Published: January 2005

Apoptosis is a form of naturally occurring cell death that plays a fundamental role during development and is characterized by internucleosomal DNA fragmentation. In this study we used specific in situ labeling of DNA breaks (Gavrieli et al. [1992] J. Cell. Biol. 119:493–501) to analyze the distribution of apoptotic cells in rat cerebral cortex and thalarnus at different developmental stages from embryonic day 16 to adulthood. Control experiments and electron microscopy confirmed that the reaction product was confined to the nucleus of selected cells. Plotting and counting of labeled nuclei in counterstained paraffin sections showed that apoptosis occurred mainly during the first postnatal week and was absent in embryonic and adult samples. In the cortex, the number of apoptotic cells progressively increased from birth to the first postnatal week, with a peak between postnatal (P) day 5 and P8, and subsequently decreased. At the time of maximal expression of apoptosis, labeled nuclei were present mainly in layer VIb and underlying white matter and at the border between cortical plate and layer I. Only a few apoptotic cells were found scattered in the thalamus, without a particular concentration in selected areas, but with a peak at P5. Differences in the number of apoptotic cells between cortex and thalamus suggest that apoptotic cell death may have a different functional significance in the two brain areas. © 1995 Wiley‐Liss, Inc.
Localization of α7 nicotinic receptor subunit mRNA and α‐bungarotoxin binding sites in developing mouse somatosensory thalamocortical system
Authors: Bina Keshavan G. , Guzman Patricia , Broide Ron S. , Leslie Frances M. , Smith Martin A. , O'Dowd Diane K.
Published: January 2005

Previous studies in rat, showing a transient pattern of expression of the α7 nicotinic acetylcholine receptor in the ventrobasal thalamus and barrel cortex during the first 2 postnatal weeks, suggest that these receptors may play a role in development of the thalamocortical system. In the present study, in situ hybridization and radiolabeled ligand binding were employed to examine the spatiotemporal distribution of α7 mRNA and α‐bungarotoxin binding sites in the thalamocortical pathway of mouse during early postnatal development. As in the rat, high levels Of α7 mRNA and α‐bungarotoxin binding sites are present in the barrel cortex of mouse during the first postnatal week. Both α7 mRNA and its receptor protein are observed in all cortical laminae, with the highest levels seen in the compact cortical plate, layer IV, and layer VI. When viewed in a tangential plane, α7 mRNA and α‐bungarotoxin binding sites delineate a whisker‐related barrel pattern in layer IV by P3–5. Quantitative analysis reveals a dramatic decrease in the levels of expression of α7 mRNA and α‐bungarotoxin binding sites in the cortex by the end of the second postnatal week. Unlike in the rat, only low levels of α7 mRNA or α‐bungarotoxin binding sites are present in the ventrobasal complex of the mouse thalamus. The broad similarities between the thulamocurticul development of rat and mouse taken together with the present results suggest that α7 receptors located on cortical neurons, rather than on thalamic neurons, play a role in mediating aspects of thalamocortical development. © 1995 Wiley‐Liss, Inc.
Expression of brain‐type creatine kinase and ubiquitous mitochondrial creatine kinase in the fetal rat brain: Evidence for a nuclear energy shuttle
Authors: Chen Lulu , Roberts Robert , Friedman David L.
Published: January 2005

To test the hypothesis that embryonic brain cells utilize a creatine phosphate energy shuttle, we examined the pattern of creatine kinase (CK) isoform expression and localization in the fetal rat brain. Moderate levels of CK activity are present at embryonic day 14 (7 U/mg protein) and decrease slightly until 3 days postpartum followed by a rapid, fourfold up‐ regulation to adult levels by 1 month (18 U/mg protein). In parallel with changes in enzyme activity, there is a biphasic and coordinate pattern of expression of brain‐type CK (BCK) and ubiquitous mitochondrial CK (uMtCK) determined by nondenaturing electrophoresis and immunoblot analysis. The localization of CK isoforms was examined by immunocytochemistry, and, during the fetal period, BCK and uMtCK immunoreactivity was detected throughout the central and peripheral nervous system, especially in neuroepithelial regions of the cerebral vesicles and spinal cord. In large cells within the olfactory neuroepithelium and ventral spinal cord, differential compartmentation of CK isoforms was evident, with BCK localized primarily in cell nuclei, whereas uMtCK immunoreactivity was present in the cell body (but not within nuclei). In olfactory bulb neuroepithelium, both isoforms were expressed in the middle zone of the germinal layer associated with DNA synthesis. In embryonic skeletal and cardiac muscle, which also express BCK, the same compartmentation of BCK was seen, with BCK localized primarily in the cell nucleus of cardiac and skeletal myoblasts. These results demonstrate a coordinate pattern of expression and compartmentation of BCK and uMtCK isoforms in the fetal brain that, in some cells, provides the anatomic basis for a nuclear energy shuttle. © 1995 Wiley‐Liss, Inc.
Analysis of unsteady pipe flow using the modified finite element method
Authors: Szymkiewicz Romuald , Mitosek Marek
Published: January 2005

A modified finite element method is proposed to solve the unsteady pipe flow equations. This approach yields a six‐point implicit scheme with two weighting parameters. An accuracy analysis carried out using the modified equation approach showed that the proposed scheme has higher accuracy compared to other methods. A comparison of experimental data and the results of numerical solution showed that the required damping and smoothing of a pressure wave can be obtained when numerical diffusion is produced by the applied method. It suggests that the physical dissipation process observed in the water hammer phenomenon is not represented properly in its mathematical model. Therefore, the classical system of water hammer equations seems to be incomplete. Copyright © 2004 John Wiley & Sons, Ltd.
Anticonvulsant activity of a new 1,4‐benzodiazepine in rodents and the baboon Papio papio
Authors: Piper David C. , Meldrum B. S. , Gardner C. R.
Published: January 2005

RU 31124, a new anticonvulsant 1,4‐benzodiazepine was compared with clonazepam in a series of tests in rats and mice. It demonstrated greater anticonvulsant potency whilst having equivalent sedative properties to clonazepam. This profile of activity was confirmed in the photosensitive baboon, Papio papio, in which RU 31124 provided long‐lasting protection against convulsions at doses having little or no sedative side effects.
Receptor binding and the discovery of psychotherapeutic drugs
Authors: Hamblin Mark , Creese Lan
Published: January 2005

The identification of useful new drugs, when not due entirely to serendipity, has often relied on in vivo techniques that are both difficult to interpret and to perform. The receptor binding technique, however, by allowing the direct study of the specific biochemical site of action of most psychotherapeutic drugs has provided a simple, selective, and sensitive method to study drug‐receptor interactions. The biochemical locus of action for a family of drugs can often be identified by comparing their absolute potencies in in vivo systems with their affinities at a number of drug and/or neurotrans mitter receptor binding sites. Once a particular binding site is identified as therapeutically relevant, affinity for this binding site can be used as a screen for novel compounds that may show similar in vivo activity. Detailed structure‐activity relationships can be determined in vitro without the problems of metabolism and differential absorption that complicate in vivo studies. Such studies allow the pinpointing of active sites within the drug molecule for further synthetic manipulations. Receptor binding studies have been essential in the elucidation of the therapeutic mechanisms of neuroleptics, tricyclic antidepressants, opiates, and benzodiazepines. Receptor binding studies are not only useful in the identification and quantification of therapeutically useful drug receptor interactions but have also been invaluable in the study of similar interactions that manifest themselves as drug‐induced side effects. Such studies may eventually allow the development of drugs that are not only more therapeutically potent but are also free of side effects. Radioreceptor assays have also been introduced to measureserum drug levels of neuroleptics, antidepressants, anticholinergics, benzodiazepines and P‐adrenergic antagonists. These methods have the advantage of being quick, sensitive, selective, and inexpensive.
The effect of fluoxetine on morphine analgesia, respiratory depression, and lethality
Authors: Hynes Martin D. , Fuller Ray W.
Published: January 2005

The analgesic effect of morphine in a mouse writhing assay was enhanced by the simultaneous administration of fluoxetine, an inhibitor of serotonin uptake. Fluoxetine reduced the ED50 for morphine and extended the duration of morphine analgesia. The potentiation of morphine analgesia was particularly striking in mice made tolerant by repeated morphine injections. Potentiation of morphine by fluoxetine was also observed in a rat tail jerk test for analgesia. The acute lethality of morphine in rats and mice was altered by fluoxetine, yet the therapeutic index of morphine (ratio of LD50 to ED50) was unchanged. The decrease in blood pO2 produced by morphine at doses of 1 and 4 mg/kg in rats was attenuated by fluoxetine, which by itself increased blood pO2. These findings strengthen earlier evidence for an involvement of serotoninergic neurons in the analgesic effects of morphine and support the idea that enhanced serotoninergic function might be a useful means of enhancing morphine's actions in clinical therapy.
Isoxsuprine‐induced changes in maternal and fetal hemodynamics and fetal electroencephalogram
Authors: Ayromlooi Jahangir , Desiderio Denise M. , Tobias Mitchell D. , Leff Richard
Published: January 2005

Isoxsuprine has been used in obstetrics in the treatment of premature labor. Its maternal and fetal effects were studied in five ewes with dated gestations of 137 ± 1.25 days (term approximately 147 days).

Isoxsuprine (1 mg/min) was infused over a 30‐minute period to the anesthetized ewes while maternal and fetal blood pressures, uterine and fetal cerebral blood flows, and fetal brain function were studied. In addition, fetal and maternal acid‐base values and fetal cerebral metabolism were measured at baseline, 10, 20, 30, 45, and 60 minutes.

Isoxsuprine caused maternal hypotension, tachycardia, and metabolic acidosis and temporary reduction of PO2 without affecting oxygen saturation, O2 content, or uterine blood flow. In the fetus hypotension, tachycardia, temporary metabolic acidosis, transient reduction in PO2 and O2 saturation occurred while PCO2, cerebral blood flow, brain glucose consumption, and the electroencephalogram remained essentially unchanged. Fetal pH, PO2, and O2 saturation returned toward baseline values at the end of the experiment.
The effect of electrostimulation on barbiturate‐induced sleeping times in rats
Authors: Capel I. D. , Pinnock M. H. , Withey N. J. , Williams D. C. , Patterson M. A.
Published: January 2005

Female rats, anaesthetized with hexobarbital, regained their righting reflex more rapidly following electrostimulation than sham‐treated controls. The extent of the decreased sleeping times in these animals varied according to the frequency (cycles per second) of the electrostimulation applied. The frequency which produced the largest decrease in sleeping time was 10 Hz. Determination of the activity of some microsomal enzymes indicated that the decreased sleeping time was not the result of increased hepatic enzyme activity. Animals which had received prior treatment with naloxone exhibited increased sleeping times following barbiturate administration, but the effects of electrostimulation on the sleeping time at 10 Hz was diminished, while the effect of electrostimulation at high frequency (500 Hz) was enhanced. Although repeated daily administration of hexobarbital progressively decreased sleeping times for all the animals, electrostimulation decreased the sleeping times of the treated rats by a similar percentage of the control animals on each successive day. Electrostimulation at a frequency of 10 Hz produced a significant decrease in serum corticosterone levels, whereas 500 Hz resulted in an increase.
Naloxone‐induced reversal of clonidine, but not hydralazine, hypotension
Authors: Bennett Debra A. , DeFeo John J. , Elko Edward E. , Lal Harbans
Published: January 2005

Normotensive rats of the Sprague‐Dawley strain were administered either the centrally acting hypotensive drug clonidine (0.16 mg/kg IP) or the peripherally acting hypotensive drug hydralazine (1.25 mg/kg IP) to induce reliable hypotension (blood pressure reductions of 60–90 mm Hg), as measured by a tail cuff procedure. The opiate antagonist, naloxone (10–20 mg/kg IP), reversed clonidine but not hydralazine hypotension. Naloxone also failed to reverse hydralazine's hypotensive action in rats made hypertensive by renal ligation. Naloxone's reversal of clonidine (0.01 mg/kg IV) hypotension was confirmed in experiments in which blood pressure was measured through direct cannulation of the carotid artery. It is suggested that naloxone's antagonism of clonidine hypotension is located at a central nervous system site, and that clonidine hypotension may be mediated through an interaction with the brain opiate systems.
The brain renin‐angiotensin system
Authors: Severs Walter B. , Summy‐Long Joan Y. , Keil Lanny C.
Published: January 2005

Considerable evidence suggests that angiotensin interacts with the central nervous system (CNS) to increase blood pressure and alter peripheral hydration. Blood‐borne angiotensin may affect circumventricular organs resulting in increased water intake and vasopressin release. In addition, current literature documents the presence of a complete renin‐angiotensin system (RAS) in the brain. Angiotensin, presumably of central origin, increases sodium excretion; an effect opposite to blood‐borne peptide. This effect, along with increased water turnover, could dilute body fluids. The relative activities of the peripheral (renal) and central RASs thus may be of considerable importance in both normal and pathophysiological control of blood pressure and hydration. Indeed, some models of spontaneous hypertension in rats are associated with an altered brain RAS; central administration of converting enzyme inhibitors or angiotensin receptor antagonists returns elevated blood pressure toward normal.
Renal vasodilators and hypertension
Authors: Ackerman Dennis M. , Weinstock Joseph , Wiebelhaus Virgil D. , Berkowitz Barry
Published: January 2005

SK&F 82526 is a potent renal vasodilator in dogs, monkeys, and hypertensive rats. It is orally active and has a specificity for the renal vasculature greater than dopamine. Its activity is owing, at least in part, to stimulation of renal dopamine receptors and has no effect on α‐ or β‐adrenergic receptors. This compound should be valuable in further examining the importance of renal blood flow in essential hypertension.
Antihypertensive effect of a calcium antagonistic drug: Regression of hypertensive cardiac hypertrophy by nifedipine
Authors: Kazda Stanislav , Garthoff Bernward , Thomas Günther
Published: January 2005

The cardiac hypertrophy which develops in models of sustained hypertension in experimental animals cannot be prevented or reversed by all antihypertensive drugs. Clearly, blood pressure is only one of numerous factors which contribute to the development of hypertensive cardiomegaly. The ability of drugs to reduce cardiac hypertrophy depends primarily on their mode of action, rather than on the degree of blood pressure decrease. Vasodilators effectively control high blood pressure but enhance cardiac hypertrophy in rats. In currect experiments, minoxidil lowered blood pressure, but caused increases in heart weight and plasma‐renin activity (PRA) in spontaneously hypertensive rats (SHR). In contrast, the calcium antagonist, nifedipine, reduced blood pressure or prevented its increase in SHR concurrently reducing heart wight and decreasing PRA. Moreever, nifedipine prevented salt‐induced hypertension and heart hypertrophy in SD (sensitive)‐Dahl rats. It is suggested that in contrast to the vasodilator minoxidil, nifedipine reduces the high renovascular resistance in hypertensives thus enhancing sodium and water elimination. Thus, the action of the calcium antagonist, nifedipine, involve both renal vasodilation and reduction of renin‐angiotensin mediated renal vasoconstriction. In this way, the decreased volume load together with the decreased arterial afterload will contribute to the prevention or regression of hypertensive cardiac hypertrophy.
A double‐blind dose‐determination study with flutroline: A new neuroleptic
Authors: Wilson W. H. , Guy W. , Ban T. A. , Adelson L. M. , Perez‐Payan H.
Published: January 2005

In a 4‐wk double‐blind clinical trial four doses (1, 5, 10, and 20 mg) of flutroline were compared in newly admitted schizophrenic patients. Although there were few statistically significant differences among the four dosage groups, there were at least five indications of greater thereapeutic effectiveness in the higher dosages. The most favorable changes were seen in the 20‐mg group, which was the only group to show improvement in all five factors of the Brief Psychiatric Rating Scale and in which a significant elevation of serum prolactin level occurred at a 6‐hr post‐dose sampling. In a previous clinical trial in which three different daily doses of flutroline (1, 20, and 100 mg) were compared, 20 and 100 mg were found to be equal in their therapeutic effects and superior to 1 mg. Since no dosage between 1 and 20 mg were employed, the possibility that therapeutic effects with flutroline may already be present in daily doses below 20 mg could not be ignored. While the present findings are in favor of this contention, they also indicate that therapeutic efficacy with 20 mg is greater than with 1‐, 5‐, or 10‐mg daily doses.
Effect of neuromuscular blocking agents pancuronium bromide and its monoquaternary analogue Org NC 45 on regional blood flow and cardiac metabolism in pigs
Authors: Mohan Dhasmana K. , Verdouw Pieter D. , Prakash Om , Saxena Pramod R.
Published: January 2005

The effects of pancuronium bromide (60, 120, 300, and 600 μg.kg−1, i.v.) and its monoquaternary analogue Org NC 45 (300,750, and 1500 μg.kg−1, i.v.) on the systemic and regional hemodynamic variables were studied in the anesthetized pig. Pancuronium exhibited a dose‐dependent positive chronotropic and inotropic activity. The enhanced oxygen requirement of the myocardium was successfully met by a combination of higher blood supply to, and oxygen extraction by, the tissue. No changes were noticed in cerebral, renal or hepatic arterial blood flow. On the other hand, Org NC 45, which unlike pancuronium lacks vagolytic and sympathomimetic actions, did not cause an increase in heart rate or left ventricular dP/dtmax (LV dp/dtmax). Instead, in the two highest doses (750 and 1500 μg.kg−1) Org NC 45 decreased arterial blood pressure, LV dP/dtmax and the blood supply to the brain, kidneys, and liver. Neither compounds showed any effect on cardiac metabolism of glucose, lactate, or free fatty acids (FFA), although arterial blood glucose concentration did decrease following the two highest doses of each compound. Since Org NC 45, in a dose of 300 μg/kg−1, which is seven to ten times the ED90 for neuromuscular paralysis in man, is completely devoid of systemic and regional hemodynamic effects, and pancuronium in similar dose ratio is not, Org NC 45 might be preferred for use in cardiac anesthesia.
Studies on the profile of desmethylimipramine as a gastric antisecretory agent
Authors: Pendleton Robert G. , Miller Darlene A.
Published: January 2005

Desmethylimipramine (DMI) and atropine were compared in a variety of organ system tests in rats involving parasympathetic function in order to evaluate the specificity of these compounds as gastric antisecretory agents. DMI was similar to atropine in its effects on the stomach; each markedly inhibited gastric acid secretion and stomach emptying and protected against restraint‐induced gastric ulceration. However, unlike atropine, DMI did not substantially increase pupil size, reduce fecal pellet output, cause urinary retention, or increase heart rate. From these data, it is possible that at least certain antidepressant type drugs could be developed for the treatment of peptic ulcer disease.
Effects of d‐amphetamine, Org 2766, scopolamine, and physostigmine on repeated acquisition of four‐response chains in rat
Authors: Howard James L. , Pollard Gerald T.
Published: January 2005

Adult rats were trained to emit a different four‐response sequence on three levers for food reinforcement in each daily two‐hour session. Four sequences of putatively equal difficulty were used, with each sequence recurring every fourth session. Within‐session errors declined as a function of practice. Most subjects showed a significant idiosyncratic sequence bias. d‐amphetamine, tested at 0.1–2.0 mg/kg, increased errors as a function of dose. Org 2766 had no effect. Scopolamine and physostigmine, tested at 0.01–1.0 mg/kg, increased errors only at the highest doses, which produced tremor or ataxia. Results were generally consistent with previous results from other species. It was concluded that repeated acquisition in the rat is feasible for behavioral pharmacology and toxicology but that long training times and sequence bias limit its practicality.
The effects of lidocaine and hexamethonium on prostaglandin F2‐alpha‐ and histamine‐induced bronchoconstriction in sulfur dioxide‐treated beagle dogs
Authors: Malo P. E. , Griffin R. L.
Published: January 2005

The effects of local deposition of the topical anesthetic lidocaine and of ganglionic blockade by hexamethonium were investigated in pharmacologic bronchoconstriction with sulfer dioxide (SO2)‐induced hyperreactive beagle dogs. Control bronchopulmonary provocations, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN), were accomplished by aerosols of prostaglandin F2‐alpha (PGF2α) and histamine (HIST) after a six‐month chronic inhalation study using 500 ppm SO2. Pretreatment with a lidocaine aerosol (2.0%; 30 breaths) failed to produce any inhibition of bronchospasm induced by aerosols of PGF2α or HIST. An IV infusion of hexamethonium (10.0 mg/kg) significantly inhibited PGF2α‐induced percent changes in both RL (226.4 ± 45.2% vs. 134.7 ± 28.7%) and CDYN (52.6 ± 10.8% vs. 35.9 ± 8.8%) but failed to produce significant inhibition against HIST‐induced bronchospasm. These results suggest that the bronchial hyperreactivity attributed to SO2 exposure in our model is probably due in fact to an increased sensitivity of the afferent portion of the cholinergic pathway due to lidocaine's failure to provide inhibition at this site. No change occurs at the ganglia based on the similar action of hexamethonium in this study as to previously published work.
Ineffectiveness of a purine analogue, EMD 28422, in two animal tests of anxiolytic action
Authors: Lal Harbans , Gherezghiher Tseggai , Carney John
Published: January 2005

EMD 28422 was compared to chlordiazepoxide for antianxiety activity in two behavioral tests known to predict the anxiolytic action of drugs. In the conflict test, male rats were trained to respond for food reinforcement in which some of the reinforced responses also resulted in the delivery of footshock. Treatment of these rats with chlordiazepoxide but not with EMD 28422 antagonized the foot‐shock‐induced suppression of responding. In the drug discrimination test, male hooded rats were trained to discriminate the anxiogenic action of pentylenetetrazol from saline by responding for food reinforcement on one of two levers after pentylenetetrazol treatment (subconvulsant dose) and on the other lever after saline injection. Pretreatment with chlordiazepoxide and not with EMD 28422 antagonized the pentylenetetrazol stimulus. Ineffectiveness of EMD 28422 in both tests sensitive to chlordiazepoxide action suggests lack of anxiolytic efficacy of this drug, despite its reported enhancement of benzodiazepine binding in the brain.
Changes in γ‐aminobutyric acid and glutamic acid decarboxylase in discrete regions of rat brain following lithium administration and withdrawal
Authors: Ahluwalia Pardeep , Grewaal Darshan S. , Singhal Radhey L.
Published: January 2005

The influence of low dose (1 mmol/kg/day) chronic lithium (Li) treatment was studied on γ‐aminobutyric acid (GABA) levels and glutamic acid decarboxylase (GAD) activity in discrete regions of rat brain. In Li‐treated animals, GABA levels of striatum, midbrain, and ponsmedulla were significantly elevated in comparison to controls. Following 2 days of withdrawal from Li, GABA remained significantly higher in midbrain and pons‐medulla, but returned to control values in striatum. Administration of aminooxyacetic acid (AOAA) 1 hr prior to sacrifice produced an approximately twofold increase in regional GABA content in all three experimental groups. The activity of GAD was enhanced in striatum (11%) and pons‐medulla (22%), but decreased slightly in midbrain (5%) of Li‐treated animals. Li withdrawal caused a significant reduction in GAD activity of hypothalamus and pons‐medulla when compared to control or Li‐treated rats. Acute injection of AOAA enhanced GAD activity in midbrain of the Li‐treated animals and hypothalamus of the Li‐withdrawal group. Our data demonstrate that long‐term Li administration and its subsequent withdrawal has differential effects on both GABA and GAD in various regions of rat brain. However, whether these changes brought about by Li are due to its direct effect, or are exerted indirectly through other neurotransmitter systems, needs to be clarified.
Effects of EMD 15,700 and disulfiram on ethanol intake in rats under schedule‐induced polydipsia
Authors: McMillan D. E.
Published: January 2005

Rats received 196 food pellets per day under a fixed‐time 90‐sec schedule with both 5% (w/v) ethanol and water freely available. More than 80% of the total daily fluid consumption was the 5% ethanol solution. Disulfiram, and a new aldehyde dehydrogenase inhibitor, EMD 15,700, both markedly decreased 5% ethanol intake and slightly increased water intake. These effects lasted for several days. The schedule‐induced polydipsia model of ethanol consumption in rats appears to be sensitive to the effects of drugs that inhibit ethanol intake in man.
Second generation antidepressants: The pharmacological and clinical significance of selected examples
Authors: Maxwell Robert A.
Published: January 2005

Until recently, tricyclic antidepressants and monoamine oxidase inhibitors were the only therapies available for mental depression. These compounds, while effective, have significant cardiovascular and autonomic side effects and it was recognized that there was room for improvement. As a result of the labors of chemists and pharmacologists over the last 10 years, new or “second generation” compounds are being studied in man. Many of these compounds are structurally, biochemically, and pharmacologically distinct from tricyclic compounds and monoamine oxidase inhibitors and therefore hold out the promise of more effective therapy with fewer side effects. As an interesting offshoot of these structural, biochemical, and pharmacological differences it appears that the prevailing catecholamine theory of affective disorders and of the mode of action of therapeutic agents is challenged. Iprindole, mianserin and bupropion are discussed as examples of second generation antidepressants.
Dopamine receptor agonists in cardiovascular therapy
Authors: Lokhandwala Mustafa F. , Barrett Richard J.
Published: January 2005

Dopamine receptor agonists exert marked cardiovascular and renal actions that result from activation of specific dopamine receptors located at various sites within the cardiovascular system. The presence of at least two distinct subtypes of dopamine receptors is reported. (1) Neurotropic dopamine receptors, also referred to as δ2 or DA2 receptors, are located at various sites within the sympathetic nervous system, activation of which leads to inhibition of sympathetic nervous system activity. (2) Postsynaptic dopamine receptors, also referred to as δ1 or DA1 are located on vascular smooth muscles of blood vessels as well as at various sites in the kidney, and their activation causes, vasodilatation, inhibition of aldosterone release, and sodium and water reabsorption. The pharmacological responses to activation of neurotropic and postsynaptic dopamine receptors consist of hypotension, bradycardia, diuresis, and natriuresis. Since an elevated sympathetic nervous system activity and retention of salt and water appear to be responsible for several cardiovascular disorders, it is proposed that dopamine receptor agonists may represent a novel class of therapeutic agents for the treatment of certain cardiovascular diseases.

Further research efforts in this area are required to understand better the role of endogenous dopamine and dopamine receptors in the maintenance of cardiovascular homeostasis and to develop more selective compounds for experimental and clinical studies in different disease states.
Comparison of the cardiovascular effects of intravenously administered GABA, THIP, and isoguvacine in the anesthetized rat
Authors: Mesdjian E. , DeFeudis F. V. , Jadot G. , Valli M. , Brugerolle B. , Bouyard P.
Published: January 2005

Mean arterial blood pressure and heart rate were monitored in pentobarbital‐anesthetized rats after intravenous injections of GABA, THIP, or isoguvacine‐HCl (all at 0.1–100 mg/kg). GABA produced dose‐dependent hypotension and bradycardia; THIP produced no appreciable effect on either parameter; and isoguvacine produced hypotension, but no marked change in heart rate. The transient hypotension and bradycardia produced by GABA (1 mg/kg) were partially blocked by pretreatment of the animals with bicuculline or bicuculline‐methobromide. After pretreatment with bicuculline or bicuculline‐methobromide, the hypotensive effect of isoguvacine (1 mg/kg) occurred more rapidly (i.e., during the first 5 min, rather than during 5–15 min after injection of isoguvacine). As THIP penetrates the blood‐brain barrier more readily than GABA or isoguvacine, as GABA and isoguvacine exerted more pronounced cardiovascular effects than THIP, and as bicuculline and bicuculline‐methobromide affected the cardiovascular actions of GABA and isoguvacine, it is suggested that activation of peripheral GABA receptors might explain part of the cardiovascular effects produced by intravenously injected GABA. Further study of isoguvacine and its derivatives might lead to the development of hypotensive (antihypertensive) agents that act on peripheral GABA‐ergic systems.
Effect of a prostaglandin analogue, SC‐30249, on canine gastric secretion
Authors: Dajani Esam Z. , Driskill Doyle R. , Bianchi Robert G. , Phillips Esther L. , Woods Emmett M. , Colton Douglas G. , Collins Paul W. , Pappo Raphael
Published: January 2005

We previously reported the prostagladin analogue SC‐29333 [(±)(16RS)‐15‐deoxy‐16 hydroxy,‐16‐methyl prostaglandin E1 methyl ester] to be a potent inhibitor of gastric secretion in animals. SC‐29333 is comprised of four stereoisomers in approximately equal proportions. It is believed the major antisecretory activity of SC‐29333 results from one isomer, SC‐30249 (16S‐16‐hydroxy‐16‐methyl, 15‐deoxy‐PGE1 methyl ester). Our purpose was to investigate the canine gastric antisecretory action of SC‐30249 relative to SC‐29333. The studies were carried out in maximally stimulated (histamine) Heidenhain pouch (HP) and gastric fistula (GF) dogs. Administered intravenously (i.v.) to HP dogs at the steady‐state plateau of gastric secretion, SC‐30249 was found to be approximately three times more potent than SC‐29333. Administered intragastrically to GF dogs, SC‐30249 is approximately ten times more potent as an inhibitor of gastric secretion than SC‐29333. SC‐30249 (1.0 μg/kg, i.v.) completely inhibited meal‐stimulated gastric secretion but had no significant effect on postprandial serum gastrin concentration. SC‐30249 shared with SC‐29333 the capability of totally antagonizing the histamine‐stimulated gastric secretion in HP dogs without reducing gastric mucosal blood flow. These studies indicate that SC‐30249 is a potent gastric antisecretory agent that merits clinical evaluation.
Meperidine and normeperidine convulsions in mice: Possible opiate and serotonergic mechanisms
Authors: Bader Steven Roy , Moore Paul A.
Published: January 2005

The effects of naloxone and 5‐hydroxytryptophan (5‐HTP) pretreatment on convulsions induced by meperidine and normeperidine were studied in male Swiss‐Webster mice. The CD50 (95% confidence limits) was found to be 17.5 mg/kg (15.6–19.6) for meperidine and 38.0 mg/kg (36.2–39.9) for normeperidine administered intravenously. Convulsions induced by meperidine (17.5 mg/kg) were significantly attenuated by naloxone (30 mg/kg) pretreatment but not by 5‐HTP pretreatment alone. Normeperidine (38.0 mg/kg) induced convulsions were significantly attenuated by 5‐HTP pretreatment, but not by naxolone pretreatment. The administration of a combined dose of meperidine and normeperidine does not produce a supra‐additive response.
Enhancement of benzodiazepine binding by progabide (SL 76002) and SL 75102
Authors: Koe B. Kenneth
Published: January 2005

The new GABA derivatives, progabide (SL 76002) and SL 75102 (the corresponding carboxylic acid), enhanced [3H]diazepam binding to rat cortical membranes. SL 75102 was as effective as GABA, and both were less active than muscimol. Similar to other GABA agonists, progabide and SL 75102 enhanced binding in vitro by an increase in affinity. The elevation of [3H]diazepam binding in the presence of SL 75102 was antagonized by bicuculline. In ex vivo experiments, brain membrane preparations of mice pretreated with progabide were found to bind a greater amount of [3H]diazepam. This increased binding was characterized by an elevation in Bmax, while KD was unaffected. [3H]Flunitrazepam binding to brain in vivo was also enhanced in mice pretreated with progabide. Other GABA agonists (muscimol, THIP, isoguvacine) and GABAergic agents (sodium valproate) elicited an increase in [3H]flunitrazepam binding in vivo. Binding of intravenous [3H]flunitrazepam in vivo may be useful for discovering enhancers of benzodiazepine binding.
Effects of anticholinergic drugs on learning and memory
Authors: Spencer David G. , Lal Harbans
Published: January 2005

Declines in cognitive function during normal aging and in dementic disorders have frequently been hypothesized to involve a decline in cholinergic transmission in the brain. Muscarinic cholinergic receptor blockade produces behavioral effects in animals reminiscent of aging‐related performance deficits. The purpose of the present review is to analyze the results of previous behavioral experiments with antimuscarinic drugs in order to generate an hypothesis of the cognitive effects of muscarinic blockade. Given this hypothesis, it is suggested that experiments may be designed in which the antagonism of antimuscarinic drug effects may be used in the development of geriatric and antidementic drugs.
The effect of several “new and novel” cardiotonic agents on key subcellular processes involved in the regulation of myocardial contractility: Implications for mechanism of action
Authors: Weishaar Ronald E. , Quade Mary , Boyd Denise , Schenden Janet , Marks Steven , Kaplan Harvey R.
Published: January 2005

The effect of several recently synthetized cardiotonic agents on a variety of key metabolic processes involved in regulating calcium homeostasis in the cardiac cell was evaluated in an effort to determine the mechanism of action of these compounds. The agents examined were amrinone, WIN 47,203, AR‐L 57, AR‐L 115 (vardax), carbazeran, and RMI 82,249. The results of this study indicate that amrinone and vardax, at concentrations that stimulate myocardial contractility, have no effect on calcium transport, uptake or EGTA‐induced calcium release from isolated sarcoplasmic reticulum vesicles, or on mitochondrial calcium transport or uptake. Amrinone, vardax, and RMI 82,249 also have no effect on mitochondrial respiration. AR‐L 57 and vardax, but not amrinone, WIN 47,203, or carbazeran, inhibit cardiac Na+, K+‐ATPase activity (IC50 = 140 μM and approximately 1,000 μM, respectively). All of the agents examined inhibit phosphodiesterase activity; WIN 47,203 and carbazeran are the most potent inhibitors, and amrinone, the least. Vardax, amrinone, and carbazeran also potentiate the inotropic response to the beta‐receptor stimulant isoproterenol, and these three agents, in addition to WIN 47,203, also elevate cyclic AMP levels in isolated rabbit papillary muscles. These results indicate that inhibition of phosphodiesterase activity may represent the cardiotonic mechanism of action of amrinone, WIN 47,203, and carbazeran, and perhaps AR‐L 57 and vardax as well. Further studies are required to establish the degree to which Na+, K+‐ATPase inhibition or other actions are also involved in the cardiotonic activity of AR‐L 57 and vardax.
Failure of repeated peer separations to induce depression in infant rhesus monkeys
Authors: Porsolt Roger D.
Published: January 2005

Three rhesus monkeys (two female, one male) were separated from their mothers shortly after birth and were brought up together in a group cage. After 90 days together, they were subjected to eight repeated separations of 4–6 days during which they were housed in individual cages. Separations 7 and 8 were preceded by “vertical chamber” confinement of 3 and 8 days, respectively. Separation caused a marked increase in vocalizations. Although at times signs of depression (decreased locomotion, huddling) were apparent, they were neither frequent nor stable and did not seem to depend on either the length or the number of separations. It was concluded that social separation, although inducing clear signs of distress, does not invariably cause depression in infant rhesus monkeys.
Central effects and effective dose determination of suriclone (double‐blind, controlled, phase I safety and quantitative pharmaco‐EEG study)
Authors: Itil Turan M. , Menon Gopi N. , Dreyfus Jean‐Francois , Bozak M. Mahir , Songar Ayhan , Lucadamo Frank
Published: January 2005

Suriclone, a nonbenzodiazepine drug, shown to be anxiolytic in animal pharmacology, was investigated within a single dose tolerance and efficacy study using quantitative pharmaco‐EEG. The investigation showed that suriclone is tolerable in single oral doses of up to 0.8 mg, the highest dose given in healthy volunteers. The minimum effective dose producing statistically significant CNS action was 0.3 mg. Suriclone produced significant dose‐ and time‐related CNS effects. The onset of these effects was later than that of diazepam and its duration of action was longer. Suriclone was classified by the HZI computer EEG drug data base as anxiolytic at high doses. Among a variety of anxiolytics, the CNS effect of suriclone was most similar to that of diazepam. The optimal anxiolytic effective single dose of suriclone was predicted to be 0.6 mg.
Pharmacological profiles of two new angiotensin‐converting enzyme (ACE) inhibitors: CGS 13945 and CGS 13934
Authors: Chen Dong‐Sheng , Watkins Barry E. , Ku Edmond C. , Dotson Ronald A. , Burrell Richard D.
Published: January 2005

CGS 13945 and CGS 13934 are two nonthiol ACE inhibitors having novel chemical structures. CGS 13945 is a monoester derivative of the free dicarboxylic acid CGS 13934. Based on studies from in vitro inhibition of ACE and in vivo inhibition of angiotensin I pressor responses, CGS 13945 must be hydrolyzed to CGS 13934 to express its optimal biological activity. Studies with rats reveal that CGS 13945 and CGS 13934 are orally effective inhibitors of ACE. Both inhibitors have a longer duration of action and are somewhat less effective than captopril. After oral administration, the bioavailability of the monoester CGS 13945 is greater than that of the free dicarboxylic acid CGS 13934. In the dog, CGS 13934 (i.v.) effectively inhibits angiotensin I pressor responses, but the esterified compound (CGS 13945) has only weak activity. This difference is presumably due to limited hydrolytic capacity of endogenous plasma esterase(s) in this species. However, both CGS 13945 and CGS 13934 potentiate the vasodepressor responses to bradykinin without affecting angiotensin II pressor responses.
The castor oil test in rats: An in vivo method to evaluate antipropulsive and antisecretory activity of antidiarrheals?
Authors: Niemegeers C. J. E. , Awouters F. , Janssen P. A. J.
Published: January 2005

Castor oil‐induced diarrhea in rats is described to be an appropriate model of the complex, prolonged processes of hypersecretion and accelerated transit that characterize secretory diarrhea. Suprofen, a prostaglandin biosynthesis inhibitor, was found to postpone diarrhea over a wide dose range, but suprofen failed to reduce the diarrheal excretion. In contrast to suprofen, loperamide not only increased the diarrhea‐free period but also produced a dose‐related decrease of the diarrheal excretion.
(Na+‐K+)‐ATPase inhibitors: Implications for new drug discovery
Authors: Shlevin Harold H.
Published: January 2005

The (Na+‐K+)‐ATPase is a ubiquitous membrane‐bound enzyme that actively transports Na+ out of the cell in exchange for a smaller ratio of extracellular K+. The current report focuses on the role of modifiers of (Na+‐K+)‐ATPase activity in the development of new pharmacological agents. More versatile biological test systems are proposed. Possible use of Na+‐K+‐ATPase activity modulators in treatment of hypertension and other diseases are discussed. It is concluded that the ubiquitous distribution and crucial role of the enzyme in normal and diseased cell function merits a critical biological and chemical reappraisal of the enzyme beyond the current narrow viewpoint dealing with the application of glycosides in the treatment of congestive heart failure.
Angiotensin II antagonists—saralasin
Authors: Moore Alan F. , Fulton Robert W.
Published: January 2005

Saralasin is the only marketed member of a class of compounds described as angiotensin II receptor antagonists. Its pharmacology is characterized by three general properties: (1) no actions unrelated to the renin‐angiotensin system; (2) a small partial agonist effect in some tissues in vitro and in some animal models in vivo, and (3) a blood‐pressure lowering response to saralasin evident only in animals with an activated endogenous renin angiotensin system. It is suggested that the natriuretic effect of angiotensin II mediated via central nervous system (CNS) mechanisms may be future productive area of research in which to study the actions of angiotensin II antagonists.