bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the cardiovascular effects of arecoline in the anesthetized dog
Authors: Beil Michael E. , Goodman Frank R. , Shlevin Harold H. , Smith Edward F.
Published: January 2005

Arecoline has been reported to improve memory deficits, but a relatively short half‐life and adverse cardiovascular effects have limited its use. The purpose of this study was to compare the cardiovascular effects of a bolus administration with those of an infusion of arecoline in anesthetized beagle dogs. Arecoline was administered either as a 15 sec bolus (group I), as a constant infusion (group II), or as an infusion after pretreatment with 0.1 mg/kg methyl scopolamine (group III). In group I, mean arterial blood pressure (MABP) was immediately reduced (i.e., which 1 min) after each dose of arecoline, but had returned to the baseline value by 5 min after doses of 0.01 to 10 μg/kg, and by 20 min after a 30 μg/kg dose. However, blood pressure was still depressed 20 min after a 100 μg/kg dose of arecolin. Cardiac output (CO) was significantly reduced only after the 30 or 100 μg/kg doses. In group II, MABP, heart rate (HR), and CO were unchanged after a 0.3 or 1.0 μg/kg/min infusion of arecoline. An infusion of 3.0 or 10 μg/kg/min produced dose‐dependent decreases in MABP (–15 and –56%, respectively) and HR (–13 and –71%, respectively). CO was unchanged at 3 μg/kg/min but was reduced by 50% at 10 μg/kg/min (P < 0.05). Plasma levels of arecoline were 46.9 ± 5.5 ng/ml after an arecoline infusion of 10 μg/kg/min. Pretreatment with methyl scopolamine significantly attenuated the cardiodepression produced by 10 μg/kg/min arecoline. Moveover, infusions of 30 and 100 μg/kg/min of arecoline produced less than 40% reductions in MABP, HR, and CO. After pretreatment with methyl scopolamine, plasma arecoline levels were 29 ± 4 and 259 ± 38.7 ng/ml with an infusion of 10 or 100 μg/kg/min, respectively. These data indicate that the continuous administration of a low dose of arecoline may minimize the undesired cardiovascular effects. Pretreatment with methyl scopolamine further attenuated the cardiovascular responses produced by arecoline, suggesting that a greater therapeutic ratio may be achieved in the presence of a peripheral muscarinic blocking agent.
Lethal drug interaction: Isoniazid and methylxanthines
Authors: Harris Cynthia M. , Springfield Angela C. , Ranschaert Erik R. , Lal Harbans
Published: January 2005

Nonlethal doses of methylxanthines (caffeine or theophyline) produced dose‐dependent lethality in rats pretreated with isoniazid. Isoniazid pretreatment did not alter theophylline concentration in blood or brain, suggesting that the drug interaction was not due to altered distribution or metabolism of theophylline. Death was associated with tonic‐clonic seizures and pulmonary congestion. The toxicity of the drug combination was blocked by the anticonvulsants diazepam, barbital, and trimethadione, but not by chlorpromazine, a sedative drug which lacks anticonvulsant activity. Thus, there is a fatal drug interaction between isoniazid and theophylline which may be due to convulsions that trigger a shock lung syndrome.
Carbonic anhydrase: General perspective and advances in glaucoma research
Authors: Maren Thomas H.
Published: January 2005

The chemistry and physiology of carbonic anhydrase are reviewed in relation to pharmacological progress in the development of sulfonamide inhibitors. The major organ systems are briefly dicussed. From the medical point of view, the major thrust is now for the treatment of glaucoma. The physiology of aqueous humor formation with respect to ion transport is discussed, and it is shown that a key event is the catalytic formation of HCO3− from CO2 and OH−. The newly formed HCO3− is linked to NA+ and fluid movement to produce aqueous humor. Inhibition of HCO3− sunthesis sulfonamides reduces aqueous formation and lowers pressure in normals and in glucoma.

Four sulfonamides have been used sytemically, the chief being acetazolamide. None of these works topically; they do not reach the ciliary process in adequate concetrations. New programs have begun, searching for sulfonamides of different properties that cross the cornea in effective concetrations to inhibit carbonic anhydrase in the ciliary porcess. The key to the problems seems to be to search for a balance between water and lipid solubility, maintaining high activity against the enzyme. This has been achieved, and new structures described from this and other laboratories lower pressure in the rabbit nearly as well as systemic sulfonamides.

Corneal permeabilities to test compounds (in vitro) in rabbit and man are similar, but accession to the auqeous (in vivo) is less in man. This may make the goal difficult, and the reasons for this difference are being explored.
Immunology and skin disorders
Authors: Bergstresser Paul R.
Published: January 2005

Concepts of the function of skin have changed in the last decade from that of a barrier against microbiologic and chemical invasion to include its important role in immunity. This transition began with the recognition that skin could serve as a sensitive target of immunologic injury, typified by diseases such as lupus erythematosus and cutaneous vasculitis. Recently, a more complicated picture has emerged as investigators have established a role for skin in the initiation and regulation of immune responsiveness. Considerable effort in this area has focused on Langerhans cells and Thy‐1+ dendritic epidermal cells, both of which reside as bone marrow‐derived immigrants in normal epidermis. Not only do these cells contribute to immune processes in skin, but their function, in turn, is modified by the keratinocytes that surround them. More importantly, pharmacologic and physical manipulation of one cell or one structure in skin often has impact on its neighbors. This phenomenon may be documented by the wide‐reaching cutaneous effects of ultraviolet radiation, bone marrow transplantation, and drugs such as cyclosporine. Our changing concepts of the function of skin also create for us a model for the current evolution in science; our problem and our fortune lie in the mutual interdependence of cells, tissues, systems, and disciplines.
Lipids are major components of human immunodeficiency virus (HIV): Modification of HIV lipid composition, membrane organization, and protein conformation by AL‐721®
Authors: Crews F. T. , McElhaney M. R. , Klepner C. A. , Lippa A. S.
Published: January 2005

The lipid composition of human immunodeficiency virus (HIV) was investigated. Several strains of HIV were found to contain considerable amounts of lipid. The major lipid constituents were cholesterol and phospholipid with a molar ratio close to one. This lipid composition and membrane apparent microviscosity, as determined by diphenylhexatriene fluorescent polarization, indicate that the HIV envelope is an extremely rigid membrane. A previous in vitro study and two recent clinical reports have indicated that AL‐721®, a lipid mixture designed to alter membrane lipid composition and organization by extraction of membrane cholesterol, has anti‐HIV activity. We found that AL‐721® modifies the lipid composition of HIV, reducing the cholesterol content and the cholesterol to phospholipid molar ratio. Both DPH fluorescent probe and endogenous protein fluorescent studies suggest that AL‐721® alters HIV envelope organization and/or apparent microviscosity. Membrane perturbation of HIV by AL‐721® may represent a new approach to AIDS therapy.
Tissue specificity of cAMP‐phosphodiesterase inhibitors: Rolipram, amrinone, milrinone, enoximone, piroximone, and imazodan
Authors: Pang David C. , Cantor Elinor , Hagedorn Alfred , Erhardt Paul , Wiggins Jay
Published: January 2005

The effects of nine cAMP‐phosphodiesterase inhibitors, including amrinone, milrinone, enoximone, piroximone, imazodan (Cl‐914), CK‐2438 (4,5‐dihydro‐6‐[pyridin‐4‐yl]‐3‐[2H]pyridazinone), rolipram, ZK‐73433 4[(3,4‐dimethoxy‐phenyl)methyl]‐2‐pyrolidinone), and IBMX (3‐isobutyl‐1‐methylxanthine) were determined on crude enzyme fractions prepared from heart, brain, and thoracic aorta of dogs. Inhibitors, such as amrinone, milrinone, enoximone, piroximone, imazodan, and CK‐2438, were found to be specific for the enzyme from the heart, but not that from the brain and thoracic aorta. On the other hand, rolipram and ZK‐73433 were potent inhibitors of the brain enzyme, but not of enzymes from the heart and thoracic aorta. None of these compounds effectively depressed cGMP‐phosphodiesterase from the thoracic aorta. Conversely, IBMX was nonspecific because it was equally active on the cAMP‐phosphodiesterases from all three tissues and the cGMP‐phosphodiesterase from the thoracic aorta. The abilities of these compounds to inhibit the cAMP‐phosphodiesterase from the three tisses were not a function of their different lipid solubilities. It is concluded that most inhibitors exhibited tissue specificity on the cAMP‐phosphodiesterases from various organs of one animal species. These data also suggest the existence of isoforms of cAMP‐phosphodiesterase (PDE‐III) in different tissues.
Assessment of hypnotic effects in the rat: Influence of the sleep‐awake cycle
Authors: Meltzer Leonard T. , Serpa Kevin A.
Published: January 2005

The influence of the sleep‐awake cycle of the rat on the apparent hypnotic effects of two benzodiazepine hypnotics, triazolam (short half‐life) and flurazepam (long half‐life), was assessed. Cortical electroencephalographic recordings from freely moving animals were used to determine whether the rats were awake or asleep. When tested during the dark phase of the light‐dark cycle, when rats sleep approximately 50% of each hour, both agents increased sleep, with flurazepam having a longer duration of action than triazolam. In contrast, when tested during the light phase of the light‐dark cycle, when rats sleep approximately 70–90% of each hour, the sleep‐inducing effects of the two agents could not be distinguished. These data emphasize the importance of baseline levels of sleep in assessing hypnotic‐drug effects.
Simple alternation of components in a multiple fixed‐interval fixed‐ratio schedule of food reinforcement in the rat
Authors: Howard James L. , Pollard Gerald T.
Published: January 2005

Three rats pressed a lever on a multiple fixed‐interval 60‐sec (FI) fixed‐ratio 30‐response (FR) schedule of food reinforcement. After 1 year of training in which the FI and FR components were programmed to occur with a probability of 0.5 (random alternation), stimulus control was weak: the response rates early in the FI were high and variable. When FI and FR components were programmed to occur one after the other (simple alternation), stimulus control was strong: the response rates early in the FI were low while the rates late in the FI remained high. Results indicate that simple alternation might facilitate the acquisition of a stable baseline for drug testing.
Alzheimer's “syndrome”: Prognosis of subsets with different etiology and preliminary effects of immunotherapy
Authors: Fudenberg H. Hugh , Singh Vijendra K.
Published: January 2005

Based on our current work, we have found aberrations of both cellular immunity and humoral immunity in patients with Alzheimer's disease (AD), suggesting that the bodyapos;s immune system plays an important role in the etiology and/or pathophysiology of at least one subset of AD (we consider AD as a “syndrome”, not a disease). Depending upon the nature of the immune deficits and patientsapos; responsiveness to appropriate immunomodulate therapy, we have thus far differentiated four subsets of AD patients: one subset with defect of a specific T cell (e.g., membrane flexibility) and response to therapy with pyrrolidone compounds; a second subset with autoantibodies to neuron‐axon filament proteins–these patients show clinical improvement after therapy with dialyzable leucocyte extract (DLE) containing transfer factor (TF); a third subset with antibodies to brain antigens (autoimmune) for which therapy is not yet developed; and a fourth subset with none of the abnormalities mentioned above, probably heterogeneous due to one or another biochemical abnormality. We believe that different therapeutic modalities will be necessary for different subsets, much like the situation with other “diseases” such as anemia and diabetes. Our therapeutic results provide additional evidence that AD is a syndrome, not a single disease. Moreover, the clincal improvement demonstrates that the defective function in AD is not due to death of neuronal cells, but rather atrophy or physiologic “suppression.”
Bradykinin‐antagonists: Therapeutic perspectives
Authors: Taylor J. E. , DeFeudis F. V. , Moreau J. P.
Published: January 2005

In vitro and in vivo studies of the actions of various antagonists and agonists of bradykinin (BK) B1 and B2 receptors have been reviewed and analyzed. It seems apparent that certain B2‐antagonists, such as [Thi5,8,D‐Phe7]‐BK and D‐Arg0‐[Hyp3,Thi5,8,D‐Phe7]‐BK will serve as valuable model substances for developing new anti‐inflammatory/analgesic drugs. Further development of B1‐antagonists, based on modifications of the structure of des‐Arg9,[Leu8]‐BK, or combined B1/B2‐antagonists might be useful in controlling disease states involving chronic tissue injury and/or prolonged vasopasm.
Comparison of fixed‐ratio and tandem schedules of reinforcement in discrimination of nicotine in rats
Authors: Stolerman I. P.
Published: January 2005

There have been few comparisons between different schedules of reinforcement for establishing drugs as discriminative stimuli. Fixed‐ratio (FR‐10) and tandem variable‐interval 1‐min FR‐10 schedules have, therefore, been compared directly in a conventional, drug‐saline discrimination paradigm with food reinforcement in rats. The drug used for training was nicotine (0.4 mg/kg s.c., “faded” to 0.1 mg/kg s.c.). The discrimination was acquired rapidly under both schedules, with stimulus control by nicotine being slightly superior under the FR‐10 schedule. In 5‐min extinction tests with nicotine, the FR‐10 schedule gave a clear dose‐response curve with a bar‐selection (quantal) index but with generally poor results when the percentage of drug‐appropriate responding (quantitative index) was calculated. In contrast, the tandem schedule yielded clear dose‐response data with both indices. In tests with (+)‐amphetamine, full generalization was obtained with both FR‐10 and tandem schedules and with both quantitative and quantal indices. Tests for generalization to morphine were negative regardless of the training schedule. The results confirm that orderly data may be obtained with either an FR‐10 or a tandem schedule provided that an appropriate index of discriminative response is employed. The results generally support the validity of current practices, and there will probably not be very marked differences between conclusions depending on which schedule is used.
Compound drug discrimination learning
Authors: Järbe Torbjörn U. C. , Hiltunen Arto J. , Swedberg Michael D. B.
Published: January 2005

Data are summarized which indicate that drug discriminative stimuli (DDS) and exteroceptive, sensory stimuli interact in a systematic manner. Thus recent work revealed that phenomena such as overshadowing, blocking, and conditional discrimination are operable in drug discrimination learning (DDL) experiments involving exteroceptive cues and DDS. Additionally, in a reversal learning experiment, a contextual change differentially affected rate of reversal learning and subsequent generalization test data.
Individual differences in cocaine discrimination
Authors: Goudie Andrew J. , Leathley Michael , McNally Jayne , West C. R.
Published: January 2005

This study involved an attempt to develop a screening test to select animals that would learn a cocaine drug discrimination (DD) rapidly and an analysis of factors affecting rates of acquisition of cocaine DD. Rats (n = 18) were trained initially in a conditioned taste aversion (C.T.A.) procedure with cocaine (36 mg/kg). Subjects were then trained to discriminate cocaine (5 mg/kg) in an operant procedure, and the cocaine generalization curve was determined. Subjects were then tested for cocaine‐induced hyperthermia. Animals that showed weak C.T.A. showed relatively rapid acquisition of DD (rs = –0.56, P > 0.05, two tailed). Cocaine‐induced hyperthermia did not predict speed of acquisition reliably, nor did cocaine's effects on operant responding. Animals were allocated retrospectively to groups of “rapid” and “slow” discriminators. These groups did not differ in generalization ED50s, in sensitivity to cocaine's effects on operant responding, or in hyperthermic responses to cocaine. Thus speed of DD acquisition was not dependent on individual sensitivity to cocaine. Furthermore, “rapid” and “slow” discriminators probably cannot be dissociated in terms of learning ability, since animals that acquired marked C.T.A. showed slow learning of DD. The C.T.A. data suggest that animals sensitive to dysphoric effects of cocaine are less sensitive to the drug's cueing properties and thus that the cocaine cue at 5 mg/kg may be related to its euphoriant actions. It is possible that C.T.A. procedures can be used to select animals that will learn cocaine DD rapidly.
Discriminative stimulus‐ and schedule‐induced rate effects of ethanol in combination with the proposed ethanol antidote Ro 15‐4513
Authors: Hiltunen Arto J. , Järbe Torbjörn U. C.
Published: January 2005

Two different groups of rats were trained to discriminate, 15 min after the injections, between i.p. administered (1) ethanol (ETOH, 1.2 g/kg) or (2) pentylenetetrazol (PTZ, 15 mg/kg) from a non‐drug condition according to a drug discrimination learning (DDL) procedure. Thereafter, combinations of ETOH and Ro 15‐4513 were evaluated in both groups, as well as in a third group, which was trained according to an FR‐10 bar‐pressing procedure. Results indicated that rats trained to discriminate ETOH from saline generalized combinations of ETOH (0.9 and 1.2 g/kg) and Ro 15‐4513 (3 and 10 mg/kg) to the ETOH stimulus. Rats trained to discriminate PTZ from saline (1) disclosed generalization to the PTZ stimulus with Ro 15‐4513 (10 mg/kg) but not with ETOH 0.3–1 g/kg, (2) generalized the effects of combinations of Ro 15‐4513 (10 mg/kg) and ETOH (0.3–1 g/kg) to the PTZ stimulus, and (3) diazepam (DZP, 3 mg/kg) and Ro 15‐1788 (10 mg/kg) antagonized the PTZ‐like discriminative stimulus effects of Ro 15‐4513 (10 mg/kg). Rats trained to press a bar disclosed increases in the response time after treatments with ETOH (0.9 and 1.2 g/kg) and Ro 15‐4513 (3 and 10 mg/kg) as did the DDL animals. Thus, (1) Ro 15‐4513 did not seem to reverse any of the recorded behaviors induced by ETOH, and (2) both DZP and Ro 15‐1788, however, reversed the generalization of Ro 15‐4513 to the PTZ stimulus.
Does the pentylenetetrazole (PTZ) cue reflect PTZ‐induced kindling or PTZ‐induced anxiogenesis?
Authors: Andrews J. S. , Turski L. , Stephens D. N.
Published: January 2005

The discriminative stimulus induced by a subconvulsive dose of pentylenetetrazole (PTZ) in rats is suggested to be anxiogenic in nature; therefore, antagonism of the discriminative stimulus indicates anxiolytic and not anticonvulsant activity. Repeated administration of subconvulsive doses of PTZ eventually leads to seizures, a process known as kindling. The effects of several anxiolytic and anticonvulsant drugs in antagonizing the discriminative stimulus in rats were compared with the effects of the same substances in preventing seizures in rats treated acutely with a high dose of PTZ or in rats exhibiting kindled seizures following repeated low‐dose PTZ treatment. Irrespective of status as an anxiolytic or an anticonvulsant substance, only compounds that antagonized PTZ‐kindled seizures antagonized the PTZ discriminative stimulus. These results illustrate the difficulty in separating the anxiolytic from the anticonvulsant properties of a substance in this model.
Pentobarbital blocks the pentylenetetrazole‐like effect of withdrawal from chronic diazepam
Authors: Mathis D. A. , Emmett‐Oglesby M. W.
Published: January 2005

Rats trained to detect the stimulus properties of an anxiogenic drug, pentylenetetrazole (PTZ), substitute preciptated withdrawal from chronic administration of diazepam (DZP) for the PTZ stimulus. The present studies tested pentobarbital (PB), ethanol (ETOH), and clonidine (CL) for their ability to block this withdrawal stimulus. Rats were trained to discriminate PTZ (20 mg/kg) in a two‐lever choice task. Prior to chronic administration of DZP, the benzodiazepine (BDZ) antagonist Ro 15‐1788 (0.64–320 mg/kg) did not substitute for PTZ. PB blocked PTZ in a dose‐related manner, but ETOH and CL did not. Following these tests, rats were given DZP (20 mg/kg, ip) every 8 hr for 10 days. On days 7–10 of this regimen, they were tested for substitution of the PTZ stimulus by Ro 15‐1788 (10 mg/kg) and for blockade of this substitution by PB, ETOH, or CL. Ro 15‐1788 substituted fully for PTZ, and this substitution was blocked by PB but not by ETOH and CL. These data parallel recent reports from human studies that CL is ineffective in treating BDZ withdrawal, and they suggest that discrimination of PTZ may have utility for investigating treatments that will suppress the subjective aspect of BDZ withdrawal.
Naloxone as a stimulus for drug discrimination learning
Authors: Kautz Mary A. , Geter Beth , McBride Sharon A. , Mastropaolo John P. , Riley Anthony L.
Published: January 2005

Animals injected with the opiate antagonist naloxone hydrochloride prior to a saccharin‐LiCl pairing and with its vehicle prior to saccharin alone rapidly acquired drug discrimination, avoiding saccharin following the administration of naloxone and consuming saccharin following its vehicle after only three conditioning trials. Control subjects for which naloxone never signalled a saccharin‐LiCl pairing consumed saccharin following both naloxone and vehicle administration. During dose substitution sessions, animals displayed greater drug‐appropriate responding as the dose of naloxone increased. When a range of doses of naltrexone was given in place of naloxone prior to saccharin access, subjects displayed dose‐dependent naloxone‐appropriate responding. When a range of doses of morphine was substituted for naloxone, subjects displayed vehicle‐appropriate responding at all doses. The fact that naloxone was an effective stimulus at low doses and with minimal training suggests that the conditioned taste aversion procedure is a sensitive index of drug discrimination learning.
Asymmetrical cross‐generalization in drug discrimination with lorazepam and pentobarbital training conditions
Authors: Ator Nancy A. , Griffiths Roland R.
Published: January 2005

Depressants have been characterized as showing lower specificity as training drugs than drugs from other pharmacological groups, because drug–lever responding has been occasioned by drugs that are very diverse. In contrast, recent work with lorazepam as a training drug under a food‐maintained drug vs. no‐drug discrimination procedure found unreliable pentobarbital generalization, although pentobarbital‐trained animals showed generalization to lorazepam. Exploration of the limits of this asymmetrical cross‐generalization has included manipulation of species and training doses and studies with a variety of classic and novel sedative‐anxiolytic drugs. To date, comparison of lorazepam to other benzodiazepines used as training drugs suggests that the lorazepam training condition appears to result in a lower probability of generalization to other sedative/anxiolytic drugs than other benzodiazepine training conditions. Review of drug discrimination studies with sedative/anxiolytic drugs suggests that there may be more specificity among the depressants as training drugs than initially appeared to be the case.
Sex differences in luteinizing hormone releasing hormone‐induced conditioned place preference in the rat
Authors: de Beun Rene , Geerts Nora E. , van de Poll Nanne E. , Slangen Jef L. , Vreeburg Jan T. M.
Published: January 2005

Conditioned place‐preference was measured in male and female Wistar rats after association of 5 μg/kg i.p. injections of LHRH with one side of a spatial preference box. Gonadectomized males and females received silastic implants, containing testosterone (T) and estradiol (E), respectively. During an adaptation session of 60 min, at the start of experimentation, possible basic preference for one or the other (black or white) compartment was established. Alternatingly, on 8 subsequent days, LHRH treatment was paired with one compartment (4 × 30 min), and vehicle treatment (saline), with the distinctive second compartment (4 × 30 min). Animals were injected 15 min before the association sessions, which was sufficient to increase circulating LHRH during the first 10–13 min. Finally, at the preference test (non‐drug condition), animals had access to both compartments (test duration 60 min). Male rats spent significantly more time in the part of the test box associated with LHRH treatment, whereas no preference developed in females. The results indicate that injection of a dose of LHRH that was sufficient to activate the pituitary‐gonadal axis in intact rats (unpublished data) is rewarding for male but not for female rats.
Alpha2 agonists and GABAergic agents reverse isoniazid‐induced convulsions in mice
Authors: Aley K. O. , Kulkarni S. K.
Published: January 2005

The effects of GABAergic agents (GABA, fengabine, baclofen) and alpha2 agonists (clonidine and BHT‐920) on isoniazid (INH)‐induced convulsions in mice were studied. All the GABAergic agents and alpha2 agonists employed in the study provided significant protection against INH‐Induced convulsions and death. The protective effects of alpha2 agonists were sensitive to blockade by yohimbine or idazoxan. When a subeffective dose of alpha2 agonist or GABAergic agent was concomitantly administered with a subeffective dose of diazepam, a potentiation of the anticonvulsant effect of diazepam was observed. Alpha2 agonists through GABAergic mechanism offer protection against INH‐induced seizures in mice.
Single‐Subject design for locomotor activity
Authors: Pollard Gerald T. , Howard James L.
Published: January 2005

Rats were given daily 1‐hr sessions in photocell cages until baseline locomotion stabilized. d‐Amphetamine 0.5–2.0 mg/kg p.o. significantly increased locomotion. Chlorpromazine 2.5–20 mg/kg p.o. and pentobarbital 5.0–20 mg/kg p.o. significantly decreased locomotion. N = 4 per drug. Results demonstrate the appropriateness of using chronic single subjects to assess the effects of drugs on locomotion. An attempt to generate cumulative dose‐effect curves in rats run once a week was less successful because of intrasubject variability. The method could also be used for multiple drug studies in lesioned or cannulated preparations.
Excitotoxicity and N‐methyl‐D‐Aspartate receptors
Authors: Olney John W.
Published: January 2005

A great deal of new information has been generated over the past decade in the excitatory amino acid (EAA) field. Not only have endogenous EAA such as glutamate and aspartate become recognized as the leading neurotransmitter candidates at the majority of excitatory synapses in the mammalian central nervous system, but it is becoming increasingly evident that the well‐established neurotoxic (excitotoxic) properties of these agents may play an important role in the pathophysiology of neurodegenerative diseases. Several EAA receptor subtypes have been identified through which the excitotoxicity of EAA might be expressed. One of these—the N‐methyl‐D‐aspartate (NMDA) receptor—has become a primary focus of attention because of evidence suggesting it may be involved in a wide range of both neurophysiological and pathological processes. Antagonists that powerfully block both the excitatory and neurotoxic actions of EAA agonists at the NMDA receptor or associated ion channel have been identified and are being developed as potential neuroprotective agents for use in the management of neurological disorders. In this article, the potential role of excitotoxic mechanisms in neurodegenerative diseases and the prospects for controlling such disease processes by the application of antiexcitotoxin drugs will be examined.
Excitatory amino acid antagonists: Behavioral and biochemical approaches for the development of new central nervous system therapeutic agents
Authors: Wilmot Carole A.
Published: January 2005

A general summary of behavioral and biochemical procedures that have been used for the evaluation of excitatory amino acid (EAA) antagonists, primarily those of the N‐methyl‐D‐aspartate (NMDA) subtype, is presented. The effects of both competitive NMDA receptor antagonists and noncompetitive ion channel blockers are compared. In some tests, a specificity by 2‐amino‐5‐phosphonovaleric acid (AP5), phencyclidine, and MK‐801 for antagonism of NMDA receptors vs. other subtypes of EAA receptors has been demonstrated. Antagonists of the quisqualate or kainate subtypes of EAA receptor have been less well characterized.
Cognitive enhancers prevent the hypoxia‐induced disruption of conditioned avoidance response
Authors: Groóa Dóra , Pálosi Eva , Szporny László
Published: January 2005

Six cognitive enhancer compounds, the new class of central nervous system (CNS)‐active drugs (vinpocetine, vincamine, dihydroergotoxine, nicergoline, piracetam, and meclofenoxate) were tested before acquired two‐way active avoidance response of spontaneously hypertensive (SH) rats had been disrupted by lowered environmental oxygen concentration (6% oxygen). Exposure to normobaric hypoxia reduced the number of conditioned avoidance responses (CAR) by 44%; at the same time the spontaneous locomotor activity of the animals (measured by the alteration in the number of intertrial crossings) was not considerably decreased, and latency times of conditioned responses were not lengthened significantly. The compounds tested showed protective effect against hypoxia‐induced performance deficit without stimulating spontaneous activity. Vinpocetine antagonized nearly completely CAR blockade in the 1.25‐5.0 mg/kg p.o. dose range, restoring the ratio of avoidance responses to normal level. Vincamine exerted activity at a dose of 20 mg/kg p.o. Dihydroergotoxine and nicergoline were effective at 10 mg/kg p.o., Piracetam and meclofenoxate showed moderate protective activity at 2,000 and 500 mg/kg p.o., respectively. For comparison, the effect of dopaminergic drugs of a different mechanism of action (amphetamine, apomorphine, bromocriptine, and methylphenidate) was also tested in a similar situation. Only amphetamine (at 1.0 mg/kg i.p.) and low doses of apomorphine (0.1 and 1.0 mg/kg) had a favorable effect against hypoxia‐induced CAR blockade; this effect was accompanied by an increase in locomotor activity. On the basis of these data, the relatively simple behavioral method applied by us, protection of acquired conditioned response against the disruptive effect of hypoxia in SH rats, seems suitable to detect nootropic activity.
Effects of endothelium‐derived constricting factor and calcium antagonists on calcium uptake into aortic vascular smooth muscle cells
Authors: Pang David C. , Sperelakis Nicholas , Highsmith Robert F.
Published: January 2005

Edothelial cells in culture secrete a protein termed endothelium‐derived constricting factor (EDCF) that elicits vasoconstriction in isolated arteries. In this study, the effect of EDCF on Ca2+ influx into cultured rat aortic smooth muscle cells and on force development in coronary arteries was evaluated and compared to that elicited by depolarization with K+. In addition, the effects of the Ca2+ antagonists bepridil, verapamil, and nitrendipine on EDCF‐ and K+‐induced changes in smooth muscle Ca2+ uptake and contractile force were also quantified and compared. EDCF, but not conditioned media from control cultures of fibroblasts or pituitary cells, enhanced Ca2+ influx into monolayer cultures of rat aortic smooth muscle cells in a time‐ and dose‐dependent manner. The time course of Ca2+ uptake in response to EDCF was similar to that elicited by K+. EDCF also resulted in a time‐ and dose‐dependent increase in isometric force in isolated deendothelialized rings of porcine coronary artery, which was more resistant to washout than that induced by K+. The increase in both Ca2+ influx and isometric tension induced by EDCF was abolished by heating the EDCF preparation to 80°C for 15 min. Bepridil (10 m̈M), verapamil (1 m̈M), and nitrendipine (1 m̈M) either markedly attenuated or completely blocked both EDCF‐ and K+‐induced increases in Ca2+ uptake and contractile force. The similarity between the effect of the Ca2+ antagonists on K+‐ and EDCF‐induced changes in vascular smooth muscle function suggests that a site of action of EDCF may be directed at the voltage‐sensitives Ca2+ channel.
In vivo assessment of class III agents and their antiarrhythmic activity
Authors: Gibson J. K. , Kersten J. A.
Published: January 2005

A variety of in vivo models have been used to detect and develop novel antiarrhythmic/antifibrillatory agents. However, most of these models primarily have identified the class I agents that block sodium ion currents during the upstroke of the cardiac action potential. Since we are interested in identifying agents with a class III electrophysiologic action, i.e. delayed repolarization of the cardiac action potential, we have focused our drug discovery process on a specific, somewhat uncommon in vivo canine model. These studies have demonstrated that class I agents such as encainide, disopyramide, or U58797, a novel benzamide, are clearly identified in the ouabain‐toxic dog or the postinfarction (24–48 hr) conscious dog. In contrast, class III agents such as clofilium sotalol are identified in an acute canine model of coronary artery occlusion and reperfusion. This occlusion‐reperfusion model allows us to further identify the antiarrhythmic and antifibrillatroy actions of novel class III agents.
Electrophysiological specificity of antiarrhythmic drugs: Is it necessary?
Authors: Sullivan Mark E. , Argentieri Thomas M. , Sansone Kenneth J. , Michael Doroshuk C.
Published: January 2005

Many factors have been identified in the genesis of cardiac arrhythmias. The relative importance of any given factor over another can vary from individual to individual, and may change with time. Successful antiarrhythmic drug therapy, therefore, must be effective against a multifaceted and evolving matrix. Clinically, the more successful antiarrhythmic agents have complex pharmacological profiles. For example, quinidine and amiodarone have several mechanistic actions which contribute to their antiarrhythmic efficacy. Multiple unfocused actions often result in side effects such as proarrhythmia, which has been demonstrated for both the above agents. Another approach to treating arrhythmias is to use different, selective agents in combination. Using programmed electrical stimulation techniques in dogs, we demonstrated that propranolol was ineffective in preventing reentrant tachycardia. However, subtherapeutic doses of the class III agent sematilide when combined with propranolol prevented reentry. A multivalent approach may also be useful in solving the problem of proarrhythmia. Using standard microelectrode techniques in vitro, we demonstrated that clofilium produced early after depolarizations, as well as an increase in triggered activity. In vivo, clofilium increased the number of ectopic events in infarcted dogs. The addition of a class I or a class IV antiarrhythmic agent in these animals was effective in suppressing the increased ectopic activity. These data suggest that combination therapy, by combining either single agents with selective actions or developing agents with multiple, focused actions may be an effective way to increase antiarrhythmic efficacy and decrease side effects.
GM1 ganglioside treatment of central nervous system injury: Clinical evidence for improved recovery
Authors: Samson Jaap C.
Published: January 2005

Monosialoganglioside GM1 is a new pharmacological agent used to enhance recovery after central nervous system (CNS) injury. This agent is a natural component of cell membranes, and its clinical use is based on extensive experimental work which demonstrates that many parameters of brain function in CNS‐injured animals are positively influenced by the parenteral administration of monosialoganglioside GM1. The key mechanism through which monosialoganglioside GM1 is able to exert its clinical effects is by enhancing the neuroplasticity of the CNS. The recovery‐promoting effect is mediated through neuroprotective and neuronotrophic activities exerted or enhanced by monosialoganglioside GM1. The neuroprotective activity is based on the prevention of the neuronotoxic consequences of indiscriminate excitatory amino acid receptor activation, particularly of glutamate receptors. In vitro and in vivo evidence indicates that the product enhances the trophic response of neurons to neurotrophic factors induced as a response to the lesion. The neuropharmacological effects of monosialoganglioside GM1 in humans have been confirmed in controlled clinical trials in head and spinal cord injury and stroke. The therapeutic use of monosialoganglioside GM1 is a significant innovation in an area of neuropharmacology that has been neglected until the functional significance of CNS neuroplasticity was recognized.
Human behavioral pharmacology of benzodiazepines: Effects on repeated acquisition and performance of response chains
Authors: Bickel Warren K. , Hughes John R. , Higgins Stephen T.
Published: January 2005

One scientific concern with benzodiazepine is their effects on learning (acquisition). One procedure that permits a detailed study of learning processes is the repeated acquisition of behavioral chains procedure. The repeated acquisition of behavioral chains allows for the repeated study of learning in individual subjects and also permits a comparison with comparable performance behavior. This paper reviews the effects of acute and chronic benzodiazepines on the repeated acquisition and performance of response chains. With acute administration, diazepam, alprazolam, and triazolam are all found to produce dose‐related increases in percent errors in the acquisitions component, while generally not affecting percent errors in the performance component. Diazepam showed less activity than either alprazolam or triazolam. With chronic administration, acquisition showed tolerance to the errors‐increasing effects of diazepam at a slower rate than did performance. Clinical implications of these findings are discussed.
Marijuana and behavioral contingencies
Authors: Foltin Richard W. , Fischman Marian W. , Brady Joseph V. , Kelly Thomas H. , Bernstein Daniel J. , Nellis Margaret J.
Published: January 2005

Twenty‐four adult male research volunteers, in groups of three subjects each, lived in a residential laboratory for up to 18 days. All contact with the experimenters was through a networked computer system, and subject behavior was continuously monitored and recorded. During the first part of each day, subjects remained in private rooms doing planned work activities, and during the remainder of each day they were allowed to socialize. One or two cigarettes containing active marijuana (1.8‐2.7% Δ9‐THC) or placebo were smoked during both the private work period and the period of access to social activities. Following the determination of baseline distributions of activities, contingency conditions requiring subjects to engage in a low‐probability activity (instrumental activity) in order to earn time that could be spent engaging in a high‐probability activity (contingent activity) were then introduced. Baseline and contingency conditions were studied under periods of placebo and active marijuana administration. Under placebo conditions, introduction of the contingency resulted in increases in instrumental activity and decreases in contingent activity under both placebo and active marijuana conditions. The response to combining marijuana administration with contingencies varied across private work and social access conditions. During work periods, active marijuana administration increased instrumental activity to a larger extent than was observed under placebo conditions. The decreases in contingent activity were similar to those seen under placebo conditions. During social periods, active marijuana administration increased instrumental activity to a smaller extent than observed under placebo conditions. The decreases in high‐probability contingent activity were similar across drug conditions. Smoking active marijuana was thus observed to produce increments in instrumental activity under motivational involving contingencies for “work activities” while producing instrumental decrements under motivational conditions involving recreational contingencies.
Neurochemical correlates of behavioral processes
Authors: Barrett James E. , Nader Michael A.
Published: January 2005

Cumulative developments in the experimental analysis of behavior and behavioral pharmacology, together with relatively recent technical advances in the field of neuroscience, have provided a strong impetus to build on previous research and combine these disciplines into an integrated approach focusing on behavioral neurochemistry. Neither behavioral nor neurochemical changes are static independent processes but interact in dynamic and complex ways. Neurotransmitter activity can be conditioned using both classical Pavlovian and operant conditioning procedures. Neurochemical changes also occur when behavior is brought under the control of its environmental consequences. Behavioral variables such as the schedule‐controlled rate of responding, prior history, and environmental context have been shown repeatedly to determine the effects of drugs and appear to have definable and distinctive neurochemical correlates. These variables may modify neurochemical substrates involved in drug action. Ongoing changes in behavior and neurochemistry are now concurrently accessible for experimental analysis. The synthesis of these two fields permits the exploration of behavioral and neurochemical interactions that were not easily accessible only a short time ago and promises to yield considerable information about both behavioral and neurochemical processes. This article summarizes the development of research in behavioral neurochemistry and attempts to show how a continuation of these endeavors can provide a better understanding of the interrelationships between behavior and neurochemistry as determinants of drug action.
Behavioral contingencies determine changes in drug‐induced neurotransmitter turnover
Authors: Smith James E. , Dworkin Steven I.
Published: January 2005

Evidence from several research areas suggests that response‐dependent and independent presentation of environmental events have different neurobiological consequences. Investigations of neurotransmitter turnover rates and cholinergic muscarinic receptor densities in brain regions of rats receiving contingent and noncontingent intravenous morphineresulted in the identification of two neuronal networks that are involved in response dependent morphine presentation. These circuits are concordant with brain regions showing increased glucose utilization in animals receiving response‐dependent electrical stimulation of either the substantia nigra or ventral tegmental area. These data indicate substantial differences between contingent and noncontingent presentation of environmental events and suggest that neurobiological investigations of reinforcement that use response independent delivery of a putative reinforcer must be interpreted with some caution.
Protective role of pentoxifylline and propentofylline against the increase in osmotic fragility of the human red cell induced by protoporphyrin photosensitization
Authors: Cassoly Robert , Deprette Christiane
Published: January 2005

Pentoxifylline and propentofylline are potent drugs used in impaired blood‐flow pathologies. As an approach to understand their mode of action we studied their influence on protoporphyrin‐photosensitized damage of the human red cell membrane. Both compounds are shown to exert a strong protection against the increase in osmotic fragility of the red cell which follows their irradiation at 390 nm in the presence of protoporphyrin. They do not, however, prevent cross‐linking of the membrane skeleton proteins, which occurs slowly following irradiation. The results emphasize the ability of pentoxifylline and propentofylline to scavenge toxic photoactivated radicals, a property which could explain their mode of action in vivo. We also show that the two methyl xanthine derivatives considered in this study significantly protect red cells from hemolysis and spontaneous microvesiculization of their plasma membrane, which normally occurs when whole blood is stored for several weeks.
How surface‐bound drugs inhibit thrombus formation
Authors: Wilson Joseph E.
Published: January 2005

This article presents the new concept that surface‐bound drugs can remove coagulation promoters from the bloodstream and thus produce much needed improvement in the surface thromboresistance of polymeric devices such as catheters, vascular grafts, and artificial organs. For example, calcium plays a central role in promoting coagulation, which suggests that surface thromboresistance could be improved by bonding a polymer to a calcium chelator which removes calcium from circulation. This technique has been tried and found successful in animal tests using hydroxyproline as the calcium chelator (Wilson and Jones: Biomater. Artif. Organs 17:437–445, 1989. An alternative design for a thromboristance polymer is proposed: Chemically bond a commercial polymer to a suitable drug containing cationic groups capable of complexing blood coagulation factors and rendering them inactive. The feasibility of this approach is based on two lines of evidence: (1) Several blood coagulation factors are routinely isolated by complexation on ion exchange resins containg cationic groups (tertiary amines). (2) A number of polymers containing cationic groups (tertiary amines) have been patented on the basis of their thromboresistance. In this article an ion exchange equilibrium is postulated between each anionic coagulation factor adsorbed on the polymer and dissolved in the liquid phase, with the surface affinity of each anionic factor being greater the more cationic (basic) the polymer surface. Data on the competitive adsorption of proteins on cationic polymers have been analyzed mathematically. The results suggest more attention should be given to cation/anion interactions in studies of polymeric thromboresistance and protein adsorption).
Initial human safety and tolerance study of a GABA uptake inhibitor, Cl‐966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania
Authors: Sedman Allen J. , Gilmet Gregory P. , Sayed Albert J. , Posvar Edward L.
Published: January 2005

An initial double‐blind, placebo‐controlled safety and tolerance study of single doses of a GABA uptake inhibitor (CI‐966) being developed for the treatment of epilepsy was conducted in healthy volunteers. Drug doses of 1 to 10 mg were well tolerated. A volunteer who received 25 mg of CI‐966 developed transient short‐ and long‐term memory deficits. Both volunteers following administration of 50 mg drug doses presented with a constellation of physical and mental disturbances. Physical abnormalities including tremor, myoclonus, increased muscle rigidity, cogwheeling, and short‐ and long‐term memory impairment of 12–24 hr duration were observed. In addition, striking psychiatric symptoms of many days' duration resembling those seen in patients with mania and schizophrenia were evident. These findings suggest that GABA may modulate memory and dopaminergic pathways responsible for posture and muscle control. In addition, GABA may be a potentially important mediator in the pathogenesis of schizophrenia and mania.