bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropeptide Y: An overview
Authors: Lehmann John
Published: January 2005

Neuropeptide Y (NPY) has a broad distribution and numerous physiological functions in the peripheral and central nervous systems. The gene transcription and fundamentals of peptide processing have been elucidated. NPY levels and release are exquisitely sensitive to pharmacological and physiological manipulation. NPY receptors have been partially characterized pharmacologically. The effects of NPY on target organs and their implications for drugs interacting with the NPY system are described.
Antagonizing bradykinin (BK) obliterates the cardioprotective effects of bradykinin and angiotensin‐converting enzyme (ACE) Inhibitors in ischemic hearts
Authors: Linz Wolfgang , Martorana Piero A. , Grösch Horst , Bei‐Yin Qi , Schölkens Bernward A.
Published: January 2005

Bradykinin (BK) (1 × 10 −12−1 × 10−8 mol/l) and the ACE inhibitor ramiprilat (2.58 × 10 −9−2.58 × 10−5 mol/l) markedly reduced the incidence and duration of reperfusion arrhythmias in the isolated ischemic rat heart. Pretreatment with ramipril (1 mg/kg p.o.), enalapril (10 mg/kg p.o.), but not captopril (50 mg/kg p.o.) had similar effects. Active compounds also improved cardiodynamics and reduced lactate dehydrogenase (LDH) and creatine kinase (CK) activities, as lactate formation in coronary venous effluent. Cardiac tissue levels of glycogen, adenosine triphosphate (ATP), and creatine phosphate (CP) were preserved. The BK antagonist D‐Arg‐[Hyp2, Thi5,8, D‐Phe7]BK abolished the beneficial effects of BK, ramipril, and ramiprilat in a competitive way. Increased concentrations of BK or ramiprilat were able to reverse the antagonism. In anesthetized dogs an infusion of BK, at the dose of 1 ng/kg/min during coronary occlusion and reperfusion was devoid of cardiovascular effects but reduced mortality and the decrease of LDH activity and lactate concentration in coronary sinus blood and preserved tissue levels of glycogen and energy‐rich phosphates in the ischemic myocardium.
Cocaine tolerance: Interactions among random‐ratio and random‐interval reinforcement‐schedule parameters and repeated exposure to cocaine
Authors: Branch Marc N.
Published: January 2005

Food‐deprived pigeons were trained to peck a key under either a three‐component multiple random‐ratio 5, random‐ratio 25, random‐ratio 125 schedule or a three‐component multiple random‐interval 10‐sec, random‐interval 30‐sec, random‐interval 125‐sec schedule of food presentation. Following determination of acute effects of cocaine (1.0‐13.0 mg/kg), are‐sponse‐rate‐reducing dose was given before each daily session. Once performance under conditions of daily administration had become stable, other doses occasionally were substituted for the usual daily dose so that dose effects could be assessed. Tolerance, i.e., a rightward shift in the dose‐effect curve was observed in all subjects. For subjects studied under the random‐ratio schedules, however, the robustness of the tolerance usually was related to the schedule‐parameter value; tolerance was great at lower random values. By contrast, subjects whose responding was maintained by random‐interval schedules were less likely to show tolerance that was schedule‐parameter dependent. The results also provide suggestive evidence that dose may be an important factor in determining effects of repeated cocaine exposure; repeated administration of larger doses may be less likely to result in tolerance than similar exposure to smaller doses.
Elevation of blood pressure as the basis for discriminative stimuli produced by methoxamine
Authors: Lal Harbans , Yaden Senka , Forster Michael J.
Published: January 2005

Male, hooded rats were trained to detect methoxamine using a discrimination paradigm in which responding under an FR10 schedule was reinforced on one lever following an injection of methoxamine (1.25 mg/kg) and on an alternate lever following an injection of saline. The rats learned the methoxamine‐saline discrimination to a criterion of correct lever selection on 10 consecutive days in an average of 35 training sessions. In subsequent tests, selection of the methoxamine‐appropriate lever was found to be both time dependent and dose dependent, and these effects closely paralleled time‐ and dose‐related increases in systolic blood pressure. In addition, the ability to increase blood pressure was a common property of those drugs that substituted for methoxamine in the discrimination test. These findings suggest that interoceptive stimuli related to elevated blood pressure provide the basis for methoxamine discrimination. Drug discrimination paradigms may, therefore, be useful within programs for management of hypertension, as a method for enhancing conscious awareness of blood pressure changes.
Use of classical conditioning procedures in behavioral pharmacology
Authors: Schindler Charles W. , Harvey John A.
Published: January 2005

While operant conditioning clearly dominates the field of behavioral pharmacology, over the past 10 years, classical conditioning has been used more frequently to study the effect of drugs on behavior. In particular, the rabbit nictitating membrane response (NMR) has been used to study the effects of drugs on learning. This procedure offers a number of advantages over other assessments of learning in mammals to the study of drug effects on learning. First, because the rabbit NMR is well characterized behaviorally, it is possible to relate a drug effect to a particular behavioral process (e.g., to an effect directly on learning vs. an effect on the psychological processing of the unconditioned stimulus). In addition, with recent advances in determining the neuroanatomical basis of the conditioned NMR, it may also be possible to relate a drug effect on learning to an effect at a particular anatomical locus. Finally, because the conditioned response is acquired rapidly, the effect of a drug on learning can be assessed rapidly within a large group of animals. The current paper details the behavioral techniques which have been developed to study the effects of drugs, in particular the opioids, on classical conditioning. A number of studies which have used classical conditioning procedures in the rabbit to study drug effects on acquisition, maintenance, and differentiation of conditioned responses are reviewed.
The role of beta‐endorphin and related peptides in the pathogenesis and treatment of Alzheimer's disease
Authors: Riekkinen Paavo , Helkala Eeva‐Liisa , Jolkkonen Jukka , Riekkinen Paavo , Soininen Hilkka
Published: January 2005

Beta‐endorphin (B‐EP)‐like immunoreactivity of cerebrospinal fluid (CSF) was compared in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Somatostatin (SS)‐like immunoreactivity (SLI) was measured in AD patients. We were able to demonstrate a decrease in both B‐EP and SS during the progression of Alzheimer's disease. The decline of SS had occurred already in moderately affected patients, reflecting the pathological changes of cortical interneurones. The decline of B‐EP reached significance in severely demented patients, which demonstrated the spread of cell death into hypothalamic neurones. The different time courses observed for alterations of CSF, SS, and B‐EP levels in AD fit well with the proposed chronological progression of the disease. B‐EP levels of the PD group did not differ from the values of the control group, which supports the idea of different pathological changes in AD. We failed to show any clear‐cut differences between the behavioral correlates of SS and B‐EP deficits using various cognitive tests and clinical rating scale. The effects of ACTH 4‐9 derivate (ORG 2766) were evaluated in 77 AD patients. The effects observed in experimental animals on the memory function and CSF monamine markers could not be replicated in humans; nor could we find any slowing of the changes on EEG after drug treatment.
Prophylactic effects of novel dihydropyrazolopyridine (83‐0256) and dihydrothienopyridine (83‐0312, 83‐0327) calcium antagonists in stroke‐prone spontaneously hypertensive rats
Authors: Masui Masao , Kawakami Masaru , Nakajima Masatoshi , Hara Seijiro , Ueda Motohiko , Ito Hiroyuki
Published: January 2005

The prophylactic effects of several Ca antagonists against the incidence of cerebral stroke in stroke‐prone spontaneously hypertensive rats (SHRSP) (9‐17 weeks of age) fed a stroke‐prone (SP) diet (Na, 0.39%) were investigated for 8 weeks. The control SHRSP administered 1% gum arabic solution showed 87.5% mortality due to cerebral stroke during the experimental period. Daily oral administration of nifedipine or dihydrothienopyridine derivatives (83‐0312, 83‐0327) at 3 mg/kg or of nicardipine or dihydropyrazolopyridine derivative (83‐0256) at 10 mg/kg markedly inhibited the incidence of cerebral stroke and decreased mortality in SHRSP. Also markedly inhibited were the early appearances of proteinuria and occult blood in the urine observed with control SHRSP. Potencies of prophylactic effects of Ca antagonists on the incidence of stroke decreased in the following order: 83‐0327 > nifedipine ≥ 83‐0312 ≥ 83‐0256 > nicardipine. These potencies corresponded well with those of the acute antihypertensive effects. The most potent prophylactic effect against stroke was observed following the administration of 83‐0327 and this effect was considered to be intimately related with its lasting antihypertensive effect.
Does AAMI constitute a real disease entity? A placebo‐controlled double‐blind study with sabeluzole (R58 735) in a patient population with real memory problems
Authors: Tritsmans Luc , Clincke Gilbert , Peelmans Boudewijn
Published: January 2005

Sabeluzole was studied in patients complaining spontaneously about their memory. They were screened and only included if they fitted into the AAMI‐criteria and if, additionally, they were poor performers on a Selective Reminding Procedure (SRP). Fifty‐three patients (aged between 52 and 90 years) were thus treated in a double‐blind manner with either sabeluzole 10 mg b.i.d. or placebo for 2 months. No intergroup differences were seen for any of the tests used. In the sabeluzole group, however, the learning of new semantic entities, consisting of a noun and an accompanying adjective (U, Td) in a Cued Recall Task, increased significantly (P = 0.04). Additionally, a higher Word Fluency score was obtained after sabeluzole treatment (P = 0.002), an effect not present in the placebo group. Objective improvements were paralleled by subjective improvements, as measured on Visual Analogue Scales, in the sabeluzole‐treated patients. The study drug was very well tolerated and no serious adverse reactions were seen. However, AAMI, even with the more stringent criteria we used, does not seem to define a homogeneous study population, which reflects a clinical entity. Therefore, the use of AAMI‐criteria as a research tool is questionable.
Imidazobenzodiazepine RO15‐4513 augments ethanol‐induced wheel‐running suppression in the rat
Authors: Bixler Michael A. , Lewis Michael J.
Published: January 2005

The ability of RO15‐4513 to block ethanol‐induced motor incapacitation and was assessed via ethanol‐induced suppression of wheel‐running. However, either ethanol or RO15‐4513 administration alone produced an equivalent decrease (75% and 72%, respectively) in wheel‐running performance. Administration of RO15‐4513 at 2.5, 1.25, 0.625, 0.312, 0.156, and 0.078 mg/kg doses produced a dose‐dependent suppression of wheel‐running. Finally, ethanol administration following pretreatment with RO15‐4513 (3.0 mg/kg) produced greater suppression of wheel‐running (89%) than ethanol administration alone (55%). These results demonstrate intrinsic suppressant effects of RO15‐4513, and the lack of generality in the previously reported antagonism of ethanol‐induced intoxication by RO15‐4513.
GABA receptors and GABAergic synapses as targets for drug development
Authors: Taylor Charles P.
Published: January 2005

Gamma‐amino butyric acid (GABA) is perhaps the most abundant and important rapid inhibitory neurotransmitter in the mammalian brain. Many previous studies have indicated that GABAergic synapses are involved in drug treatments or disease processes for epilepsy, anxiety, movement disorders, depression, and psychosis. In particular, the GABAA receptors, which rapidly open chloride ion channels and thereby clamp neuronal membrane potential to near the resting level, have received extensive study. GABAB receptors are functionally and structurally quite distinct, and there are subtypes of both GABAA and GABAB receptors. This brief review describes strategies that have been used to study GABA receptors and the pharmacology of drugs that act on GABAergic synapses. The eight reports that follow in this issue of Drug Development Research focus on the pharmacology of GABAA agonists and GABA uptake inhibitors as potential therapeutic agents, and they were first presented as a satellite symposium of the 1989 meeting of the Society for Neuroscience. The following reports give special reference to Cl‐966, a novel inhibitor of GABA uptake that was developed as a potential anticonvulsant based on animal studies [Taylor et al., 1990]. Unfortunately, Cl‐966 caused severe and unexpected neurological and psychological disturbances in initial clinical studies with healthy human volunteers and has been discontinued from further development [Sedman et al., 1990]. This brief review aims to give some perspective to the following papers on GABAA agonists and GABA uptake inhibitors.
GABA‐A agonists and GABA uptake inhibitors: Structure‐activity relationships
Authors: Falch Erik , Larsson Orla M. , Schousboe Arne , Krogsgaard‐Larsen Povl
Published: January 2005

Muscimol is a potent but non‐selective GABA‐A agonist. Structure‐activity studies on the (S)‐ and (R)‐forms of chiral muscimol analogues have disclosed a high degree of agonist stereoselectivity of the GABA‐A receptors. THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol) is a specific GABA‐A agonist, which has been the subject of clinical studies in different groups of patients. Even minor alterations of the structure of THIP result in substantial or complete loss of GABA‐A agonist activity. 4‐PIOL (5‐(4‐piperidyl)isoxazol‐3‐ol) shows in vivo GABA‐A agonist activity on spinal neurones, whereas the in vitro pharmacological effects in brain tissue preparations are consistent with a GABA‐A antagonist profile of 4‐PIOL in the brain. Whereas nipetcotic acid and related GABA uptake inhibitors are substrates for the neuronal and glial transport carrier, the glia‐selective GABA uptake inhibitors THPO (4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridin‐3‐ol) and probably also THAO (5,6,7,8‐tetrahydro‐4H‐isoxazolo[4,5‐c]azepin‐3‐ol) are not being transported by the glial uptake carrier. Introduction of the DPB (4,4‐diphenyl‐3‐butenyl) or BEE (benzhydryl ethyl ether) substituents on the basic nitrogen atoms of GABA uptake inhibitors, including nipecotic acid and THPO, results in markedly more potent inhibitors. However, unlike THPO, N‐DPB‐THPO interacts non‐selectively with neuronal and glial GABA uptake, and, in contrast to nipecotic acid, N‐DPB‐nipecotic acid (SKF‐89976‐A) has been shown not to be transported by the neuronal or glial GABA carriers. Whereas N‐DPB‐ and N‐BEE‐GABA are weak inhibitors of synaptosomal GABA uptake, N‐methylation of these compounds gives potent uptake inhibitors.
Neuropharmacological evidence for an interaction between the GABA uptake inhibitor Cl‐966 and anxiolytic benzodiazepines
Authors: Giusti Pietro , Guidotti Alessandro , Danysz Wojciech , Auta James , Costa Erminio
Published: January 2005

[1‐[2‐[bis(trifluoromethyl)‐phenyl]methoxy]ethyl]‐ 1,2,5,6‐tetrahydro‐3‐pyridine‐carboxylic acid, HCl (Cl‐966, Parke‐Davis) is a new specific inhibitor of GABA uptake to neurons that is severalfold more potent than for inhibition of glycine or glutamate uptake. Cl‐966 crosses the blood‐brain barrier and when injected intravenously into rats (doses up to 10.5 μM/Kg = 5.0 mg/kg) produces only marginal behavioral effects. Cl‐966 also produces a modest reversal of punished‐suppressed drinking behavior in thristy rats both in the conflict and phenylenetetrazole (PTZ)‐induced proconflict Vogel test. However an inactive dose of Cl‐966 (6.3 μM/kg i.v., 90 min prior to the test) significantly potentiated the anticonflict and anti‐PTC‐induced proconflict action of diazepam and alprazolam. The anticonflict/antiproconflict ED50 ratio for diazepam was shifted from 1.2 to 1.0 and that of alprazolam from 13.0 to 7.0 after pretreatment with Cl‐966.

These results suggest that Cl‐966, while it may produce increasing GABAergic tone throughout the CNS, selectively enhances the action of GABA at GABAA receptor subtypes whose sensitivity is preferentially increased by administration of positive allosteric modulators. Therefore Cl‐966 may represent a very useful drug to study modifications of animal behavior in relation to the function of GABAergic transmission in specific brain areas.
Influences of cholecystokinin and analogues on memory processes
Authors: Itoh Shinji , Lal Harbans
Published: January 2005

Evidence is reviewed to assign the role of cholecystokinins in the cognitive and memory processes. Rat brain contains about 550 ng of CCK‐8. When injected, icv or sc, in doses of less than 100 ng of CCK or caerulein, these peptides prevent experimental amnesia and prolong extinction of the already‐learned tasks. Caerulein is nearly 10 times as potent as CCK‐8, and the effects of both peptides are long‐lasting. Pretreatment with these peptides also prevents scopolamine‐induced amnesia, and reverses the ACh depletion in the frontal and temporal cortices as well as in the hippocampus. CCK‐8 antagonists in small doses produce complete amnesia, further supporting the hypothesis that endogenous CCK‐8 modulates the memory processes in the brain. Neurochemical data suggest participation of the NMDA receptors, protein kinase C, and protein synthesis in the action of CCK‐8 and caerulein. Sub‐diaphragmatical vagotomy abolishes the memory‐enhancing effects of these peptides when administered peripherally. Thus, CCK‐8 and caerulein are likely to affect not only the receptors localized in the CNS, but also to stimulate peripheral receptors associated with the vagus. Alternatively, the vagus may be the major pathway for CCK transport from the visceral organs to the brain.
Pharmacological profile of RWJ 20085: A new, potent, long‐acting local anesthetic
Authors: Dubinsky Barry , Shriver David A. , Sanfilippo Pauline J. , Press Jeffery B. , Tobia Alfonso J. , Rosenthale Marvin E.
Published: January 2005

RWJ 20085 is a potent, long‐acting local anesthetic that has been studied in vivo and in vitro relative to several clinically active agents. In mice, RWJ 20085 [ED50 = 0.0078% (0.0053–0.011%)] was more potent by perineural infiltration than bupivacaine [ED50 = 0.035% (0.026–0.046%)], etidocaine [ED50 = 0.025% (0.016–0.035%)], or lidocaine [ED50 = 0.18% (0.13–0.26%)]. The onset of action of each compound was 5 minutes, and the duration was 90 minutes for RWJ 20085 and 30 minutes for bupivacaine or etidocaine while lidocaine was active for only 15 minutes. In the rabbit corneal assay, RWJ 20085 [ED50 = 0.012% (0.0049–0.023%)] was more potent than bupivacaine [ED50 = 1.4% (0.47–3.05%)]. The lowest topical local anesthetic ED50 of each agent was observed within 5 or 15 minutes after administration, and RWJ 20085 was active for 300 minutes, whereas bupivacaine and etidocaine were active for 90 or 45 minutes, respectively. In the guinea pig intradermal assay RWJ 20085 [ED50 = 0.017% (0.0094–0.028%)], bupivacaine [ED50 = 0.016% (0.0078–0.028%)], and etidocaine [ED50 = 0.02% (0.0093–0.042%)] were equipotent while lidocaine [ED50 = 0.072% (0.040–0.12%)] was less potent. The onset of action of each compound was 5 minutes. The duration of action of RWJ 20085 and etidocaine was 60 minutes, whereas bupivacaine and lidocaine were active for 45 and 15 minutes, respectively. In the frog isolated‐sciatic nerve preparation, similar concentrations of RWJ 20085 (2.5 × 10−3M) and lidocaine (5.0 × 10−3M) produced a 50% reduction of the amplitude of the pretreatment action potential; however, bupivacaine and etidocaine were each effective at a lower concentration (5.0 × 10−4M). When their intramuscular therapeutic ratios (TR = lethal dose LD50/local anesthetic ED50) were calculated in mice, the therapeutic ratio of RWJ 20085 (82) was less than that of etidocaine (103) but was larger than that of either lidocaine (36) or bupivacaine (29). Calculation of the therapeutic ratios by using the intravenous LD50 values suggests that lidocaine would have the smallest margin of safety if inadvertently administered by the intravenous route. The therapeutic ratios of the other agents were larger than that of lidocaine; however, there was little difference among them. RWJ 20085 has a low potential for dermal irritation as shown in rabbits and has no liability for contact sensitization as shown in guinea pigs. RWJ 20085 may have clinical utility as an injectable and/or topical local anesthetic.
Moclobemide (Ro 11‐1163) vs. clomipramine in the treatment of depression: A double‐blind multicenter study in Belgium
Authors: Cattiez P. H. , Dierick M. , Troisfontaines B. , van Audenrode L. , Defleur J. , Hermans W. , Roelandts A. , Stenier P. , Wolfrum C.
Published: January 2005

A multicenter study to compare the antidepressant efficacy and the tolerance of moclobemide (Ro 11‐1163) to clomipramine was performed in parallel groups of patients with minor depression. The duration of the study was 6 weeks, with weekly assessments by means of Hamilton Scale of Depression (HRDS) and the Clinical Global Impression (CGI). The efficacy of moclobemide was found to be as good as that of clomipramine. The results for tolerability were possibly in favor of moclobemide. It was recommended that consumption of tyramine‐containing foods be kept to a minimum or avoided and no hypertensive crises were reported.
Ouabain pretreatment does not compromise the hemodynamic and myocardial energetic effects of CK‐3197, a selective positive inotropic agent, in dogs with propranolol‐induced heart failure
Authors: Greenberg Stan , Touhey Beatrix , Hom Gary
Published: January 2005

We examined the interaction between ouabain and CK‐3197, a new selective positive inotrope, on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol‐induced heart failure (PIHF). Mongrel dogs (13–18kg) of either sex were anesthetized with pentobarbital sodium (35mg/kg, i.v.) and instrumented for routine hemodynamic measurements using an open‐chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dp/dt max by 50% from control values with an intial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2ml, i.v., n=8/group) or ouabain (25 μ/kg, i. v., n=8/group). Thirty minutes later one‐half of the saline and ouabain treated animals (Groups I and II;n =4/group) were given two increasing doses of saline or CK‐3197 (0.1 and 0.3 mg/kg, i. v.; n= Groups III and IV; n =4/group) 30 min apart. Hemodynamic paramters were monitored continuously, while myocardial oxygen consumption (MVO2) was monitored 15 and 30 min after each dose of drug. CK‐3197 increased LV DP/dTmax and LV dP/dTmin by 41 and 78%, respectively. Mean arterial pressure increased by 16 and 6%. Heart rate decreased by 6 and 8%, while LV end diastolic pressure (LVEDP) decreased by 3mmHg after CK‐3197 (0.3 mg/Kg, i.v.). CK‐3197 increased LV work and LV contractile efficiency. Ouabain did not affect the hemodynamic and myocardial energetic profile of CK‐3197. These data support the conclusions that CK‐3197 is a selective positive inotrope which increases myocardial contractile efficiency in the dog with PIHF without any significant interaction with ouabain.
Effects of dopexamine hydrochloride, a beta‐adrenergic and dopaminergic agonist, on vascular resistances, and flow distribution between cutaneous and skeletal muscle vasculatures
Authors: Grega George J. , Staniciu Dorina , Murray Melissa , Lokhandwala Mustafa F.
Published: January 2005

Local i.a. infusions of the dopaminergic and β2 adrenoceptor agonist dopexamine HCL (DPX) into collateral‐free, innervated canine forelimbs perfused at constant flow produced dose‐dependent decreases in perfusion pressure, evidence of a vasodilator response in the forelimb vasculature. DPX produced vasodilation in both the skin (cutaneous) and skeletal muscle vasculature of the canine forelimb, as evidenced by the dose‐dependent decrease in total skin and total skeletal muscle vascular resistances. DPX produced comparable dilation of the skin and skeletal muscle vasculatures, as evidenced by the failure of this agent to produce a significant shift in blood flow between the brachial and cephalic venous outflows, that is, between the skin and skeletal muscle vasculatures. In the cutaneous (skin) vascular circuit, DPX failed to affect vascular resistances in the large artery and large vein segments, but produced a dose‐dependent decrease in vascular resistance in the small vessel segment, presumably reflecting primarily arteriolar vasodilation. The vascular smooth muscle relaxation produced by DPX was inhibited by treatment with propranolol, suggesting that the vasodilation primarily results from direct stimulation of forelimb vascular β2 adrenoceptors by DPX.
A pharmacological and biochemical examination of AHR‐16462B, a novel calcium antagonist coronary vasodilator/antihypertensive
Authors: Barrett Richard J. , Appell Kenneth C. , Proakis Anthony G. , Shanklin James R. , Kilpatrick Brian F.
Published: January 2005

A series of pharmacological and biochemical studies were conducted to characterize AHR‐16462B 4‐[bis(4‐fluorophenyl)methyl]‐1‐(2‐naphthalenylmethyl)piperidine (HCI), a novel antagonist of voltage‐sensitive calcium channels. AHR‐16462B displaced [3H]‐nimodipine binding from calcium channels on rabbit skeletal muscle membranes (IC50 = 118 nM) and inhibited depolarization‐induced changes in intracellular free calcium in cultured PC‐12 cells (IC50 = 125 nM), but had virtually no effects on binding of specific radioligands to 5‐HT1a, 5‐HT2, alpha1, alpha2, dopamine2, beta1, beta2, muscarinic M1, or histamine H1 receptors. AHR‐16462B antagonized CaCI2‐induced contractions of depolarized rabbit aortic strips (pA2 = 8.83), but had no negative chronotropic, and only slight negative inotropic effects on isolated guinea pig atria. In anesthetized dogs, cumulative doses of 0.1, 0.4, and 1.4 mg/kg, i. v., AHR‐16462B decreased coronary vascular resistance and blood pressure; the magnitude and duration of these effects were dose related. Heart rate and Lead 2 ECG waveforms remained unaltered at all doses. In conscious spontaneously hypertensive rats (SHR), 3 to 100 mg/kg, p. o., AHR‐16462B produced marked, long‐lasting, and dose‐related antihypertensive actions. Heart rate remained unaltered following 3, 10, and 30 mg/kg AHR‐16462B, and bradycardia was evoked by 100 mg/kg. Effective antihypertensive doses of AHR‐16462B had modest natriuretic and/or chloruretic actions.
Role of growth factors in the uveal tract of the eye as targeted to the development of new drugs
Authors: Tripathi Ramesh C. , Fekrat Sharon , Tripathi Brenda J. , Borisuth Navaneet S. C.
Published: January 2005

The uveal tract of the eye, which consists of the iris, ciliary body, and choroid, is responsible for the primary nutritional supply of the ocular structures, especially the retina and, through the production of aqueous and vitreous humors, for nourishment of avascular intraocular structures such as the lens, cornea, and trebecular meshwork. The growth factors that have been detected in the uveal tract include fibroblast growth factor, epidermal growth factor, transferrin, transforming growth factor‐β, nerve growth factor, epidermal growth factor, and insulin‐like growth factors. These mitogens in the uveal tract influence the metabolism and proliferative activity of intraocular structures, and have major implications for the health and disease of the eye. We discuss the possible therapeutic role of growth factors, as well as the prospects for, and hurdles in, drug development for their use in various ocular disorders such as degenerative and proliferative diseases, neovascularization, glaucoma, ocular ischemic syndromes, cataract, neoplasms, and wound healing well as in the modulation of HLA‐DR expression.
Effects of tianeptine in animal models of anxiety and on learning and memory
Authors: File Sandra E. , Mabbutt P. S.
Published: January 2005

On acute administration tianeptine (2.5–10 mg/kg) was without significant effect in the social interaction test, but after 5 days of administration it produced an overall increase in social interaction. The increase was not more marked in unfamiliar than familiar test arenas and thus the profile differed from that seen with the benzodiazepines. Tianeptine (2.5–10 mg/kg) acutely and after 5 days was without significant anxiolytic effect in the elevated plus‐maze. Overall the pattern of results in these tests of anxiety resembles those of other novel compounds acting on the 5‐HT systems and possibly possessing anxiolytic or antidepressant effects. Tianeptine was without effect on between‐day habituation in the holeboard but tianeptine (10 mg/kg) significantly improved acquisition in a spatial task relying heavily on reference memory. Tianeptine (2.5 mg/kg) significantly reduced errors of working memory in a task in which spatial cues were minimized. These results suggest that rather than impairing memory tianeptine may actually improve some aspects.
Development of antischistosomal agents: Inhibitors of hypoxanthine‐guanine phosphoribosyltransferase
Authors: Jadhav Arun L. , Sirossian Shahrokh
Published: January 2005

Derivatives of purines and 5‐phosphoribosyl 1‐pyrophosphate (PRPP), substrates for purine salvage enzymes, were tested for their ability to inhibit hypoxanthine‐guanine phosphoribosyltransferase (HPRT, E. C. 2.4.2.8) isolated from Schistosoma mansoni in vitro. The parasite enzyme exhibited different kinetic characteristics than the human enzyme. The ‐C2 and ‐C6 substituted purine derivatives, as well as PRPP‐polyamine complexes, were found to be active against the enzyme. Intact purine ring appears to be necessary for the activity against the hypoxanthine dependent reactions mediated by the parasite enzyme since benzimidazoles, quinolines, and triazoles were found to be inactive. Additionally, it appears that PRPP‐polyamine complexes which inhibit the PRPP dependent reaction may provide a novel approach to new chemotherapeutics agents for schistosomiasis.
Flumazenil (Ro 15‐1788) enhances learning in both negatively and positively reinforced tasks
Authors: Raffalli‐Sebille Marie J. , Chapouthier Georges
Published: January 2005

Flumazenil (Ro 15‐1788) is classically described as a benzodiazepine‐receptor (BZ‐R) antagonist, devoid of any intrinsic effect and thus used to selectively block the effects of others BZ‐R ligands. The present report provides evidence that flumazenil enhances learning in a multiple‐trial brightness discrimination task in mice, whether the reinforcement is negative (electric foot‐shock) or positive (food reward). However, in contrast to the negative reinforcement, we obtained a significant effect with the positive reinforcement only after a delay of a few days. The type of reinforcement might be involved in this delay necessary to observe enhanced learning. These results are discussed.
Effects of nucleotide cyclase activators on the depressor response to selective low Km cyclic AMP phosphodiesterase inhibitors in rats
Authors: Dundoreph Ronald L. , Pratt Phillip F. , Hallenbeck Wendy D. , Silver Paul J. , Buchholz R. Allan
Published: January 2005

The potential interaction between agents which promote vasodilation through cyclic AMP (cAMP)‐ and cyclic GMP (cGMP)‐dependent mechanisms was examined in conscious, spontaneously hypertensive rats (SHR). Selective inhibitors of low Km cAMP phosphodiesterase (PDE), CI‐930 (0.1−10 mg/kg) and milrinone (0.03−3 mg/kg), were administered i.v. to SHR during a steady‐state i.v. infusion of either the guanylate cyclase activator sodium nitroprusside (SNP, 5 or 15 μg/kg/min) or the adenylate cyclase activator fenoldopam (20 μg/kg/min). The depressor responses to Cl‐930 and milrinone were significantly attenuated in the presence of SNP. This attenuation of the depressor response to Cl‐930 was apparently not due to a hemodynamic floor effect since an equihypotensive dose of the calcium channel blocker verapamil (20 μg/kg/min infusion preceeded by a loading dose of 1.2 mg/kg i.v.) did not alter the response to Cl‐930. The depressor response to Cl‐930 was also attenuated during an infusion of fenoldopam, although this interaction was dependent upon the order of administration of these agents since pretreatment with Cl‐930 (0.3 mg/kg, i.v.) potentiated the depressor response to infusions of fenoldopam (10 and 20 μg/kg/min). These data suggest that activation of either adenylate or guanylate cyclase may alter the intrinsic activity of low Km cAMP PDE and functionally impair the ability of inhibitors of this PDE isozyme to lower blood pressure. Furthemore, teh interactive effects of fenoldoparm and Cl‐930 on blood pressure are dependent upon the order of administration.
Effect of repeated administration of centhaquin, a centrally acting hypotensive drug, on adrenergic, cholinergic (muscarinic), dopaminergic, and serotonergic receptors in brain regions of rat
Authors: Gulati Anil , Hussain Ghazala , Srimal Rikhab Chand
Published: January 2005

Centhaquin, a hypotensive drug, produced a dose dependent decrease in blood pressure and heart rate in urethane anesthetized rats. The hypotensive and bradycardic effects of centhaquin were absent in cervial sectioned rats. There was no effect on blood pressure or heart rate upon intrathecal injection of centhaquin in normal rats. These results indicate that centhaquin is a centrally acting hypotensive drug with supraspinal site of action. Centhaquin (0.1 mg/kg) or its vehicle was administered orally to rats for 2 months. The blood pressure was recorded indirectly in unanesthetized rats by the plethysmographic tail cuff method. The animals were sacrificed, decapitated, and specific areas of the brain, like corpus striatum, cerebral cortex, hypothalamus, and medulla were dissected out and membranes prepared for binding studies. The mean blood pressure of rats before starting the treatment was comparable in control and treated groups. A significant decrease in mean blood pressure was observed in centhaquin treated rats. Chronic administration of centhaquin in rats produced alterations in central α‐adrenergic, dopaminergic, and serotonergic (5‐hydroxytryptamine1 [5‐HT1]) receptors. In the cerebral cortex corpus striatum of centhaquin treated rats, Bmax and Kd values of 3H‐dihydroergocryptine binding did not change, while in hypothalamus and medulla, centhaquin treatment increased the Bmax value by 52% and 86%, respectively. There was no change in the Kd values. Centhaquin treatment did not affect Bmax and Kd values of 3H‐dihydroalprenolol binding to β‐adrenergic receptors, 3H‐quinuclydinyl benzylate binding to cholinergic (muscarinic), and 3H‐spiperone binding to 5‐hydroxytryptamine2 (5‐HTs) receptors in any of the four brain regions. In the cortex, centhaquin treatment decreased the Bmax value (25%) but did not change the Kd values was produced in corpus striatum, hypothalamus, and medulla of 3H‐spiroperidol binding to dopaminergic receptors. Cerebral cortex, corpus striatum, and hypothalamus of centhaquin treated rats did not show any change in Bmax or Kd values of 3H‐5‐HT binding to 5‐HT1 receptors. In medulla, centhaquin treatment increased the Bmax value (41%) of HT1 receptors but had no effect on Kd values. It can be concluded from the present study that centhaquin, a centrally acting hypotensive drug, acts on several neurotransmitter receptors. The brain regions mainly involved in cardiovascular regulation, hypothalamus and medulla, show up‐regulation of αadrenergic and serotonergic (5‐HT1) receptors and may play a role in the mechanism of hypotensive action of centhaquin.
Characterization of indorenate effects on brain monoamine metabolism
Authors: Benítez‐King Gloria , Antón‐Tay Fernando , Hong Enrique
Published: January 2005

The effect of indorenate, a central antihypertensive agent, on the catecholamine and indolamine metabolism was studied in the rat brain. Acute administration of 10 mg/kg of indorenate causes an increase in 5‐HT concentrations and a decrease on its metabolite 5‐hydroxyindolacetic acid (5‐HIAA) in the brain stem, cerebral cortex, hypothalamus, and striatum. Maximal effects were observed between 1.5 and 3 hr after indorenate administration. Additionally, a significant decrease in homovanilic acid (HVA) and 3,4‐dihydroxyphenylacetic (DOPAC) concentrations was noted after 1.5 hr of a 10 mg/kg indorenate injection. Modification of both catecholamine and indolamine metabolites was dose related. Control values were recovered 24 hr after indorenate administration. Activity of monoamine oxidase present in crude homogenates obtained from the cerebral cortex, brain stem, hypothalamus, and striatum was not affected by indorenate. The present results suggest that indorenate acts as an agonist at serotonin receptors in the central nervous system (CNS).
Labeling in vivo of sigma receptors in mouse brain with [3H]‐(+)‐SKF 10,047: Effects of phencyclidine, (+)‐ and (−)‐N‐allylnormetazocine, and other drugs
Authors: Ferris Robert M. , Russell Anne , Tang Flora L. M. , Topham Phillip A.
Published: January 2005

The sigma receptor, so named because of the distinct pharmacolgical profile produced by its prototypic agonist SKF 10,047 (N‐allynormetazocine), is believed to mediate mania and psychotomimetic effects in man. While this sigma receptor has received extensive biochemical and pharmacological characterization in vitro, little information is available on the nature of the sigma site in vivo. In the present study, we examined the binding of [3H]‐(+)‐SKF 10,047 to sigma receptors in mouse brain in vivo and to sigma receptors in mouse and guinea pig brain in vitro and determined the relative potencies of various drugs in displacing this ligand. Mice were injected with 5 μCi of [3H]‐(+)‐SKF 10,047 into the tail vein. After various time intervals, the mice were decapitated; their brains were rapidly removed, weighed, and homogenized in 50 mM Tris‐HCI buffer, pH 7.7; and total and particulate bound radioactivity were determined. Specifically bound [3H]‐(+)‐SKF 10,047 in the particulate fraction was defined as the difference in total radioactivity in the particulate fraction obtained from vehicle‐injected mice minus the radioactivity in the particulate fraction from haloperidol (2 mg/kg i.p.)‐injected mice. Specifically bound [3H]‐(+)‐SKF 10,047 in the particulate fraction reached peak levels of 30 min after i.v. injection and constituted 90–95% of the total particulate radioactivity. Labeling of the sigma sites could be blocked in vivo by injecting mice i.p. with the drug 30 min before the i.v. injection of the 3H‐ligand. Under these conditions, (+)‐SKF 10,047, (+)‐3‐PPP, cyclazocine, pentazocine, and haloperidol were found to be the most potent compounds in reducing specific [3H]‐(+)‐SKF 10,047 binding. Neuroleptics such as thioridazine and chlorpromazine had good potency, while clozapine, spiperone, and sulpiride were very weak inhibitors in vivo. Specific [3H]‐(+)‐SKF 10,047 binding was also reduced in vivo by imipramine, dl‐propranolol, bupropion, rimcazole, and phenoxybenzamine, but was not reduced by apomorphine and naloxone at doses of 50 mg/kg i.p. Phencyclidine, m‐NH2‐PCP and (−)‐3‐PPP were only weak inhibitors of (+)‐SKF 10,047 binding in vivo. The relative potencies of these agents obtained in vivo correspond well with their relative affinities obtained in vitro in mouse and guinea pig brain for displacing [3H]‐(+)‐SKF 10,047 but not with their relative affinities for displacing TCP in guinea pig brain. Comparison of the dose‐response curves for the drug revealed the presence of perhaps two sites labeled by [3H]‐(+)‐SKF 10,047 in vivo.
Chronic administration of buspirone down‐regulates 5‐HT2 receptor binding sites
Authors: Taylor Duncan P. , Hyslop Deborah K.
Published: January 2005

Buspirone (BuSpar®), a clinically effective anxiolytic, has been found in clinical trials to produce effects which suggest antidepressant efficacy. As antidepressants down‐regulate type 2 serotonin (5‐HT2) receptors when given chronically to laboratory animals, we investigated whether buspirone would have similar effects; the possibility that chronic buspirone administration would affect β‐adrenergic, D‐2 dopaminergic, and γ‐aminobutyric acid (GABA) receptor binding was also investigated. When chronically administered in a regimen which reflected activity in an animal model of anxiety, buspirone produced significant decreases in in vitro 5‐HT2 and β‐adrenergic receptor binding but was without effect on D‐2 dopaminergic of GABAergic binding. Ligand saturation experiments revealed that the decrease in 5‐HT2 binding was due to a decrease in the maximal concentration of binding sites. These data demonstrate that chronic administration of buspirone to animals produces effects which suggest the potential for antidepressant efficacy in clinical use.
Effects of p‐chloroamphetamine and a side‐chain monofluorinated analogue on levels of indoles in rat brain
Authors: Owen Michael L. S. , Baker Glen B. , Coutts Ronald T. , Dewhurst William G.
Published: January 2005

Levels of tryptophan (Trp), 5‐hydroxytryptamine (5‐HT), and 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) in rat brain were measured at 1, 2, 4, and 24 hr after intraperitoneal administration of p‐chloroamphetamine (pCA) (0.03 mmol/kg) or of p‐cloro‐α‐fluoromethylphenylethylamine (fluoro‐p‐chloroamphetamine; FpCA) (0.05 or 0.10 mmol/kg). FpCA is less potent than pCA at producing depletions of 5‐HT and elevations of Trp, and the effects with FpCA are shorter‐lasting. pCA has been reported to possess good antidepressant properties but was withdrawn from clinical studies because of reported neurotoxicity to 5‐HT systems in rat brain. The less potent effects of FpCA on 5‐HT and 5‐HIAA reduction shown here suggest that further research on this analogue as a potential antidepressant is warranted.
Effects of acrihellin, a new cardiosteroid, compared to digoxin, MDL 17043, and milrinone in the pentobarbital‐compromised dog
Authors: Czyzewski Leo B. , Asaad Mary , De Vine Cindy , Sofia R. Duane , Diamantis William
Published: January 2005

Acrihellin, digoxin, MDL 17043, and milrinone were administered intravenously in the anesthetized dog to compare their effects on the cardiovascular parameters following pentobarbital‐induced heart failure. Dogs were instrumented to record left ventricular pressure, the derivative of the left ventricular pressure (dP/dt max), mean arterial pressure, heart rate, cardiac output, stroke volume, and total peripheral resistance. Pentobarbital compromise caused significant decreases from baseline in all cardiovascular parameters and slightto‐marked increases in stroke volume and left ventricular end‐diastolic pressure. Following pentobarbital‐induced heart failure, acrihellin reversed the cardiovascular changes with dose‐dependent, positive inotropic effects (dP/dt max), decreases in left ventricular enddiastolic pressure, and increases in stroke volume and cardiac output. Acrihellin caused a significant shift upwards and to the left of the stroke volume index/left ventricular enddiastolic slope at peak inotropy (45 min). Comparable, but nonsignificant, shifts were evident with each of the three standard compounds at peak inotropy: digoxin at 45 min, MDL 17043 at 5 min, and milrinone at 5 min. The intravenous drug doses were 45 μg/kg (1 molar equivalent) for acrihellin, 70.5 μg/kg (1 molar equivalent) for digoxin, 59.75 μg/kg (3 molar equivalents) for MDL 17043, and 38.1 μg/kg (2 molar equivalents) for milrinone. The present findings indicate that acrihellin is a potent cardiotonic drug as demonstrated in the failing heart dog model following pentobarbital.
Ritanserin, a new therapeutic approach for drug abuse. Part 2: Effects on cocaine
Authors: Meert T. F. , Janssen P. A. J.
Published: January 2005

After a period of forced exposure to cocaine, rats developed a preference for cocaine when given the choice to drink either a cocaine solution or water. The development of cocaine preference was dependent on the cocaine concentration given during choice but appeared to be independent of the presence of an cocaine withdrawal phase. The serotonin antagonist ritanserin reduced cocaine (0.1 mg/ml solution) preference and cocaine intake in a dose‐related manner. The activity of ritanserin started at doses ≥ 0.04 mg/kg when given subcutaneously once daily. Changes in test procedure did not affect the effectivity of ritanserin, although shifts in the lowest active dose were present. In the active dose range (i.e., between 0.04 and 10.00 mg/kg) ritanserin reduced cocaine intake by 29 to 53% and cocaine preference decreased by 19 to 32%. At any time during treatment, the decrease in cocaine consumption was compensated by an increase in water consumption. As a consequence, total fluid intake remained at a constant level. Body weight gain in ritanserin‐treated rats was not different from vehicle‐treated animals. In additional experiments it was shown that ritanserin neither directly interacted with the discriminative stimulus properties of cocaine nor induced a cocaine aversion. The activity of ritanserin against chronic exposure to cocaine is discussed in terms of a serotonin 5‐HT2 antagonism.
Autoradiographic localization of dopexamine binding sites and dopexamine‐sensitive cyclic adenosine monophosphate generating system in the rat heart
Authors: Napoleone Paolo , Cavallotti Carlo , Strocchi Paola , Ricci Alberto , Amenta Francesco
Published: January 2005

The present study was designed to analyze the pharmacological characteristics and the anatomical localization of (3H)x‐dopexamine (DPX) in frozen sections of rat right and left ventricles. Moreover, the effect of DPX on 3′‐5′‐cyclic adenosine monophosphate (cAMP) generating system in membrane particles of rat left ventricle was investigated. (3H)‐DPX was specifically bound by sections of rat right and left ventricles. The binding was time‐, concentration‐, and temperature‐dependent and reversible. The pharmacological profile of (3H)‐DPX binding was consistent with the labeling of both β2‐adrenoceptors and DA2 receptors. In fact, the most potent displacer of (3H)‐DPX binding was the β2‐adrenoceptor antagonist ICI 118,551, followed by L‐propranolol, dopamine, noradrenaline, and L‐sulpiride. The β1‐adrenoceptor antagonist metoprolol and the DA1 receptor antagonist SCH 23390, even at high concentrations, were without effect on (3H)‐DPX binding. Autoradiography revealed a rather homogeneous distribution of (3H)‐DPX binding sites within both right and left ventricles. (3H)‐DPX is specifically bound by myocytes. The binding was antagonized primarily by ICI 118,551 and in lesser amounts by L‐sulpiride. ICI 118,551 and L‐sulpiride together reduced the density of silver grains to non‐specific binding. DPX dose‐dependently increased CAMP concentration in membrane particles of rat left ventricle. This effect was antagonized by ICI 11 8,551 but not by SCH 23390. The above data suggest that the cardiac actions of DPX are primarily mediated via an interaction with β2‐adrenoceptors. Moreover, a specific binding to DA2 receptors is also noticeable. The interaction with these different receptors most likely accounts for some of the cardiac effects of DPX.