bluuebunny/crossref_metadata_2025 huggingface dataset:
Pentylenetetrazol discriminative stimuli are selective for identifying benzodiazepine receptor modulating agents
Authors: Wilson Douglas E. , Bennett Debra A.
Published: January 2005

Pentylenetetrazol (PTZ) has been reported to produce a discriminative stimulus related to anxiety and antagonized by the classical anxiolytics. In the present investigation, a variety of compounds with either benzodiazepine (BZ)‐type anxiolytic actions or other novel mechanisms of action (serotonin and N‐methyl‐D‐aspartate [NMDA] antagonism) were tested for their ability to antagonize this stimulus. Compounds that have been shown to modulate benzodiazepine receptor function were active in blocking PTZ, the discriminative stimulus. The failure of the other compounds to block these stimuli suggests that the PTZ discrimination may be selective for substances that modulate, either directly or indirectly, the BZ receptor complex.
Modification of ischemia‐induced biochemical changes in the myocardium by Rooh‐Afza extracts
Authors: Dikshit Madhu , Srivastava Ranjana , Srimal Rikhab Chand , Dhawan Bhola Nath
Published: January 2005

In rats, myocardial ischemia was produced by isoprenaline (80 mg/kg i.p.) and in rabbits, by ligating the anterior descending branch of the coronary artery. Two extracts of Rooh‐Afza, a Unani polypharmaceutical preparation, were administered 1 hr or 15 min before inducing ischemia. Both the extracts protected the rat myocardium from isoprenaline‐induced changes. In rabbits, protection against ischemia was observed only at a higher dose. The extract containing essential oils and flavoring agents was found to be more effective. It also inhibited platelet aggregation induced by adenosine diphosphate (ADP) in vitro and ex vivo in monkeys.
A physiologist's view of the N‐methyl‐D‐Aspartate receptor: An allosteric ion channel with multiple regulatory sites
Authors: Mayer Mark L. , Vyklicky Ladislav , Sernagor Evelyne
Published: January 2005

Whole‐cell and single‐channel recording techniques have provided a great deal of information about the nature of the N‐methyl‐D‐aspartate (NMDA) receptor channel complex and are beginning to lead to quasimolecular models of drug action. Currently five ligand‐binding domains are known to exist on the NMDA receptor channel complex: 1) an agonist‐binding site for which structural analogues of L‐glutamate have been developed as competitive antagonists; 2) a divalent cation‐binding site within the ion channel pore, at which Mg binds to produce voltage‐dependent channel block; 3) a divalent cation‐binding site near the extracellular face of the membrane, at which Zn and Cd but not Mg bind to produce a voltage‐independent block; 4) an anaesthetic binding site within the pore, at which ketamine, phencyclidine, MK‐801, and desipramine bind with high affinity to produce voltage‐dependent ion channel block of long duration; and 5) a regulatory site on the extracellular face of the membrane at which glycine binds to promote NMDA receptor channel activity. This potentiating action of glycine, to a large extent, reflects a block of fast desensitization, via an increase in the rate constant for return of desensitized NMDA receptors to their resting state. Drugs that competitively displace glycine from its binding site, but that are without glycine‐like activity, act as noncompetitive NMDA receptor antagonists. The combination of these unusual physiological and pharmacological properties seems to have been exploited in the brain to allow the NMDA receptor to gate a variety of complex behaviours, including memory formation, neuronal cell death in stroke and ischemia, and electrical excitability in epilepsy. The existence of multiple ligand‐binding sites on the NMDA receptor complex provides many potential avenues for the development of new classes of centrally active drugs.
Novel approach to studying N‐methyl‐D‐aspartate receptor function in the kindling model of epilepsy
Authors: McNamara James O. , Bonhaus Douglas W. , Nadler J. Victor
Published: January 2005

Kindling is the most widely studied animal model of epilepsy. This manuscript reviews studies of the role of N‐methyl‐D‐aspartate (NMDA) receptors in the kindling model. Pharmacologic studies suggest that 1) NMDA receptor activation contributes to the development of kindling; and 2) kindled seizures may be due in part to enhanced activation of NMDA receptors. Electrophysiologic studies demonstrate that NMDA receptors participate in synaptic activation of hippocampal dentate granule cells of kindled but not control animals. Biochemical studies demonstrate an enhanced sensitivity of kindled hippocampal slices to NMDA. Raising the possibility of enhanced function of the NMDA receptor channel complex itself. Radiohistochemical studies disclose no increase in affinity or number of NMDA receptors. Major emphasis is placed on development of a novel approach to study NMDA receptor function in isolated membrances, namely NMDA control of radiolabeled uncompetitive antagonist binding to a site presumably within the NMDA channel. Application of this novel approach will permit examination of NMDA and glycine receptor function and their control by zinc in the kindling model.
Cardiac sympathectomy with phenol acutely blunts the postsynaptic adrenergic response
Authors: Jones Carl E. , Gwirtz Patricia A. , Dodd‐o Jeffrey M. , Daniels Stephen E. , Randall John R.
Published: January 2005

Studies were performed in anesthetized dogs to determine if topical application of phenol to the heart acutely alters postsynaptic function in addition to destroying efferent sympathetic nerves. Left ventricular dP/dt max as well as segment length shortening (%SL) and maximal rate of shortening (dL/dt max) in the circumflex perfusion territory were measured. Responses to left stellate ganglion stimulation (LSS) and intracircumflex injection of norepinephrine (NE, 0.10‐0.50 m̈g) were recorded before and after application of 85% phenol to the atrioventricular junction and to the circumflex artery and its branches (stage 1) as well as to the myocardial surface (stage 2). Responses of dP/dt max, %SL, and dL/dt max to the various dosages of NE were reduced by 40‐64%, 69‐75%, and 44‐61%, respectively, 1 hr after stage 1, indicating that application of phenol to the coronary arteries and arterio‐ventricular junction attenuated the postsynaptic response to adrenergic stimulation. No further changes occurred 1 hr after stage 2. Responses of dP/dt max and dL/dt max to LSS were reduced by 36% and 57%, respectively, after stage 1 and by 75% and 71% after stage 2. Because of high variability, the response of %SL to LSS were not affected by stage 1 or stage 2 application of phenol. In a secondo of 5 dogs, only stage 2 application of phenol was used. The blunting of the LSS response was similar to that seen with stage 1 followed by stage 2, but the NE response was unaffected. These data indicate that application of phenol to the coronary Vessels and to the atrioventricular junction acutely blunts both the postsynaptic response to afferent nerve stimulation, while application of phenol to the myocardial surface blunts only the response to efferent nerve stimulation. Thus, in acute animal studies, application of phenol to the myocardial surface may provide more reliable result on the effects of ventricular denervation.
Pinaverium bromide: A calcium channel blocker acting selectively on the gastrointestinal tract
Authors: Christen Mme Marie‐Odile , Tassignon Jean‐Pierre
Published: January 2005

Evidence is reviewed which indicates that pinaverium bromide (PB) relaxes gatrointestinal (GI) structures mainly by specifically inhibiting Ca+2 influx through potential‐dependent channels that exist on the surface membranes of smooth muscle cells. Its in vivo selectivity for the GI tract appears to be due mainly to its pharmacokinetic properties. Because of its low absorption, typical for quarternary ammonium compounds, and its efficient hepato‐biliary excertion, most of the orally‐administered dose of PB remains in the GI tract. Other mechanisms possibly related to its selectivity, and comparisons between the actions of PB and those Ca2+ ‐antagonists, are also disussed. PB is the only Ca2+ ‐antagonist currently registered for treatment of functional intestinal disorders (e.g., irritable bowel syndrome). A major advantage of orally‐administered PB is that it does not elicit adverse systemic (e.g., cardiovasular) side‐effects at doses that effectively relieve GI spasm, pain, and abnormal motility.
Rats can learn simultaneous four‐drug discriminations in four‐lever boxes
Authors: Overton Donald A. , Shen C. Frank , Crawford Lawrence
Published: January 2005

Rats were required to learn a four‐drug discrimination in compartments containing four levers. The training drugs were phenobarbital 35 mg/kg, nicotine 0.8 mg/kg, fentanyl 0.04 mg/kg, and methylphenidate 5 mg/kg. Responding on a different lever was reinforced with 0.1 ml sweetened water under each drug condition. The experiment tested whether such four‐drug discriminations could be learned, and whether the rate of acquisition and/or asymptotic accuracy of the discriminations would be increased in boxes where each lever was surrounded by a unique sensory environment created by special materials on the floors, walls, and ceiling in the vicinity of the lever (e.g., plastics, wire screens). Four different training compartments were employed. The required discriminations were learned by most rats. The use of unique decorations around each lever decreased the mean number of sessions before the appearance of discriminative control from 90 to 67. It also made asymptotic accuracy significantly higher in some sensory environments than in others. suggesting that animals “preferred” some environments. The training drugs were apparently not equally discriminable at the doses employed, as both sessions to criterion and asymptotic accuracy differed for the various drugs employed.
Recent development in 2‐pyrrolidinone‐containing nootropics
Authors: Gamzu Elkan , Hoover Toni M. , Gracon Stephen I. , Ninteman Monica V.
Published: January 2005

This paper reviews the development of the concept of nootropics‐‐compounds whose activity appears to be specific to enhancement and protection of those functions of plasticity of the central nervous system that we now call cognition. The rest of the review focuses on clinical and preclinical results reported on 2‐pyrrolidinone‐containing noortropics since 1986. Although the clinical efficacy of these compounds remains to be proved definitively, there are some double‐blind trials that demonstrate superiority against placebo. Preclinically, a wide variety of laboratories continue to demonstrate and expand protective effects of nootropics against various insults of the CNS.
Propentofylline increases the survival rate in gerbils after brain ischemia: Influence on serotonin metabolism
Authors: Mrsulja Bogomir B. , Stefanovich Vladimir
Published: January 2005

Following the bilateral occulusion of common carotid arteries in gerbils for 15 min, the survival rate and serotonin metabolism were evaluated in groups of animals treated over a period 7 days by propentofylline or pentobarbitalor both propentofylline fo pentobarbital. In the non‐treated group as well as in animals treated by pentobarbital only, survival rate was about 29%, and serotonin metabolism was inhibited, both in the cerebral cortex and basal ganglia. Contrary to that, survival rate of animals treated by propentofylline or propentofylline and pentobarbital was about 70% at the 7th day after 15 min of ischemia, and serotonin metabolism was at the normal rate. These results show the superior effect of propentofylline in comparison to pentobarbital on the survival rate and serotonin metabolism after brain ischemia.
Cardioprotective effects of nicorandil on calcium paradox‐induced injury
Authors: Hamaguchi Tomoyuki , Azuma Junichi , Takihara Keiko , Ohta Hideyuki , Harada Hisato , Sperelakis Nicholas , Kishimoto Susumu
Published: January 2005

Nicorandil, a new antianginal drug, exerts a coronary vasodilation effect by mechanisms different from either nitrates or slow‐channel Ca++ entry blockers. This agent has been demonstrated to increase membrane K+ conductance, elevate cyclic guanosine monophosphate (GMP) content, and depress Ca++ current kinetics in vascular smooth muscle cells. In the myocardium, however, the direct effects of the agent have not been elucidated. We examined whether or not nicorandil could antagonize myocardial injury in the Langendorff‐perfused chick heart induced by the Ca++ paradox. The Ca++ paradox was produced by 15 min of Ca++‐free perfusion, followed by 10 min of Ca++ reperfusion. Nicorandil was added to the perfusing solution only during the Ca++ reperfusion phase. In the Ca++ paradox hearts, the following were observed: (1) depression of myocardial creatine phosphokinase and adenosine triphosphate (ATP) contents; (2) elevations of myocardial H2O, Na+, and Ca++ contents; and (3) ultrastructural derangement, which included contraction bands, interstitial edema, and mitochondrial swelling. Nicorandil treatment significantly attenuated the histological perturbation and part of the biochemical alterations. The present study suggests that nicorandil partially protects the myocardium against the Ca++ paradox‐induced injury.
HP 818: A centrally acting analgesic with neuroleptic properties
Authors: Locke Kenneth W. , Dunn Robert W. , Hubbard John W. , Vanselous Cheri L. , Cornfeldt Michael , Fielding Stuart , Strupczewski Joseph T.
Published: January 2005

HP 818 (1‐benzoyl‐6‐fluoro‐3‐(1‐methyl‐4‐piperidinyl)‐1H‐indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED50 values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self‐stimulation assays (ED50 values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine‐ and apomorphine‐induced stereotypy, indicative of D2‐dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.
Open fixed dose trial of fluoxetine in the treatment of obsessive compulsive disorder
Authors: Kim Suck Won , Dysken Maurice W.
Published: January 2005

Twelve non‐depressed DSM‐III obsessive compulsive disorder (OCD) patients were treated with fluoxetine in a 12 week open fixed dose study. After a 2 week washout period, patients were treated with 20 mg/day of fluoxetine for 1 week. The dosage was then raised to 40 mg/day for the remainder of the study. The Yale‐Brown Obsessive Compulsive Scale (Y‐BOCS) score (mean ± SD) decreased from 25.8 ± 4.5 to 15.4 ± 7.0 (P < 0.01) and the Symptom Check List‐90‐Obsessive Compulsive Subscale (SCL‐90‐OC) score (mean ± SD) also showed a decrease from 2.4 ± 0.8 to 1.3 ± 0.9 (P < 0.005). The results suggest that fluoxetine is effective in non‐depressed OCD patients. Our results also show that a 40 mg/day dosage is effective in contrast to previous studies that used 80 mg/day. Our finding of a significant treatment reduction in the SCL‐90‐OC is also in contrast to a previous OCD study in which the SCL‐58‐OC was not significantly reduced.
Influence of trapidil and trapidil derivatives on the content of cyclic nucleotides in human intima cells cultured from atherosclerotic plaques
Authors: Heinroth‐Hoffmann I. , Krüger J. , Tertov V. V. , Orekhov A. N. , Mest H.‐J.
Published: January 2005

Trapidil and some other 5,7‐disubstituted s‐triazolo(1,5‐a) pyrimidine derivatives (TD's: AR 12455, AR 12456, AR 12463, AR 12465), which have been shown to possess inhibitory effects on proliferative activity in cultured cells, influenced the cyclic nucleotide level in human intima cells cultured from atherosclerotic plaques. The intracellular cAMP content was increased by all tested substances in concentrations of 10−4M and 10−5M, respectively. The effects of these substances were similar to those of the phosphodiesterase inhibitor methylisobutylxanthine. A significant decrease of intracellular cGMP level was provoked by trapidil and the TD's AR 12456 and AR 12463. It is discussed that trapidil and TD's have antiatherosclerotic properties mediated by changes of the intracellular cyclic nucleotide content.
Inhibition of guinea pig aortic sarcolemmal Ca2+‐Mg2+ ATPase and cAMP phosphodiesterase activity by milrinone
Authors: O'Connor Bernard , Silver Paul J.
Published: January 2005

Milrinone is a positive inotrope/vasodilator that inhibits cardiovascular low Km cAMP phosphodiesterase (PDE) and not Na+−K+ ATPase activity. To explore other possible mechanisms of action, we quantitated the effects of milrinone on Ca2+‐stimulated Mg2+ ATPase activity in guinea pig aortic smooth muscle plasma membranes. Milrinone inhibited Ca2+‐ stimulated activity, but not basal activity, in aortic microsomes. Maximum inhibition (70%) occurred at 1 μM, which coincided with the inflection of a parabolic dose‐response curve. In a sarcolemmal‐enriched (F1) aortic preparation, 1 μM cAMP, 1 μM Cl‐930 (another low Km cAMP PDE inhibitor), and 100 μM W‐7 (a calmodulin antagonist) all inhibited Ca2 ‐stimulated Mg2+ ATPase activity. This F1 preparation contained cAMP PDE activity which was inhibited by 1 μM milrinone (26%) and 1 μM Cl‐930 (40%) but not by 100 μM W‐7. The inhibition of F1 Ca2+ ‐Mg2+ ATPase activity by 1 μM milrinone could be diminished by increasing the concentration of CaCl2 in reaction mixtures. In sum, these studies show that milrinone can inhibit vascular sarcolemmal Ca2+ ‐stimulated Mg2+ ATPase activity. However, inhibition may be direct or direct or may be secondary to cAMP PDE inhibition in vascular sarcolemma, since inhibition also occurs with cAMP and another low‐Km cAMP PDE inhibitor, Cl‐930.
Effects of chlordiazepoxide, buspirone, and serotonin receptor agonists and antagonists on responses of squirrel monkeys maintained under second‐order schedules of intramuscular cocaine injection or food presentation
Authors: Nader Michael A. , Barrett James E.
Published: January 2005

Lever pressing of squirrel monkeys was maintained under second‐order schedules of either food presentation or cocaine injection. The first response after 3 min produced a 2 sec change in the color of a visual stimulus; the tenth stimulus presentation was followed by either an i.m. injection of cocaine (0.3, 1.0, or 2.0 mg/kg) or the delivery of food. The benzodiazepine chlordiazepoxide (0.3‐5.6 mg/kg) increased responding maintained by food at doses that decreased cocaine‐maintained responding. In contrast, buspirone, a novel nonbenzodiazepine anxiolytic (0.001‐0.03 mg/kg), its analog gepirone (0.003‐0.03 mg/kg), and the N serotonin 1A (5‐HT1A) agonist 8‐hydroxy‐2(di‐n‐propylamino)tetralin (8‐OH‐DPAT; 0.0003‐0.001 mg/kg) increased cocaine‐maintained responding at doses that decreased responding maintained by food. The inverse agonist at benzodiazepine receptors β‐carboline‐3‐carboxylic acid ethyl ester (βCCE) only decreased response rates irrespective of the maintaining event. m‐Chlorophenylpiperazine (mCPP), an agonist at 5‐HT1b receptors, increased responding maintained by food while only decreasing cocaine maitained responding (0.001‐0.03 mg/kg), whereas metergoline (0.1‐0.3 mg/kg), a serotonin antagonist with affinity for both 5‐HT1 and 5‐HT2 receptors, produced large response rate increases in both groups of monkeys. Administration of the 5‐HT2 antagonist ketanserin (0.03‐3.0 mg/kg), the 5‐HT1A compound spiroxatrine (0.0003‐0.03 mg/kg), or the nonselective 5‐HT agonist quipazine (0.003‐1.0 mg/kg) resulted in dose‐dependent response rate decreases in both groups. These results further differentiate buspirone and related compounds from typical anxiolytics and suggest a differential involvement of 5‐HTIA receptors in behaviors maintained by cocaine or food presentation.
Effects of RO 15‐4513 and FG 7142 alone and in combination with ethanol on avoidance in the rat
Authors: Galizio Mark , Biddison Elizabeth S.
Published: January 2005

Rats were trained on a complex avoidance schedule in which responses on one lever postponed shock and responses on another lever occasionally (variable‐interval 45 sec schedule) produced 2 min periods of timeout from avoidance. As shown in previous experiments, ethanol (1.5 or 2.0 g/kg) produced an increase in timeout responding relative to avoidance lever rates. These effects were attenuated in five of the six rats by 6 mg/kg RO 15‐4513, a dose that did not produce consistent intrinsic effects. In contrast, FG 7142 (10 mg/kg) reliably reversed ethanol effects in only one of the six rats tested. These results support the notion that RO 15‐4513 possesses specific ethanol antagonist properties.
Reconciling differences in drug effects on behavior punished or maintained by response‐produced shock
Authors: Galbicka Gregory
Published: January 2005

Comparable patterns of behavior maintained by different events are affected similarly by certain drugs and differently by others. The present paper argues that patterns of behavior maintained by response‐produced shock (“shock‐maintained behavior”), although similar in appearance to lever pressing maintained by more conventional positive reinforcers, are generated through differential punishment of long interresponse times; hence, drug effects on this behavior should more closely resemble drug effects on pressing suppressed by punishment. Because the operants suppressed in these procedures are diametrically opposed (long interresponse times vs. pressing), the baseline patterns of behavior will differ (suppressing long interresponse times produces high rates of pressing, punishing pressing produces low rates). Furthermore, any drug‐induced changes in the frequency of the punished operant will result in what appear to be dissimilar drug effects if the rate of only one operant class serves as the dependent variable. That is, drugs that increase the rate of pressing that has been suppressed by punishment should increase long interresponse times similarly suppressed. This results in an overall increase in pressing rate under typical punishment procedures, but a decrease in overall pressing rates (an increase in the rate of punished long interresponse times) under shock‐maintenance procedures. Hence, similar drug effects on these inversely related operants should generate opposite changes in pressing rate under the two sets of procedures. A review of the literature revealed this to hold true in 12 of 15 cases. Drug effects on comparable patterns of pressing maintained by shock or food presentation split more evenly. The literature indicates that, of 21 such, comparisons between pressing maintained under fixed‐interval schedules of food or shock, ten yielded comparable drug effects under both, and 11 yielded dissimilar effects. These results suggest that what appear to be dissimilar drug effects on pressing maintained or suppressed by shock may in fact be similar effects on the inversely related operants differentiated under these procedure.
Second‐order schedules and the analysis of human drug‐seeking behavior
Authors: Goldberg S. R. , Schindler C. W. , Lamb R. J.
Published: January 2005

Behavior maintained by drug injections can be enhanced by using simple schedules as components of more complex second‐order schedules. Under second‐order schedules, completion of the component schedule, rather than an individual response, produces the drug injection according to another schedule. Each component schedule terminates with the brief presentation of a stimulus that has been associated with drug injection. Research over the past 30 years using these procedures with monkeys and human subjects has allowed an evaluation of the role of conditioned environmental stimuli in the acquisition, maintenance, extinction, and reinstatement of drug‐‐seeking behavior. These results have provided a cross‐validation of human and animal models of drug abuse which would not have been possible using simple schedules of reinforcement.
Behavioral toxicology of solvents
Authors: Glowa John R.
Published: January 2005

Volatile organic solvents exhibit a range of behavioral effects from the insidiously toxic to the beneficial. Solvents impair performance in a concentration‐dependent manner that depends on the unique physicochemical properties of each solvent. The toxic effects of solvents range greatly but, at sufficient concentrations, or after prolonged exposure, neurotoxic effects are often seen. Many solvents are both self‐administered and exhibit noxious properties. Solvents may produce some of their primary behavioral effects by altering γ‐amino‐butyric acid (GABA) function. Further studies related to mechanism may lead to a better understanding of means to protect individuals from the effects of solvent exposure, as well as further our knowledge of solvent abuse. Solvents activate the stress axis and, as such, their neuroendocrine effects deserve further characterization, because chronic exposure may result in altered neuronal activity similar to that associated with chronic stress. Methods have been developed to assess for risk of the effects of exposure to solvents, detailing the lowest levels of solvent expected to produce behavioral impairment. Results from these procedures should be applied to the different end points described.
Evidence for an action of heptaminol hydrochloride (Hept‐a‐mylR) on the central nervous system based on an increase in intracranial self‐stimulation behavior in the mouse
Authors: Durantou F. , Cazala P. , Pourrias B.
Published: January 2005

The effects of intraperitoneal injections of heptaminol hydrochloride (Hept‐a‐mylR) on intracranial self‐stimulation (ICSS) in the lateral hypothalamus (LH) were studied in BALB/c mice. In a first experiment, performed in a lever press box, we observed that ICSS induced by brief (0.2 sec) electrical stimulation was enhanced by heptaminol. However, at the two doses administered (34.6 and 60 mg/kg), increases of the lever‐pressing rate were observed only in animals showing high levels of performance before the treatment. In a second experiment, mice were trained in a shuttle‐box to initiate and terminate a continuous stimulation of the LH. In animals showing a weak approach response before the treatment, heptaminol induced a significant reduction of approach latency but only at the dose of 60 mg/kg. In contrast, animals showing a strong approach response appeared more sensitive to heptaminol since a reduction of approach latency was observed at the two doses administered. No concomitant modification of escape latency was observed. These results suggest (1) that heptaminol modulates activity of certain neuronal mechanisms involved in ICSS regulation and (2) that a relationship exists between the reactivity to heptaminol and the sensitivity of hypothalamic sites to electrical stimulation.
Effects of the steroidal antiandrogen win 49596 on fertility and sex accessory tissue growth in the rat
Authors: Batzold Frederick H. , Winneker Richard C. , Snyder Ben W. , Reel Jerry R.
Published: January 2005

Daily administration (20–500 mg/kg) of the steroidal androgen receptor antagonist, Win 49596, to mature male rats for 72 days caused a significant dose‐related inhibition of sex accessory tissue growth that also correlated with Win 49596 blood levels. Cohabitation of treated males with cycling females for up to 7 days after 29 and 65 days of treatment resulted in no significant effects on insemination or pregnancy rates as compared to vehicle‐treated controls. Furthermore, testicular growth was normal and there was no histomorphological evidence for effects on spermatogenesis. The data suggested that the androgen antagonist, Win 49596, selectively inhibited prostatic and seminal vesicle growth without compromising reproductive function. This tissue selectivity is explicable on the basis of the high levels of androgen in testicular fluid as compared to prostatic tissue.
Activation of the cAMP system by medorinone correlates with positive inotropy or vasorelaxation
Authors: Silver Paul J. , Lepore Rhonda E. , Canniff Paul C. , O'Connor Bernard , Lemp Bernhard , Harris Alex L.
Published: January 2005

Medorinone is a structurally novel positive inotropic/vasodilator agent that selectively inhibits cardiovascular low Km cAMP phosphodiesterase (PDE). As inhibitors of this PDE isozyme would be expected to activate the cAMP system, the objectives of the present study were to quantitate changes in cAMP content, activation of cAMP protein kinase (cAPK), and positive inotropy in isolated guinea pig papillary muscles or vasorelaxation in aortic smooth muscle by medorinone. In papillary muscles, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.92; P <0.01) or cAPK activity ratio, an index of activation of cAPK (r = 0.78, P <0.05) for concentrations of medorinone from 1 to 300 μM. Similar correlations were evident in aortic smooth muscles frozen during medorinone‐mediated relaxation of phenylephrine contractions (r = 0.89, P <0.05). These correlations and lines of regression were similar to those obtained for milrinone, papaverine, and isoproterenol; the correlation was similar for forskolin while the slope of the regression line was less. The temporal sequence of these events was also quantitated for a concentration of medorinone (100 μM) that produced approximately a 100% increase in papillary muscle isometric force and 90% vasorelaxation. Significant increases in either cAMP content or cAPK activity ratio paralleled increases in force development (papillary muscle) or vasorelaxation (aortic smooth muscle). In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with modulation of cardiac or vascular force by medorinone and thus support the hypothesis that inhibition of the low Km cAMP PDE is a mechanism by which medorinone effects positive inotropy and vasodilation.
Effects of novel catechol ether imidazolidinones on calcium‐independent phosphodiesterase activity, [3H]rolipram binding, and reserpine‐induced hypothermia in mice
Authors: Koe B. Kenneth , Lebel Lorraine A. , Nielsen Jann A. , Russo Lorena L. , Saccomano Nicholas A. , Vinick Fredric J. , Williams Ian H.
Published: January 2005

A series of new catechol ether imidazolidinones incorporating structural features of rolipram and Ro 20‐1724 were synthesized as inhibitors of the calcium‐independent phosphodiesterase (IPDE) from rat cerebral cortex. Several compounds were found to be more potent than rolipram as IPDE inhibitors; all of the compounds studied were more potent than Ro 20‐1724. The new imidazolidinones also showed affinity for the [3H]rolipram binding site in mouse brain membranes and reversed reserpine‐induced hypothermia in mice at relatively low doses. In vitro, the potency of these compounds as IPDE inhibitors did not correlate with their affinity for the [3H]rolipram binding site. Reversal of reserpine hypothermia by the imidazolidinones (“antidepressant effect”) could not be linked definitively to either in vitro activity.
Dose‐response analysis of the effects of fenoldopam, dopamine‐1 receptor agonist, on renal function
Authors: Dlewati Abdallah , Lokhandwala Mustafa F.
Published: January 2005

The present study was carried out to perform a dose‐response analysis of the effect of fenoldopam, a DA‐1 receptor agonist, on renal sodium excretion. Infusions of fenoldopam for 30 min at doses of 0.125, 0.25, 0.5, and 1.0 μ/kg/min in four separate groups of pentobarbital‐anesthetized dogs cused dose‐dependent hypotension and renal vasodilation. The reflex tachycardic response was not dose‐dependent and seen only with the three higher doses. There was no change in glomerular filtration with any of the four doses of fenoldopam. At the doses of 0.25 and 0.5 μ/kg/min fenoldopam caused significant increases in urine volume, urinary sodium excretion, and fractional excretion of sodium during the infusion as well as during the first recovery period of 30 min. At the highest dose of 1 μ/kg/min no diuresis or natriuresis was seen during the infusion; however, significant increases in urine volume and sodium excretion were seen during the two recovery periods. At the lowest dose (0.125 μ/kg/min) fenoldopam caused minimal hemodynamic changes but produced maximum increases in urine volume and urinary sodium excretion. These effects of fenoldopam were antagonized by the DA‐1 receptor antagonist, SCH 23390. The results of our study show that the tublar effects of fenoldopam leading to increased renal sodium excretion are evident at doses lower than those required to cause changes in systemic and renal hemodynamics. In addition, at higher doses when the magnitude of hypotension is very pronounced, this effect may limit the increase in sodium excretion produced by fenoldopam.
Cork gnawing in the rat as a screening method for buspirone‐like anxiolytics
Authors: Pollard Gerald T. , Howard James L.
Published: January 2005

Male Long‐Evans rats were individually allowed access to No. 11 corks for 30 min per day. After 30 sessions, the mean amount gnawed away, 0.10 g per session, was stable enough to allow drug testing; it reached asymptote at 0.03 g after 140 sessions. Drugs were injected PO 30 min before testing, except as noted. On the asymptotic baseline, the novel anxiolytic buspirone (8–32 mg/kg) and its congener gepirone (8–32 mg/kg) produced large, doserelated increases in cork gnawing. The standard anxiolytics chlordiazepoxide (16–32 mg/kg) and meprobamate (128 mg/kg, 60 min pretreatment) and the new sedative zopiclone (4–32 mg/kg) also produced substantial increases. Diazepam, oxazepam, and alprazolam produced marginal increases, and pentobarbital had no effect at behaviorally relevant doses. The non‐anxiolytics d‐amphetamine, chlorpromazine, acute imipramine, morphine (IP), and valproic acid either decreased or did not change cork gnawing. Phencyclidine (IP) and scopolamine produced marginal increases. Apomorphine (5 mg/kg SC) produced intense stereotyped gnawing of cage mesh but abolished gnawing of cork. Cork gnawing is proposed as a simple, economical behavioral method to identify buspirone‐like anxiolytics.
Pharmacology and safety of phenylpropanolamine
Authors: Johnson David A.
Published: January 2005

Phenylpropanolamine (PPA) is a phenylethylamine found commonly in cough medicines, nasal decongestants, and over‐the‐counter (OTC) diet aids. Since its discovery more than 70 years ago, the pharmacology of this drug has periodically been reexamined as the result of advances in the understanding of the sympathetic nervous system and adrenergic receptor function. This review presents a brief overview of the pharmacology of PPA, with an emphasis on how the drug effects smooth muscle tissues. Additionally, since the safety of PPA has recently been called into question, research pertaining to its toxicity is also reviewed.
Unusual binding of [3H] MDL 72222 in guinea pig hippocampus
Authors: Meyerson Laurence R. , Park Hyoungsup
Published: January 2005

[3H] MDL 72222 labeled a non‐homogeneous population of sites in guinea pig hippocampal membranes (Kd1 = 1 nM; Kd2 = 60 nM). The binding was not sodium dependent. Competition studies with a variety of characterizing agents showed displacement of [3H] MDL 72222 binding by 5‐HT uptake inhibitors. [3H] MDL 72222 binding was not effectively displaced by established 5‐HT3 antagonists. MDL 72222, fluoxetine, fluvoxamine and citalopram competitively inhibited the uptake of [3H] 5‐HT into guinea pig hippocampal synaptosomes with Ki values of 1.97, 0.02, 0.023, 0.049 μM, respectively. The results demonstrate that [3H] MDL 72222 labels a non‐homogeneous population of sites in guinea pig brain, as well as inhibiting 5‐HT uptake into synaptosomal preparations.
Vasoactive properties of phenylpropanolamine (d, I‐norephedrine) and its enantiomers in isolated rat caudal artery
Authors: Johnson David A. , Maher Timothy J.
Published: January 2005

The sympathomimetic properties of PPA and its individual component enantiomers d‐ and l‐norephedrine (NOR) were examined in isolated perfused/superfused caudal arteries from Sprague‐Dawley (SD) rats. Segments of caudal artery were cannulated, mounted in a tissue bath, and perfused with a modified Kreb's solution. PPA, d‐ and I‐NOR were alternately injected into the perfusion stream, and vasoconstriction was measured as the rise in perfusion pressure. Various drugs were added to the perfusion buffer to determine the activity of PPA, d‐, and I‐NOR at specific adrenoceptor subtypes and to determine whether the actions of these vasoconstrictors were influenced by calcium channel antagonists, cocaine, or reserpine. The results demonstrated that the norephedrines acted as partial agonists primarily via direct stimulation of postjunctional alpha1‐adrenoceptors with relatively low potency; however, I‐NOR did have significant activity at beta‐adrenoceptors with relatively low potency; however, I‐NOR did have significant activity at beta‐adrenoceptors as well. When the enantiomers of PPA were compared, d‐NOR had only minor vasoconstrictor activity, relative to I‐NOR, which was well over 100 times less potent than the endogenous.
Reversal of both QNX‐induced locomotion and habituation decrement is indicative of M1 agonist properties
Authors: Carlezon William A. , Cornfeldt Michael L. , Szewczak Mark R. , Fielding Stuart , Dunn Robert W.
Published: January 2005

Scopolamine, a non‐selective muscarinic antagonist at M1 and M2 receptors, has been shown to cause hyperactivity and memory deficits in rodents. However, the relative role of activation at M1 and M2 receptors is unclear. The effects in rats of a putative M1 antagonist 3‐quinuclidinyl‐xanthene‐9‐carboxylate hemioxalate hydrate (QNX) were assessed in a paradigm that measures locomotion and habituation, a form of non‐associative learning, to a locomotor activity box. On day 1, subcutaneous administration of QNX (1.0 mg/kg) elicited a large (370%) increase in locomotion. On day 2, control animals demonstrated habituation 24 hr after their first exposure to the locomotor box, as shown by significant decreases (−47%) in locomotor activity, while on day 2 the locomotor activity scores of animals that had been treated on the previous day with QNX did not differ from the day 1 scores of control animals. The selective M1 agonist 4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyl‐trimethyl ammonium chloride (McN‐A‐343, 10.0 mg/kg) significantly attenuated both the QNX‐induced locomotion and habituation deficit, while neither the non‐selective muscarinic agonist oxotremorine (0.125 mg/kg) nor the acetylcholinesterase inhibitor physostigmine (0.06 mg/kg) had a significant effect on these behaviors. These data suggest that, in this model, the M1 cholinergic receptor mediates both locomotion and habituation. Furthermore, M1 agonists can be identified by reversal of both QNX‐induced locomotion and memory decrement in this paradigm.
Review of chirality and its importance in pharmacology
Authors: Maher Timothy J. , Johnson David A.
Published: January 2005

While many pharmacologists have become increasingly aware of the importance of chirality and the role it plays in accounting for the oftentimes dramatic differences in the pharmacodynamics and pharmacokinetics of pure enantiomeric forms of therapeutic agents, there continues to be a significant lack of diligence regarding the need for properly identified stereochemicals in the scientific literature. All too frequently published reports and textbooks fail to adequately identify the stereochemical nature of the drugs utilized in a study Since the individual components of an enantiomeric pair typically have significant differences in their pharmacologic activities, the need for unambiguous descriptive nomenclature is evident. This review presents a summary of the various types of nomenclature utilized in the pharmacologic literature and their chemical bases. Several examples are described which illustrate the significant differences between enantiomeric forms of drugs and suggest possible theoretical bases for such differences. The need for continued awareness on the part of pharmacologists and the proper, unambiguous identification of stereolsomers in the scientific literature and labeling is stressed.
Anticonflict and discriminative stimulus effects of the 5‐HT1A compounds WY‐47,846 and WY‐48,723 and the mixed 5‐HT1A agonist/5‐HT2 antagonist WY‐50,324 in pigeons
Authors: Barrett James E. , Zhang Lei
Published: January 2005

The effects of the pyrimidinylpiperazinyl imide WY‐47,846 (zalospirone), the substituted arylpiperazine WY‐48,723, and the adamantyl piperazine derivative WY‐50,324 were studied under punishment (conflict) procedures with pigeons to evaluate potential anxiolytic activity. These compounds were also studied in pigeons trained to discriminate administration of the serotonin (5‐HT)1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin [8‐OH‐DPAT] (0.3 mg/kg) or buspirone (1.0 mg/kg), both administered i.m., from saline. All three compounds have high affinity for the 5‐HT1A receptor site and WY‐50,324 also has high affinity for 5‐HT2 receptors, with activity as an antagonist at this site. Increases in punished responding occurred with all three drugs, with the magnitude of the increases in the order WY‐50,324 > WY‐48,723; > WY‐48,846; increases with WY‐50,324 reached almost 15,000% of control levels. Increases in punished responding occurred at doses that did not affect unpunished responding. Doses producing maximal effects of the three drugs were comparable (1.0 mg/kg), although WY‐48,723 and WY‐50,324 also produced large increases at doses as low as 0.1 mg/kg. All three drugs also substituted for 8‐OH‐DPAT and buspirone, with WY‐48,723 and WY‐50,324 producing complete substitution at 0.1–0.3 mg/kg, whereas WY‐47,846 did not substitute in 8‐OD‐DPAT‐trained pigeons until a dose of 10 mg/kg; in pigeons trained with buspirone, a dose of 1.0 mg/kg WY‐47,846 resulted in complete substitution. All three drugs appear to have potential anxiolytic and/or antidepressant activity through actions mediated at the 5‐HT1A receptor. The unique combination of 5‐HT1A agonist activity with 5‐HT2 antagonist activity appears to confer potent anxiolytic‐like actions on WY‐50,324 that prompt additional exploration of the interactions between these receptor subtypes and their role in anxiety and other disorders.
Use of a metabolic inhibitor to reduce dapsone‐dependent haematological toxicity
Authors: Coleman Michael Damian , Tingle Malcolm Drummond
Published: January 2005

Aside from its established use as an antileprotic and anti‐inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose‐dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose‐6‐dehydrogenase deficient individuals. It is also responsible for occasional life‐threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone‐dependent methaemoglobinaemia could be greatly diminished by the co‐administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two‐compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 × 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N‐glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co‐administration of cimetidine might reduce toxicity while maintaining drug efficacy.
Age‐ and pathology‐dependent alterations in the efficacy of phenylephrine‐ and 5‐hydroxytryptamine‐induced contractions in isolated rat aorta
Authors: Christ George J.
Published: January 2005

Male Fischer 344 rats were made diabetic for 8–9 weeks by a single intraperitoneal injection of streptozotocin. Steady‐state contractile responses elicited by 5‐hydroxytryptamine (5‐HT) and phenylephrine (PE) activation of the 5‐HT2‐ and α1‐adrenergic receptors, respectively, were studied in aortic rings from diabetic, age‐matched control and 24‐month‐old (senescent) F‐344 rats. Concentration‐response curves (CRCs) for PE and 5‐HT were analyzed by the Black and Leff operational model of pharmacological agonism to determine efficacy (τ) and slope factor values. Efficacy estimates obtained with the operational model were compared to two commonly used model‐independent estimates of agonist efficacy; (1) Stephenson's efficacy estimate (e), and (2) the estimation of agonist receptor reserves. The estimated τ for PE in aortic rings from age‐matched control animals (12.38) was significantly reduced by both experimental diabetes (4.52) and senescence (7.12), and these findings were in agreement with results obtained using the model‐independent efficacy estimates. However, with respect to 5‐HT‐induced contractions, the estimated τ in age‐matched control animals (2.46) was also significantly reduced by both diabetes (1.58) and senescence (1.69), but these alterations were not detected by the model‐independent efficacy estimates. In all cases, a decrease in operational efficacy,τ, was associated with a decrease in the asymptote of the PE or 5‐HT CRC expressed as the agonist maximal effect (Emax)/tissue maximal effect (Tmax) and/or alterations in the fractional occupancy/response relationship. In addition, τ was sensitive to small changes in agonist efficacy that occurred in the absence of any apparent alterations in the occupancy/response relationship. As such, these studies extend our previous observations in rat aorta to highlight the advantages of using the Black and Leff efficacy estimate, τ, rather than other commonly used model‐independent estimates of agonist efficacy. © 1992 Wiley‐Liss, Inc.