bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiology of 5‐HT1A receptors in the rat hippocampus and cortex
Authors: Andrade Rodrigo 
Published: January 2005

AbstractElectrophysiological recordings from hippocampus and cortex have demonstrated that one of the most prominent effects of serotonin in these regions is a membrane hyperpolarization that effectively inhibits neuronal activity. The use of the in vitro brain slice preparation has allowed for detailed pharmacological and physiological studies of this response. Pharmacological analysis using agonists and antagonists indicates that these responses are mediated by activation of receptors of the 5‐HT1A subtype. Buspirone, ipsapirone and 8‐OHDPAT are all partial agonists at this receptor with 8‐OHDPAT exhibiting an intrinsic activity approximately one‐fourth that of serotonin. The ability of 5‐HT1A receptor agonists to elicit a hyperpolarization is dependent on intracellular GTP, suggesting the involvement of a G protein in the transmembrane signalling mechanism. In agreement with this idea, injection of the stable GTP analog GTPγS renders the serotonin induced hyperpolarization irreversible, while GDPβS blunts its effects and pertussis toxin pretreatment blocks it. The 5‐HT1A receptor induced hyperpolarization is mediated by an increase in potassium conductance. While the identity of the potassium channel remains to be determined, its basic characteristics identify it as belonging to a general class of inwardly rectifying G protein activated potassium channels ubiquitously distributed in neuronal and cardiac muscle tissues. In the rat hippocampus and cortex, most pyramidal cells co‐express 5‐HT1A with either 5‐HT4 or 5‐HT2 receptors, respectively, which in turn act to increase the ability of strong stimuli to excite these cells. As a result the net effect of serotonin on membrane excitability is dependent on the strength of incoming stimuli. Weak stimuli are depressed by the coactivation of these receptor subtypes while strong stimuli are enhanced. Thus the effects of selective 5‐HT1A ligands are likely to depend not only on their direct effect on membrane excitability but also on how they alter ongoing serotonergic neurotransmission. © 1992 Wiley‐Liss, Inc.
Treatment of Alzheimer's disease by zinc compounds
Authors: Constantinidis Jean 
Published: January 2005

AbstractAt the onset of Alzheimer's disease (AD), specific lesions occur in the hippocampus, i.e., neuropile‐capillary amyloid (AM) plaques and neuronal paired‐helical filaments (PHF)‐neurofibrillary tangles (NFT). The hippocampus is the area of brain with the highest zinc content. Chemical investigations demonstrated that in AD, the cerebral zinc decreases, especially in the hippocampus. The mechanism may be the following: The primary, genetically determined, microvascular AM (asymptomatic) disturbs the blood‐brain barrier, and metals (calcium, iron, aluminium, silicon, mercury, etc.( reach the cerebral cortex, where their levels increase and displace the zinc (whose level decreases) in some enzymes which become nonfunctional. The secondary production of PHF‐NFT and the neuronal dysfunction responsible of the clinical symptoms of dementia may be related to the functional deficiency of the following zinc‐enzymes: (1) those of DNA metabolism giving rise to abnormal DNA and therefore synthesis of abnormal proteins, constituting the NFT; (2) those involved in phosphorylating mechanisms at a post‐transcriptional (ribosomal‐mitochondrial) level, producing the abnormally phosphorylated tau protein, constituting the PHF; 3) that of glutamate (GLU) catabolism, resulting in a neurotoxic increase of GLU, producing PHF by abnormal phosphorylation of the neurofilaments; 4) those of neuronal detoxification contributing to the neuronal dysfunction. In regard to potential for therapeutic intervention, the timing needed for the AM‐induced production of NFT, in the various areas of the brain, has been estimated to be about 14–67 months. During this time it may be possible to influence the AM‐induced production of NFT: The chronic administration of neuroleptics enhances it, and the chronic administration of other drugs may reduce it. Such drugs may be zinc compounds, which will give an excess of zinc in the brain, will inhibit the above‐mentioned AM induced by zinc deficiency, mechanisms producing the NFT related to the clinical symptoms of dementia, and therefore, may prevent, stop, delay, and even improve them. Preliminary trials with zinc‐aspartate give promising results. Research is in progress to consolidate this zinc theory and to find more appropriate zinc compounds for this treatment. © 1992 Wiley‐Liss, Inc.
Effect of calcium channel antagonists on the cardiac vagal tone response to submaximal exercise
Authors: Billman George E. , Halliwill John R. , Avendano Christopher E. 
Published: January 2005

AbstractReductions in cardiac vagal tone have been shown to correlate with a greater susceptibility to ventricular fibrillation. Calcium antagonists have been shown to protect against malignant arrhythmias probably as the result of direct actions on cardiac muscle. However, these drugs could also reflexively alter cardiac vagal tone as a consequence of reductions in arterial pressure. Therefore, the effects of various calcium channel antagonists on cardiac vagal tone, both at rest and during exercise, were investigated. The R‐R interval was recorded in chronically instrumented mongrel dogs (n = 39) and the amplitude of the respiratory sinus arrhythmia (0.24–1.04 Hz) was calculated using time‐series analysis techniques. Before exercise, verapamil (n = 17, 250 μg/kg), nifedipine (n = 5, 10 μg/kg; n = 9, 100 μg/kg), diltiazem (n = 10, 100 mg/kg), Ro 40‐5967 (n = 14, 1,000 μg/kg), and magnesium sulfate (n = 10, 100 mg/kg) significantly increased heart rate, while flunarizine (n = 11, 2.5 mg/kg) and a lower dose of Ro 40‐5967 (n = 5, 250 μg/kg) did not affect heart rate. During exercise, nifedipine (high dose) increased heart rate, while Ro 40‐5967 (high dose) decreased heart rate. All six drugs reduced vagal tone before exercise; magnesium and nifedipine (high dose) elicited the greatest reduction, while flunarizine produced the smallest decrease. The vagal tone response to exercise was not affected by flunarizine and Ro 40‐5967 (low dose), but it was accentuated by magnesium, nifedipine, and verapamil. Intermediate responses were noted for Ro‐40‐5967 (high dose) and diltiazem. Pronounced hemodynamic effects were noted for flunarizine, magnesium, nifedipine, and verapamil, but not for Ro 40‐5967. Thus, calcium antagonists have variable hemodynamic profiles and can elicit pronounced reductions in cardiac vagal tone, presumably due to activation of the baroreceptor reflex. © 1992 Wiley‐Liss, Inc.
Reversal of diazepam‐induced impairment in successive discrimination performance by flumazenil
Authors: Cole Sherwood O. 
Published: January 2005

AbstractThe effects of diazepam (DZ) alone and in combination with flumazenil (Ro 15‐1788) on the performance of a previously learned successive discrimination task were studied in male Sprague‐Dawley rats. DZ 4 mg/kg impaired discrimination performance in five successive sessions, although animals showed some tolerance to the drug's action. The impairment in discrimination performance was due to an increase in responding during no go periods of the task (errors of commission). The benzodiazepine (BDZ) receptor antagonist flumazenil (5 and 10 mg/kg) partially reversed the impairment in discrimination performance and reduced the number of incorrect responses in a generally dose‐dependent manner when coadministered with DZ. These findings suggest that the impairment in discrimination performance by DZ is mediated by central BDZ receptor sites. When administered alone, flumazenil 10 mg/kg (but not 5 mg/kg) produced a mild impairment in discrimination performance which, in contrast to DZ's effects, was due to both small increases in no go period responses (errors of commission) and small decreases in go period responses (errors of omission). These findings suggest that flumazenil is not a neutral antagonist but has some intrinsic action of its own. © 1992 Wiley‐Liss, Inc.
Application of fixed‐interval schedules to intracranial self‐stimulation for assessing psychomotor stimulants
Authors: Schaefer Gerald J. , Michael Richard P. 
Published: January 2005

AbstractRats were implanted with stimulating electrodes aimed at the medial forebrain bundlelateral hypothalamus (MFB‐LH) and were trained to lever‐press for brain stimulation on a fixed‐interval 15‐sec schedule of reinforcement. When behavior had stabilized, the animals were tested with graded doses of d‐amphetamine (0.1–1.0 mg/kg), cocaine (3.0–30 mg/kg), and nomifensine (1.0–10 mg/kg). Separate groups of animals were tested in a locomotor activity procedure over the same dose ranges. All three drugs produced graded increases in rates of responding which ranged from 180–295% of saline control levels following the highest dose of each drug. In contrast, there were no significant changes in numbers of reinforcements at any of the doses used. When tested in a locomotor activity device, all three drugs produced similar increases in activity with increasing dosage. Although currently little used, the fixed‐interval schedule of brain self‐stimulation can be helpful in making comparisons of the stimulant properties of abused drugs, such as amphetamine and cocaine, and less well‐known drugs with abuse potential such as nomifensine. © 1992 Wiley‐Liss, Inc.
Calmodulin antagonists bind to sodium‐dependent high‐affinty binding sites for tritiated imipramine
Authors: Helmeste Daiga Maret , Tang Siu Wa 
Published: January 2005

AbstractEffects of calmodulin antagonists on the binding of tritiated imipramine and inhibition of serotonin uptake were tested in brain and platelet preparations. Naphthalene sulfonamidetype calmodulin antagonists generally inhibited specific [3H]‐Imipramine binding (as well as serotonin uptake) with affinities greater than or equal to those reported for binding to calmodulin itself. The binding inhibition did not require the presence of calcium and was not affected by ethylenediaminetetraacetic acid. Other calmodulin antagonists which do not have naphthalene sulfonamide structures did not inhibit [3H]‐Imipramine binding. These results raise the possibility that the structural similarity between imipramine and the naphthalene sulfonamide cerivatives may be sufficient to allow direct competition at the binding site for [3H]‐Imipramine. This is of great importance for calmodulin biochemistry since at these concentrations, the inhibitors were previously thought to interact virtually exclusively with calmodulin. © 1992 Wiley‐Liss, Inc.
Involvement of nitric oxide formation in the action of ramipril and ramipril‐octil in an inhibitory avoidance task in mice
Authors: Hock Franz J. , Wiemer Gabriele 
Published: January 2005

AbstractWe tested (in an inhibitory avoidance test) ramipril and the n‐octyl‐ester of ramipril (RA‐octil; Hoe 065), which was shown to have no significant influence on plasma‐converting enzyme (CE) activity or blood pressure in spontaneously hypertensive rats. In addition, the influence of the specific NO‐synthase inhibitor NG‐nitro‐L‐arginine (L‐NNA) and the specific B2 antagonist Hoe 140 in combination with ramipril and RA‐octil were tested. Ramipril and RA‐octil showed a significant prolongation of step‐through latencies. L‐NNA and Hoe 140 by themselves showed no effects. The combination of ramipril and of RA‐octil, respectively, with L‐NNA or Hoe 140 did not produce any prolongation of step‐through latencies. © 1992 Wiley‐Liss, Inc. © 1992 Wiley‐Liss, Inc.
Effects of chronic treatment with L‐alpha‐glycerylphosphorylcholine on hippocampal cholinergic transmission in the rat
Authors: Missale Cristina , Sigala Sandra , Rizzonelli Paola , Zanelli Emanuela , Spano PierFranco 
Published: January 2005

AbstractL‐alpha‐glycerylphosphorylcholine (alpha‐GPC) has been proposed for the treatment of age‐related cognitive disturbances. In the rat the compound prevents the learning impair‐ ment and the retrograde amnesia both induced by scopolamine and this effect appears to be correlated with an increase of hippocampal acetylcholine production and release. Since drugs ameliorating learning and memory are usually administered for long periods of time, here we investigated the effects of chronic treatment with alpha‐GPC on the neurochemical parameters linked to hippocampal cholinergic transmission. The data show that an in‐ creased [3H]acetylcholine (ACh) release was detectable in rats chronically exposed to alpha‐GPC and killed 3 hr after the last administration, suggesting that tolerance did not develop in these experimental conditions. An alpha‐GPC‐induced selective desensitization of hippocampal muscarinic M‐2 receptor function was also found. This event was charac‐ terized by a decreased responsiveness of adenylate cyclase to carbachol inhibition in the absence of changes in M‐2 receptor density. This effect could be relevant in view of M‐2 receptor presynaptic location and function in inhibiting ACh release. In contrast with M‐2 receptor, M‐1 receptor density and function were not significantly changed by the treatment. The present data suggest that alpha‐GPC could be proposed as a useful drug for the chronic treatment of memory deficit. © 1992 Wiley‐Liss, Inc.
Studies on the eleterious effects of free radicals on myocardial contractility and hemodynamics in dogs: Protection by felodipine, a dihydropyridine calcium antagonist
Authors: Chintala Madhu S. , Jacinto Severina M. , Jandhyala Bhagavan S. 
Published: January 2005

AbstractThere is convincing evidence that re‐oxygenation of ischemic organs is associated with the formation of oxygen free radicals and increases in cell calcium that exacerbate the ischemic injury. The objective of the present studies was to determine whether felodipine, a dihydropyridine calcium antagonist, would be effective in preventing cardiovascular toxicity produced by oxygen free radicals. In pentobarbital‐anesthetized dogs, intravenous (i.v.) administration of xanthine plus xanthine oxidase [X + XO] resulted in a rapid fall in arterial blood pressure (by 50–60 mmHg) and heart rate (by 30–40 beats/min). All the indices reflecting cardiac function such as contractility index (max dp/dt/p), cardiac output, stroke volume, left ventricular stroke work, and left ventricular minute work were significantly attenuated during a 120 min observation period. Pretreatment of the animals with felodipine (0.01 μmol/kg, i.v.) provided moderate but significant protection from [X + XO]‐induced deterioration of cardiovascular function, whereas the higher dose (0.05 μmol/kg, i.v.) effectively prevented any adverse alterations in cardiovascular function. The results obtained in the present studies suggest that oxygen free radicals facilitate calcium overload in the ischemic cells and can account for the efficacy of several calcium channel antagonists in preventing ischemic injury such as ischemic renal failure in various experimental models. © 1992 Wiley‐Liss, Inc.
Behavioral effects of RO 41‐9067: A novel D2 dopamine receptor agonist
Authors: Belzung Catherine , Carletti Paola , Angelucci Flavia , Puglisi‐Allegra Stefano , Cabib Simona 
Published: January 2005

AbstractThe behavioral effects of a novel putative D2 dopamine (DA) receptor agonist, RO 41‐9067 (RO), were investigated in the mouse and compared with those of the classic D2 agonist LY 171555 (LY) at equimolar doses. Both RO and LY dose‐dependently increased defensive behavior in naive mice interacting with nonaggressive conspecifics at doses higher than 0.2 and 0.16 mg/kg, respectively. Moreover, low and intermediate doses of RO and LY decreased locomotor activity in mice tested individually in an automated apparatus. Finally, coadministration of the D1 selective agonist SKF 38393 and high doses of RO or LY induced the hyperactive response classically induced by high doses of the mixed D1/D2 agonist apomorphine in the mouse while the inhibitory effects of the lowest doses of RO or LY were not affected by coadministration with SKF. These results indicate that RO induces behavioral effects characteristic of a D2 selective agonist when tested in intact mice and suggest that at high doses this compound activates postsynaptic D2 receptors which also cooperate with D1 receptors in the stimulation of DA‐induced behaviors, while at low doses it selectively activates DA autoreceptors or inhibitory DA receptors of the D2 type. © 1992 Wiley‐Liss, Inc.
Investigation of the acute and chronic anti‐inflammatory properties of diphosphonates using a broad spectrum of immune and non‐immune inflammatory reactions
Authors: Dunn Colin J. , Doyle David V. , Willoughby Derek A. 
Published: January 2005

AbstractDiphosphonates are known to affect skeletal and soft tissue mineralization; however, several studies have shown that these compounds effectively suppress adjuvant‐induced polyarthritis in the rat, reducing the edematous inflammatory component as well as skeletal changes. Therefore, we investigated the specific anti‐inflammatory potential of two diphosphonates, ethane‐1‐hydroxy‐1,1 diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP), using several different models of acute, non‐immune‐ and immune‐driven inflammation in the pleural cavity of rats and guinea pigs which afforded both a qualitative and quantitative assessment of leukocyte infiltration and exudate fluid (edema) formation. EHDP and Cl2MDP, administered at doses which suppressed the chronic inflammatory lesions induced in adjuvant arthritis, failed to inhibit acute inflammation regardless of the stimulus used (carrageenan; calcium pyrophosphate dihydrate crystals; hydroxyapatite crystals; immune complexes (Arthus reaction); delayed‐type hypersensitivity to purified protein derivate). At the highest dose tested (15 mg/kg subcutaneously [sc]) both EHDP and Cl2MDP exacerbated hydroxyapatite‐ and delayed‐type hypersensitivity‐induced leukocyte infiltration; hydroxyapatite crystals precoated with EHDP or Cl2MDP caused a small but significant inhibition of the chronic inflammatory response to sc cotton pellet implantation. We conclude that EHDP and Cl2MDP may be effective in chronic rather than acute inflammation. Our observations suggest that further studies are warranted on the potential of diphosphonates as novel therapeutics for chronic inflammatory disease. © 1993 Wiley‐Liss, Inc.
Adenosine receptors in the human heart: Pharmacological characterization in nondiseased and cardiomyopathic tissue
Authors: Böhm Michael , Ungerer Martin , Erdmann Erland 
Published: January 2005

AbstractThe purpose of the present study was to characterize adenosine receptors in human atrial and ventricular preparations as well as in nonfailing and failing human ventricular myocardium. Using the antagonist radioligand 3H‐DPCPX, A1‐adenosine receptors were identified in human atrial and ventricular myocardial membranes. The rank order of potency of agonists and antagonists as well as the influence of Gpp(NH)p on agonist high affinity binding were similar in atrial and ventricular myocardium, indicating that the same receptor type probably couples in a similar guanine nucleotide‐dependent way to different effectors producing the “direct” or “indirect” effects on myocardial force on contraction. The density and coupling of ventricular adenosine receptors as well as the antiadrenergic, “indirect” effect following their stimulation were not different in failing human myocardium, despite an increase in Giα‐proteins. Thus, enhanced antiadrenergic effects of A1‐adenosine receptors do not contribute to the reduction of cAMP‐dependent positive inotropic effects in heart failure. © 1993 Wiley‐Liss, Inc.
Hypoxia, endothelium, and purines
Authors: Burnstock Geoffrey 
Published: January 2005

AbstractThe article focuses on the events involving purine nucleotides and nucleosides during the initial responses of the cerebral vascular bed to ischaemia. In particular, the role of ATP released from endothelial cells which acts on P2Y‐purinoceptors, leading to production of nitric oxide and subsequent vasodilatation, will be considered. A relation between these events and the involvement of purines in the longer term degenerative consequences of ischaemia seems unlikely. © 1993 Wiley‐Liss, Inc.
Purinergic responses in the feline pulmonary vascular bed
Authors: Neely Constance F. 
Published: January 2005

AbstractAdenosine and ATP produce dose‐dependent, tone‐dependent response in the pulmonary vascular (PV) bed, under conditions of controlled pulmonary blood flow and constant left atrial pressure in vivo in intact‐chest, spontaneously breathing cats. At low, resting PV tone, adenosine produces dose‐dependent vasoconstrictor responses by acting on “A1‐like” adenosine receptors which activate a phospholipase and thromboxane release. ATP Produces dose‐dependent vasoconstrictor responses, in part, following its metabolism to adenosine, by acting on “A1‐like” adenosine receptors and by acting on P2x receptors. At elevated PV tone, data to date support that adenosine and ATP produce dose‐dependent vasodilator responses by acting on A2 and P2Y receptors, respectively. Mechanisms to explain how a change in vascular tone alters the response of the vascular bed to a substance are not known. Moreover, the role of purinoceptors in pulmonary vascular disease is not known. Identification of selective pharmacological probes for purinoceptors in the pulmonary vascular bed is necessary to investigate their role in the development of pulmonary hypertension of acute and chronic lung disease. © 1993 Wiley‐Liss, Inc.
Prolonged agonist exposure induces imbalance of A1 and A2 receptor‐mediated functions in rat brain slices
Authors: Abbracchio Maria P. , Brambilla Roberta , Rovati G. Enrico , Cattabeni Flaminio 
Published: January 2005

AbstractAgonist‐induced desensitization of A1 and A2 adenosine receptors was studied in brain slices obtained from either rat striatum or cortex, exposed to the adenosine analogue N6‐cyclopentyl adenosine (CPA) for selected time periods (15–60 min), and repeatedly washed at the end of agonist exposure. Adenosine receptor function in control and agonist‐exposed slices was evaluated by measuring coupling with the cAMP producing system in striatum and with membrane phosphoinositide metabolism in cortex. In rat striatum, exposure to the adenosine analog resulted in a rapid, time‐and dose‐dependent desensitization of cyclase‐linked A1 receptors, as shown by a gradual loss of A1 receptor‐mediated inhibition of basal cAMP formation. Binding studies with [3H]cyclo‐hexyl‐adenosine (CHA) showed no changes of A1 receptors for the shortest agonist exposure periods utilized (i.e., 15 and 30 min), indeed suggesting an initial uncoupling of receptors from their transduction system. After a 60 min exposure to the adenosine analogue, a significant change of [3H]CHA higher affinity component was instead detected, probably reflecting later agonist‐induced receptor changes related to irreversible receptor loss. The initial agonist‐induced loss of A1 receptor function was also confirmed in rat cortex, where A1 receptor‐mediated modulation of phosphoinositide breakdown was dose‐dependently impaired by pre‐exposure of slices to the adenosine analogue. A2 receptors seemed resistant to agonist‐induced desensitization, at least for the exposure periods utilized. In striatum, changes of A1 receptor function were indeed accompanied by a concomitant increase of A2 receptor mediated stimulation of adenylate cyclase activity, suggesting an “unmasking” of A2 stimulatory receptors as a consequence of inhibitory receptors. These result therefore indicate that the over‐exposure to adenosine analogues can result in a functional unbalance between A1 and A2 adenosine receptors, which might be at the bases of changes of adenosine neuroprotective activity in brain pathological conditions characterized by an increased release of the nucleoside. © 1993 Wiley‐Liss, Inc.