bluuebunny/crossref_metadata_2025 huggingface dataset:
Synaptic inputs to single neurons in the lateral geniculate nuclei of normal and monocularly deprived squirrel monkeys
Authors: Wilson James R. , Forestner Donna M.
Published: January 2005

Neurons in the dorsal lateral geniculate nucleus (dLGN) of normal and monocularly lid‐sutured squirrel monkeys were recorded electrophysiologically, and some were injected intracellularly with horseradish peroxidase (HRP) to examine and compare their synaptic inputs. Limited tests of the receptive field properties did not show any differences between the normal, nondeprived, or deprived neurons.

Sixteen injected neurons were examined at the light microscopic level with most of these located in the P‐laminae (n = 14). Ten of these were either from normal monkeys (n = 9) or received input from the nondeprived eye of a monocularly deprived monkey (n = 1). The remaining six neurons received input from the deprived eye. The dendritic trees of deprived neurons did not differ from those of normal or nondeprived neurons. Three normal and five deprived neurons from the P‐laminae were examined at the electron microscopic level. Afferent distributions were not significantly different between normal and deprived neurons. Retinal, cortical, and gamma aminobutyric (GABA) ergic afferents accounted for nearly all inputs (avg., 42%, 23%, and 32%, respectively) and selectively contacted proximal, distal, or all parts of the dendrites.

Overall, synaptic densities (synapses per length of dendrite) were high proximally and decreased with distance from the soma. However, the synaptic densities onto deprived neurons were higher at all distances compared to those onto normal neurons. Furthermore, HRP‐filled deprived neurons received an average of 25 synapses onto their somata compared with only an average of 7 somal synapses on the HRP‐fihled normal neurons. Most of the increase in the number of synapses onto the deprived neurons was from GABAergic type profiles. This abnormality of the deprived neurons of the dLGN could be the underlying cause of their lesser responses compared with normal or nondeprived dLGN neurons. It could also be the initial stage that causes blindness in monocularly lid‐sutured primates. © 1995 Wiley‐Liss Inc.
Representation of the face and intraoral structures in area 3b of the squirrel monkey (Saimiri sciureus) somatosensory cortex, with special reference to the ipsilateral representation
Authors: Manger Paul R. , Woods Timothy M. , Jones Edward G.
Published: January 2005

Studies of the representation of the trigeminal nerve in the thalamus and cerebral cortex of mammals have revealed representations of both contra‐ and ipsilateral intraoral structures. However, the relative extent of both representations is subject to considerable species variation. The present study employed microelectrode mapping and anatomical tracing to investigate the location and extent of the ipsilateral representation in area 3b of the somatosensory cortex of squirrel monkeys. A small region, approximately 2 mm2, was found to be responsive to stimulation of ipsilateral intraoral structures. This region was located on the anteromedial border of area 3b, surrounded by the representation of the contralateral roof of the mouth. This region corresponded to areas of intense anterograde labeling following injections placed in the ventromedial portion of the ventral posterior medial nucleus of the thalamus at the only sites where neural responses could be elicited by stimulation of ipsilateral intraoral structures. The amount of thalamus and cortex given over to the ipsilateral representation in the squirrel monkey is small compared with that of the macaque monkey. This difference may be related to the lack of cheek pouches in the squirrel monkey, and therefore a different strategy for eating.

The representation of the contralateral lower lip in area 3b was split by the representation of the contralateral upper lip. This split representation is in agreement with previous studies of the trigeminal representation in area 3b of the macaque monkey and may be a general feature of the representation of the trigeminal nerve in area 3b of primate cerebral cortex. © 1995 Wiley‐Liss Inc.
Overall pattern of callosal connections in visual cortex of normal and enucleated cats
Authors: Olavarria Jaime F. , Van Sluyters Richard C.
Published: January 2005

The effect of neonatal bilateral enucleation on the overall distribution of callosal connections in striate and extrastriate visual cortex of the cat was studied using tangential sections from the physically unfolded and flattened cortex. Callosal neurons were labeled by administering the anatomical tracer horseradish peroxidase directly to the transected corpus callosum.

The pattern of callosal connections in binocularly enucleated cats showed both consistent differences and consistent similarities with the pattern in normal cats. In agreement with previous studies, it was found that callosal labeling at the 17/18 border of enucleated cats was considerably sparser than in normal cats. Moreover, we found that the strip containing the majority of labeled cells at the 17/18 border was narrower than in normal cats. In both normal and enucleated cats, scattered cells were distributed on either side of the 17/18 callosal strip, well into areas 17 and 18.

In much of extrastriate cortex, the pattern of callosal connectivity in enucleated cats looked surprisingly normal. Details of the callosal pattern that were consistently found in normal cats could also be recognized in binocularly enucleated cats, such as two to four bridges of labeling spanning areas 18 and 19. Also, four zones that were free of callosal connectivity in area 7, on the banks of the suprasylvian sulcus, and in the posterior suprasylvian sulcus were found in both normal and enucleated cats. Finally, as in normal cats, dense cell labeling occurred on the crown of the suprasylvian rus at its posterior end, from which it extended laterally across both banks of the suprasylvian sulcus and into the fundus of this sulcus. The results of this study suggest that, although the stabilization of callosal connections at the 17/18 border region appears to depend on visual input, this input plays a less prominent role in the stabilization of callosal connections in extrastriate visual cortex. © 1995 Wiley‐Liss, Inc.
Axon terminals immunolabeled for dopamine or tyrosine hydroxylase synapse on GABA‐immunoreactive dendrites in rat and monkey cortex
Authors: Sesack Susan R. , Snyder Christopher L. , Lewis David A.
Published: January 2005

Dopamine afferents to the cortex regulate the excitability of pyramidal neurons via a direct synaptic input. However, it has not been established whether dopamine also modulates pyramidal cell activity indirectly through synapses on γ‐aminobutyric acid (GABA) interneurons, and whether such inputs differ across cortical regions and species. We sought to address these issues by an immunocytochemical electron microscopic approach that combined peroxidase staining for dopamine or tyrosine hydroxylase (TH) with a pre‐embedding gold‐silver marker for GABA. In the deep layers of the rat prefrontal cortex and in the superficial layers of the monkey prefrontal and primary motor cortices, terminal varicosities immunoreactive for dopamine or TH formed primarily thin, symmetric synapses on distal dendrites. Both GABA‐immunoreactive dendrites as well as unlabeled spines and dendrites were contacted by dopamine‐ or TH‐immunoteactive terminals. Synaptic specializations were detected at some, but not all of these contacts. The relative frequency of these appositional and synaptic contacts did not appear to differ between the rat and monkey prefrontal cortex, or between the monkey prefrontal and motor cortices. Across regions and species, labeled and unlabeled targets of dopamine‐ or TH‐positive terminals received additional synaptic input from unlabeled, and occasionally GABA‐immunoreactive terminals. Close appositions between dopamine‐ or TH immunoreactive and GABA‐positive terminals were observed only rarely. These findings indicate that dopamine afferents provide direct synaptic inputs to GABA local circuit neurons in a consistent fashion across cortical regions and species. Thus, dopamine's cellular actions involve direct as well as modulatory effects on both GABA interneurons and pyramidal projection neurons. © 1995 Wiley‐Liss, Inc.
Some neurochemical properties of a new antidepressant, bupropion hydrochloride (Wellbutrin™)
Authors: Ferris R. M. , White H. L. , Cooper B. R. , Maxwell R. A. , Tang F. L. M. , Beaman O. J. , Russell A.
Published: January 2005

Bupropion is a novel antidepressant agent. In the present study, an attempt was made to gain some insight into the mechanism of the drug's antidepressant activity. In vitro studies revealed that bupropion was a weak, competitive inhibitor of norepinephrine (NE) uptake into rat hypothalamic synaptosomes and of dopamine (DM) uptake into rat striatal synaptosomes, having IC50 values of 6.5 ± 0.6 × 10−6 M and 3.4 ± 0.4 × 10−6 M, respectively. At 1 × 10−5 M, the drug produced a 20 ± 3% inhibition of serotonin (5‐HT) uptake into rat hypothalamic synaptosomes. The drug was also a weak inhibitor of the ATP‐Mg+2 stimulated uptake of NE and DM into synaptic vesicles of whole rat brain, having IC50 values of 3.3 × 10−5 M and 6.0 × 10−5 M, respectively. Bupropion had no dose‐dependent effect on the spontaneous release of NE, DM, and 5‐HT from these synaptosomal preparations in concentrations as high as 1 × 10−4 M. Brain monoamine oxidase (MAO) activity in vitro was not affected by concentrations of the drug ranging from 10−7 M to 10−5 M. Bupropion was also without effect on brain MAO, 1 hr after i.p. doses in rats as high as 100 mg/kg. The ED50 value for bupropion necessary to inhibit the uptake of 3H‐catecholamines by 50% into synaptosomes incubated in the serum from rats treated with the drug was 40 mg/kg i.p., while its ED50 value for antidepressant activity, as judged by the ability of bupropion to reverse the immobile posture of “helpless” rats, was 8 mg/kg i.p. These neurochemical properties of bupropion on uptake of biogenic amines and on MAO activity serve to distinguish it from other antidepressant drugs of the tricyclic and MAO inhibitor classes.
Inhibition of Na,K‐ATPase activity and ouabain binding by sanguinarine
Authors: Pitts Barry J. R. , Meyerson Laurence R.
Published: January 2005

Sanguinarine, an isoquinoline alkaloid belonging to the benzophenanthridine class, has been found to be a time‐dependent inhibitor of cardiac Na,K‐ATPase activity. Enzyme inhibition depended on the concentration of enzyme in the assay. Dilution and centrifugation of the enzyme following incubation with sangunarine did not decrease inhibiton. Inhibiton of ouabain binding by sanguinarine was also time‐dependent and resulted in a reduction of the equilibrium level of ouabian bound to the enzyme preparation. This suggests the possibility that the positive inotropic effect of sanguinarine on the heart may be due to interaction with the cardiac glycoside receptor site on Na,K‐ATPase. Alternatively, sanguinarine may bind nonspecifically to phospholipids associated with the enzyme and exert its effects via conformational changes.
Alfentanil (R 39 209) — a particularly short‐acting intravenous narcotic analgesic in rats
Authors: Niemegeers C. J. E. , Janssen P. A. J.
Published: January 2005

Alfentanil, N‐{1‐[2‐(4‐ethyl‐4,5‐dihydro‐5‐oxo‐1H‐tetrazol‐l‐yl)ethyl]‐4‐(methoxymethyl)‐4‐piperidinyl}‐N‐phenyl propanamide monohydrochloride monohydrate, is a chemically novel, potent, extremely short‐acting and safe intravenous morphine‐like agent in laboratory animals. As an analgesic in rats, alfentanil is 137 times as potent as pethidine (tail withdrawal reaction test: i.v. ED50 is 6.04 mg/kg for pethidine and 0.044 mg/kg for alfentanil). The safety margin in rats is 1,080 (LD50: 47.5 mg/kg i.v.). Alfentanil reaches its peak effect within 2 min after injection, and its duration of action is very short: at two times its lowest ED50 the drug has a duration of action of 10 min. This duration is 30–35 min for pethidine and fentanyl, and 120 min for morphine. The narcotic antagonist naloxone produces an immediate and complete reversal of all morphine‐like effects of alfentanil. In dogs, alfentanil is a potent antiemetic (ED50: 0.032 mg/kg i.v.) with a safety margin of over 850 (LD50: > 20 mg/kg i.v.).
The effects of colchicine derivatives on humoral antibody response in mice
Authors: Trottier R. W. , Fitzgerald T. J.
Published: January 2005

The effects of colchicine and two of its chemical derivatives (propyl and bromo substitutions on the acetamido group) were investigated on the sheep red blood cell (SRBC) humoral antibody response in mice. These drugs were shown to suppress SRBC antibody titres. Immunosuppression was dependent upon temporal relationships of antigen/drug administration, as well as on the dosage profile of the drugs. In these studies bromocolchicine was the most active agent tested. Possible pharmacologic mechanisms are discussed.
Effects of analgesics, endorphins, and other drugs in a 3H‐serotonin binding assay
Authors: Gay David D. , VonVoigtlander Philip F.
Published: January 2005

Analgesics of various classes, endorphins, and other psychotropic drugs were evaluated for activity in inhibiting 3H‐serotonin binding to a soluble serotonin binding protein (SBP) isolated from rat brain. Morphine, leu‐endorphin, and the narcotic antagonist, nalorphine, effectively inhibited binding, while other analgesics, including codeine, methadone, pentazocine, beta‐endorphin, and enkephalins were inactive. Amitriptyline partially inhibited binding, while stimulants did not. Inhibition of serotonin binding to SBP does not appear to be characteristic of narcotic analgescis or any one therapeutic class of compounds.
Antihistaminic effect of terfenadine: A new piperidine‐type antihistamine
Authors: Cheng Hsien C. , Woodward James K.
Published: January 2005

The antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine‐induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10−7 M, shifted the histamine dose‐response curve to the right in a parallel fashion without affecting the dose‐response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10−7 and 1 × 10−6 M) the histamine dose‐response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose‐response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose‐response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose‐response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine‐induced death in guinea pigs. Terfenadine produced no atropine‐like effect against pilocarpine‐induced salivation in rabbits, no demonstrable histamine H2 antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of a lack of CNS sedative effects.
The trypanocidal activity of various aromatic bisguanylhydrazones in vivo
Authors: Ulrich Peter C. , Grady Robert W. , Cerami Anthony
Published: January 2005

Seven aromatic bisguanylhydrazones and two related compounds were screened against Trypanosoma brucei (EATRO 110M) in mice. The four most active were then screened against T. congolense (TREU 1183) in mice and rats. Eradication of parasitemia through 28 (T. brucei) or 42 days (T. congolense) resulting from a single dose of drug administered IP either 4 or 24 hours (respectively) after infection was used as the criterion of activity. 1,3‐Diacetylbenzene bisguanylhydrazone dihydrochloride cleared T. congolense from 50% of the animals (ED50) at a dose of approximately 10 mg/kg and from mice infected with T. brucei at approximately 15 mg/kg. This drug was also active when given 5 days after infection with T. congolense (ED50 ≅ 15 mg/kg). The isomorphous pyridine derivative, 2,6‐diacetylpyridine bisguanylhydrazone dihydrochloride, was active against T. brucei in mice (ED50 ≅ 8 mg/kg), but noncurative against T. congolense. At therapeutic doses of these two compounds, reversal and clearance of parasitemia was often not observed for 2–4 days, suggesting a delayed mode of action. Moreover, 1–2 days after drug treatment, the infectivity of parasites obtained from treated animals was significantly reduced, if not abolished. These findings indicate that more intensive screening of aromatic bisguanylhydrazones against various species of trypanosomes is warranted.
A cholinergic link in the centrally mediated actions of angiotensin II
Authors: Moore Alan F. , Drexler Anne P.
Published: January 2005

This study was designed to determine the role of brain cholinergic mechanisms in the centrally mediated blood pressure and drinking responses to angiotensin II (ANG II). Atropine (10 mg/kg, IV), but not methyl atropine (8 mg/kg, IV), significantly inhibited drinking and BP responses to ANG II intracerebroventricularly (ICV). BP responses to IV ANG II were not inhibited. Both atropine (20 mg/kg, IP) and methyl atropine (20 mg/kg, IP) inhibited cellular‐dehydration thirst induced by injection of hypertonic saline. Hemicholinium (80 μg/kg, ICV) had similar effects to atropine on BP and drinking responses to ICV ANG II. Phentolamine (0.5 mg/kg, IV) had a small but significant inhibitory effect on the drinking but not the BP response to ANG II ICV. It is concluded that brain cholinergic mechanisms contribute both to the drinking and pressor response to ICV ANG II, and to the drinking response to cellular‐dehydration thirst. There may also be a peripheral cholinergic component to cellular dehydration but not ICV ANG II‐induced thirst.
Role of beta‐adrenergic receptors in the mechanism of action of second‐generation antidepressants
Authors: Sethy Vimala H. , Harris Douglas W.
Published: January 2005

The effect of chronic intravenous infusion of desmethylimipramine (DMI), amitriptyline, mianserin, bupropion, alprazolam, or diazepam on the density of beta‐adrenergic receptors in the rat cerebral cortex has been investigated in this study. DMI and amitriptyline significantly decreased the density of beta‐adrenergic receptors. Mainserin, bupropion, alprazolam, and diazepam had no significant effect on the density of beta‐adrenergic receptors. Results of this study indicate that mechanisms other than beta‐adrenergic receptors may be involved in the antidepressant activity of these drugs.
Air‐induced writhing: A rapid broad spectrum assay for analgesics
Authors: VonVoigtlander Philip F. , Lewis Richard A.
Published: January 2005

The injection of air into the peritoneal cavity of rats produces reliable and quantifiable behavioral responses. These responses are blocked by compounds known to have analgesic properties, including opioid agonists, opioid agonist‐antagonists, cyclo‐oxygenase inhibitors, and amine potentiators. However, psychotropic agents were generally inactive at reasonable doses. The ability of this assay to identify a wide spectrum of analgesic agents in rats was superior to the hot plate, warm plate, and tail immersion assays.
Effects of the novel antipsychotics, RMI 81582 and clopipazan, on predictors of extrapyramidal liability in squirrel monkeys
Authors: Neale Robert , Gerhardt Susan , Liebman Jeffrey M.
Published: January 2005

The neuroleptic‐induced acute dyskinetic syndrome in primates has been proposed as a predictor for extrapyramidal side effects of potential antipsychotics. Another potential predictor in monkeys is the degree to which benztropine reverses antipsychotic‐induced inhibition of Sidman avoidance performance. Assessment of these models has been hampered by the scarcity of clinically effective antipsychotics that lack extrapyramidal side effects. Recently, however, RMI 81582 and clopipazan have been reported to exert antipsychotic activity in initial clinical trials without causing extrapyramidal side effects. Using squirrel monkeys, these drugs were tested in both procedures. RMI 81582 did not cause dyskinesias at any dose tested, and its blockade of avoidance could not be antagonized by benztropine. These results are consistent with the previously proposed clozapine‐like profile of RMI 81582. However, clopipazan, like haloperidol, induced dyskinesias and its effects on avoidance were reversed by benztropine. Possible clinical implications are discussed. These results support the predictive value of these two primate models for antipsychotic‐induced extrapyramidal dysfunction.
Preliminary report: Comparison of the potencies of clonidine, B‐HT 920, and B‐HT 933 in reversing reserpine‐induced ptosis in the mouse
Authors: Deniard Marie‐Jeanne , Meignen Joelle , DeFeudis Francis V.
Published: January 2005

The potencies of the α‐adrenoceptor agonists clonidine, B‐HT 920 (2‐amino‐6‐allyl‐5,6,7,8‐tetrahydro‐4H‐thiazolo‐[5,4‐d]‐azepin), and B‐HT 933 (2‐amino‐6‐ethyl‐4,5,7,8,‐tetrahydro‐6H‐oxazolo‐[5,4‐d]‐azepin; Azepexole) in reversing reserpine‐induced ptosis in male NMRI mice were determined. Reserpine (2.5 mg/kg, i.p.) was administered 4 hr before intraperitoneal injection of the α‐adrenoceptor agonists. All three α‐adrenoceptor agonists produced dose‐dependent reversal of ptosis, this effect being maximal at about 15–30 min after injection. At 30 min postinjection, on a mg/kg basis, clonidine‐HCl was about 23 times more potent than B‐HT 920‐2 HCl and about 375 times more potent than B‐HT 933 2‐HCl in reversing ptosis. Although reversal of reserpine‐induced ptosis in the mouse is not selective for α2‐adrenoceptor agonists, these results indicate that this test can be used to compare the relative potencies of three substances with pronouced α2‐adrenoceptor agonist activity.
Effects of N6‐cyclohexyladenosine (CHA) on responses to adrenergic and cholinergic nerve stimulation in the peripheral autonomic nervous system
Authors: Kitzen Jan M. , Schwenkler Mary A. , Moeller Janice E. , Hellyer Luther D. , Wilson Sandy J.
Published: January 2005

The adenosine derivative N6‐cyclohexyladenosine (CHA), was studied in various cardiovascular and autonomic experiments. In hemodynamic studies in dogs, CHA 0.5 mg/kg, i.v., caused moderate hypotension and bradycardia. Additional studies in dogs showed that a portion of the bradycardia was the result of an inhibitory effect on the sympathetic nerves to the heart since the chronotropic reponses to cardioaccelerator nerve stimulation were inhibited while the responses to isoproterenol were slightly potentiated. CHA was more potent than adenosine in this experiment and caffeine, 3 mg/kg, i.v., antagonized the effects of CHA. CHA was also found to inhibit the pressor effects of lumbar sympathetic nerve stimulation in rats while responses to intraarterial norepinephrine(NE) were potentiated. In the isolated stimulated guinea pig ileum, both CHA and adenosine inhibited the stimulation‐evoked twitches, with CHA being the more potent. Caffeine, 0.1 mM, antagonized the inhibitory effects of both compounds. CHA had no significant effect on the negative chronotropic responses to vagus nerve stimulation in dogs. These findings indicate that CHA is qualitatively similar to adenosine but is more potent and longer lasting. CHA, like adenosine, appears to alter reponses to both adrenergic and cholinergic nerve stimulation.
Comparison of the effects of slow Ca2+ channel blockers and other agents on passive cutaneous anaphylaxis in the rat
Authors: Hertz F. , Ranson M. , DeFeudis F. V.
Published: January 2005

The actions of five slow Ca2+ channel blocking agents (nifedipine, verapamil, diltiazem, mesudipine, and D 600) were compared with those of several substances that are used clinically in treating asthma (e.g., theophylline, isoproterenol, disodium cromoglycate, and clemastine) and several other agents that are used in cardiovascular therapy (e.g., disopyramide, clonidine, cibenzoline), using the passive cutaneous anaphylaxis (PCA) reaction in the rat. High doses of all slow Ca2+ channel blockers produced a partial inhibition of the PCA reaction. Isoproterenol, theophylline, prazosin, cyproheptadine, ketotifen, phentolamine, and disodium cromoglycate produced dose related inhibition of PCA reaction, their maximum effects being greater than those of the slow Ca2+ channel blockers. As nifedipine, verapamil, and diltiazem were about as potent as the H1 antagonist clemastine in inhibiting the PCA reaction, it seems possible that certain slow Ca2+ channel blockers might be of value in treating asthma or other allergic disorders in man.
U‐48,753E: A potent, structurally novel antidepressant‐like agent
Authors: Vonvoigtlander Philip F. , Triezenberg Herman J. , Losey Elizabeth G. , Gay David D.
Published: January 2005

U‐48, 753E (trans‐3,4‐dichloro‐N‐(2‐(dimethylamino)‐cyclopentyl)‐propionanilide maleate) was compared to imipramine in a number of tests of antidepressant‐like activity and mechanisms of action. Although not structurally related to imipramine or other nontricyclic antidepressants, U‐48,753E was considerably more potent than imipramine in tests of norepinephrine potentiation, tetrabenazine antagonism, and behavioral despair. U‐48,753E displayed only moderate anticholinergic and no monoamine oxidase inhibitory activities. In vivo measurements of biogenic amine uptake indicated that U‐48,753E blocks norepinephrine, epinephrine, and serotonin uptake and that it is much more potent than imipramine, particularly regarding epinephrine uptake. U‐48,753E is most markedly distinguished by its potency in a test of alpha2‐adrenergic desensitization. Extremely low repeated doses and single doses of U‐48,753E were effective at antagonizing the hypothermia induced by the alpha2 agonist, clonidine. In contrast, imipramine required much higher, repeated doses to display similar activity. The alpha2 desensitization by U‐48,753E is also manifest by a reduced biochemical sensitivity to clonidine; clonidine‐induced slowing of norepinephrine synthesis is antagonized by U‐48,753E pretreatment. Thus, U‐48,753E shares many antidepressant‐like properties with imipramine, but generally has greater potency and a much greater predilection for blocking epinephrine uptake and altering alpha2‐adrenergic sensitivity.
Inosine and N6‐substituted adenosine analogs lack anxiolytic activity in the pentylenetetrazol discrimination model of anxiety
Authors: Spencer David G. , Gherezghiher Tseggai , Lal Harbans
Published: January 2005

Although some in vitro studies have raised the possibility that endogenous purines mediate the therapeutic effects of the benzodiazepines, no behavioral studies have been performed to confirm or reject this hypothesis. Consequently, inosine and the adenosine A1 receptor agonists N6‐ (L‐phenylisopropyl) adenosine (L‐PIA) and 2‐chloroadenosine (2CA) were evaluated for diazepam‐like anxiolytic activity in the pentylenetrazol‐saline discrimination model of anxiety. Rats were trained to press one of two levers for food reward after pentylenetetrazol (PTZ) injection (20 mg/kg) and to press the other after saline injection. During testing in these rats, diazepam (10 mg/kg) blocked the PTZ‐induced selection of the PTZ‐appropriate lever (i.e., rats selected the saline‐correct lever). Inosine, L‐PIA, and 2CA neither blocked selection of the PTZ‐appropriate lever after PTZ administration nor did they reverse the diazepam blockade. It is suggested that adenosine or inosine may not act endogenously to mediate the anxiolytic effects of benzodiazepines.
Meeting the challenge of cardiovascular new drug discovery
Authors: Smith Ronald D.
Published: January 2005

The general challenge of new drug discovery is to translate a new idea in science or medicine into a useful therapeutic agent. The specific challenge of cardiovascular new drug discovery (CVNDD) is to translate a new idea in science or medicine into an agent for the treatment of cardiovascular disease such as hypertension, congestive heart failure, or ischemic heart disease. CVNDD has a fundamental and increasingly important role in providing a maturing world population with medicaments designed to assist the human organism adjust to aging and to changes in its environment. The economic impact of CVNDD is critical to the world pharmaceutical industry. The economic impact of CVNDD is insignificant, however, compared to the potential world health impact of successful CVNDD that generates effective new cardiovascular drugs.

There can be no doubt that present cardiovascular drugs have enhanced the quality of life of millions of people worldwide and have contributed to a reduction in the morbidity and mortality of cardiovascular disease. Although the gains have been modest in some areas such as sudden cardiac death, they have been dramatic in other areas, such as stroke. The length and quality of life have been enhanced by the rational discovery, development, and therapeutic use of cardiovascular drugs. The future holds the promise of even more impressive gains through new generations of drugs—more efficacious, safer drugs [Fisher, 1980; Pletscher, 1980; Kaplan and Smith, 1981; Smith, 1983].
Cognitive analysis of neuropharmacological treatments
Authors: Weingartner Herbert , Strupp Barbara J.
Published: January 2005

Several types of drug strategies have been investigated because they may be potentially valuable in the treatment of cognitive dysfunctions. Research efforts in this area have primarily considered how such drugs alter specific systems in the central nervous system and how these may relate to changes in behavior of laboratory animals. For the effective development of cognitively focused drug treatments, it is necessary that we appreciate the ways that drugs might alter different and specific cognitive systems. A number of methods of approach can be used to effectively define and contrast the psychobiological determinants of the cognitive response of drug treatments. These approaches are built upon findings that have shown that 1) cognitive failures in various syndromes are determined by different mechanisms 2) components of information processing are psychologically and biologically distinct; and 3) different types of nonspecific changes produced by a drug can differentially affect components of cognition.
High‐affinity (3H)‐dexoxadrol binding to rat brain membranes
Authors: Sethy Vimala H. , McCall John M.
Published: January 2005

Specific binding of (3H)‐dexoxadrol to rat brain membrane was saturable. The specific binding represented 74 to 82% of total binding. Scatchard analysis of the data demonstrated the existence of high‐ and low‐affinity binding sites. The kinetic constants for the corresponding binding sites were as follows: Kd1 = 1.68 nM, Bmax1 = 0.4 pmol/mg protein, Kd2 = 26.1 nM, and Bmax2 = 3.7 pmol/mg protein. Binding reached equilibrium within 5 minutes of incubation at 25°C. Optimum binding was observed between the pH range of 7.4 to 9. Binding was dependent on protein concentration and was reduced by denaturation of protein and by proteolytic enzyme. (3H)‐dexoxadrol binding was inhibited by drugs pharmacologically similar to phencyclidine (PCP) and bound (3H)‐dexoxadrol could be rapidly displaced by cold PCP.
New developments in the diagnosis of the dementias
Authors: Blass John P. , Barclay Laurie L.
Published: January 2005

The most common errors in the diagnosis of dementia are underdiagnosis and overdiagnosis. Underdiagnosis is best avoided by careful use of psychometric screening tests to detect cognitive impairment in patients unaware of their own defect. Overdiagnosis can be avoided by not applying the label of “dementia” until the diagnosis is unequivocal. Complete evaluation is necessary to rule out treatable causes of dementia, and should include medical, neurological, and psychiatric history and examination, simple psychometric tests, laboratory battery, computerized transaxial tomographic brain scan, and electroencephalogram. Ultimately, the diagnosis of dementia may change at follow‐up examination, and the unequivocal diagnosis of a specific form of dementia still requires autopsy and neuropathological examination of the brain. The most common causes of cognitive impairment in the elderly include Alzheimer's disease, multi‐infarct dementia, depression, and other specific illnesses such as tumors, Jakob‐Creutzfeldt disease, and normal pressure hydrocephalus. Even systemic disease can present as dementia. The evaluation outlined above may help distinguish among these causes. New diagnostic techniques may eventually be helpful as well.
Methodological issues in drug assessment research
Authors: Buckalew L. W.
Published: January 2005

Increased sensitivity to methodological issues in drug assessment research is needed in light of challenges to research design, conduct, and outcomes. Major issues presented include (a) the nature and adequacy of placebo controls, (b) problems in maintaining the integrity of “blind” conditions, and (c) the potential design‐compromising effects of informed consent. The necessity of true matching placebos, particularly concerning physical/perceptual characteristics and the ability to produce transitory changes in subjects, was stressed. Though the double‐blind condition has conceptual integrity, the operation of drug and placebo side effects and associated guess bias may confound research results. Use of a triple‐blind condition and addition of a drug‐disguised group is suggested. Last, the issue of informed consent and its implications for the integrity of drug research is a problem deserving more attention.
Selective inhibition of the cyclooxygenase pathway of the arachidonic acid cascade by the nonsteroidal antiinflammatory drug isoxicam
Authors: Pugsley Thomas A. , Spencer Carolyn , Boctor Amal M. , Gluckman Melvyn I.
Published: January 2005

The effects of the nonsteroidal antiinflammatory drug isoxicam on prostaglandin formation by HSDM1C1 mouse fibrosarcoma cells grown in culture and 5‐HETE(5(S)‐5‐hydroxy‐6‐trans, 8,11,14‐cis eicosatetraenoic acid) formation by human leukocytes were determined. Isoxicam inhibited the formation of the cyclooxygenase product prostaglandin E2 with an IC50 of 2.0 μM. In comparison, the reference standards piroxicam and indomethacin had IC50 values of 0.55 μM and 0.14 μM, respectively. Nordihydroguaiaretic acid (NDGA) was inactive up to 10 μM. Isoxicam, piroxicam, and indomethacin were relatively devoid of any significant inhibitory property on 5‐lipoxygenase activity exhibiting IC50 values > 500 μM. In comparison, the compounds BW755C and NDGA, known lipoxygenase inhibitors, had IC50 values of 11 μM and 0.6 μM, respectively. The present findings indicated that isoxicam exhibited a selective inhibition of the cyclooxygenase pathway of the arachidonic acid cascade and that this effect may at least in part be responsible for its antiinflammatory activity observed in animals and humans.
Fluradoline (HP 494), a centrally acting analgesic with antidepressant properties: Antidepressant pharmacology
Authors: Spaulding T. , Fielding S. , Cornfeldt M. , Wilker J. , Ellis D. B. , Novick W. J. , Ong H. H.
Published: January 2005

Fluradoline (HP 494), a tricyclic dibenz (b, f) oxepine derivative with an analgesic profile, was tested for antidepressant activity. After oral administration, fluradoline was twice as potent as imipramine and similar in potency to desmethylimipramine in blocking tetrabenazine‐induced ptosis. Like standard antidepressants, fluradoline selectively increased response rates for electrical stimulation of the median forebrain bundle using internal capsule‐lesioned rats. Response rates in nonlesioned rats were unaffected. There was partial protection against yohimbine toxicity and no potentiation of 5‐hydroxytryptophan‐induced seizures in mice. When administered to squirrel monkeys, the EEG profile from cortically‐placed electrodes resembled that found for imipramine. Using in vivo and in vitro techniques, it was shown that fluradoline was not a monoamine oxidase inhibitor; however, the compound did block the reuptake of norepinephrine, serotonin and dopamine in brain homogenates. These results suggest that in addition to the analgesic profile, there is a concomitant antidepressant profile which may enhance the spectrum of activity of fluradoline.
The cardioselectivity of β‐adrenergic blocking agents revealed by interaction with salbutamol and isoproterenol in the KCN test in rats
Authors: Awouters F. , Niemegeers C. J. E. , Janssen P. A. J.
Published: January 2005

The interaction of seven β‐adrenergic blocking agents with salbutamol and isoproterenol was studied in the potassium cyanide test in rats. Salbutamol was used at a dose that provided protection from KCN lethality and isoproterenol at an overdose that failed to protect, presumably because of latent cardiotoxicity. Salbutamol‐induced protection was abolished at the following doses (s.c., mg/kg): timolol (0.0085), bunolol (0.010), propranolol (0.038), pindolol (0.15), metoprolol (3.93), atenolol (5.69), and practolol (> 10.0). Survival was restored dose‐dependently in isoproterenol‐overdosed rats only by atenolol (0.44), practolol (0.51) and metoprolol (1.06). The cardioselectivity ratio (i.e., salbutamol antagonism/isoproterenol antagonism) for these three compounds was as follows: practolol (> 19.6), atenolol (12.9), and metoprolol (3.82). The described interaction tests appear to provide experimental data that are useful for the evaluation of cardioselective β‐adrenergic blockade.
A comparison of the cardiovascular and the behavioral changes following naloxone as measures of the degree of physical dependence on morphine in rats
Authors: Marshall Dennis C. , Buccafusco Jerry J.
Published: January 2005

Behavioral and cardiovascular changes evoked by naloxone (0.5 mg/kg) were evaluated in unrestrained rats made physically dependent by a constant infusion of morphine at increasing doses over 7 days. The relationship between the duration of morphine administration and the naloxone‐induced cardiovascular changes was investigated to determine the reliability and sensitivity of blood‐pressure measurements in assessing the degree of physical dependence produced in these animals. No significant behavioral or cardiovascular changes from preaddiction levels were observed during morphine infusion. Arterial pressure increased significantly in a dose‐ and time‐dependent manner in response to naloxone injected on days 1, 3, 5, or 7 of the morphine infusion schedule. Heart rate changes which accompanied the increase in blood pressure, however, were similar in magnitude over the course of increasing physical dependence. The frequency of counted behavioral signs precipitated by naloxone over the same infusion schedule indicated a significant, progressive increase only for escape attempts, whereas withdrawal body shakes and writhing peaked early in the schedule and actually declined to very low frequencies by day 7. A high dose of morphine (50 mg/kg) was injected following naloxone‐precipitated withdrawal in an attempts to reverse the abstinence symptoms. The only symptoms significantly inhibited by morphine were the increase in arterial pressure and the occurrence of diarrhea. These results indicate that the absolute increase in arterial blood pressure produced by naloxone in opiate‐dependent animals may serve as a simple, objective, and sensitive measurement, along with traditional behavioral signs, in the assessment of narcotic dependence liability.
A direct vasoaction of inosine in small intramural coronary arteries
Authors: Randall John R. , Mass Howard J. , Jones Carl E.
Published: January 2005

The direct vasoaction of inosine was examined and compared to that of adenosine in small coronary arterial rings (0.3–0.6 mm o.d.) from the dog heart. Rings were contracted with KCI, and relaxation responses to increasing nucleoside concentrations were recorded. Both inosine (16 rings) and adenosine (12 rings) elicited relaxation responses that were linearly related to the logarithm of nucleoside concentration. In eight rings for which both inosine and adenosine responses were obtained, the geometric mean ED50 for adenosine was 0.54 μM, compared to 242 μM for inosine (p < 0.001). The Rmax for the two nucleosides were not significantly different (p > 0.05). In four rings studied, aminophylline abolished the response to adenosine. In five rings studied, aminophylline abolished the response to adenosine. In five rings studied, aminophylline abolished the inosine response in only two rings; in the remaining three rings, the inosine response was attenuated but not abolished. These results indicate that inosine exerts a direct vasodilatory action on small coronary arteries and that this vasoaction is in part aminophylline‐sensitive.
Ultraviolet light‐induced photorelaxation of agonist‐contracted rabbit aorta: Further characterization and the estimation of drug‐receptor rate constants
Authors: Raffa Robert B. , Robinson Mary Jane , Tallarida Ronald J.
Published: January 2005

Isolated strips of rabbit thoracic aorta, contracted to a steady‐state isometric tension by measured doses of α‐adrenoceptor agonists, exhibit a transient loss in tension when exposed to a flash of ultraviolet light. This response consists of an initial decrease in tension followed by a spontaneous restoration to equilibrium tension. The time course of the return to equilibrium from maximum relaxation is a biphasic exponential, resolvable into a fast phase and a slow phase. Previous work has shown that the fast phase of recovery is drug‐independent, but that the slow phase of recovery is drug‐dependent; i.e., the rate of return to equilibrium tension is unique for each agonist used to produce the initial contraction. When a system in equilibrium is perturbed in a manner such as this, the return to equilibrium is characterized by a time constant that is a function of the drug concentration. A plot of this time constant against drug consentration yields a straight line of slope and y‐intercept equal to the forward and reverse rate constants, respectively, of the chemical reaction. In this study, equilibrium perturbation by UV light was used to determine the forward and reverse rate constants (k1 and k2) of the drug‐receptor interaction and the dissociation constants (KA = k2/k1) of each of three α‐adrenoceptor agonists, norepinephrine, phenylephrine, and methoxamine. The values of KA reported here for all three agents and for different degrees of passive stretch (0.25‐g and 10‐g preload for norepinephrine, 10‐g preload for phenylephrine and methoxamine) are not significantly different from the corresponding values reported using the method of partial irreversible blockade of receptors. These findings are compatible with the hypothesis that the radiation disrupts the drug‐receptor equilibrium. Regardless of mechanism, however, the photorelaxation phenomenon may provide an additional tool for classifying vasoactive compounds.
Effects of prenalterol, a partial beta adrenoceptor agonist, on the left ventricular function in anesthetized cardiac denervated beagle dogs
Authors: Ek Lars , Bjökman Jan‐Arne , Jandhyala Bhagavan S.
Published: January 2005

Cardiovascular effects of prenalterol, a partial beta adrenoceptor agonist, were investigated in pentobartial anesthetized dogs. In these preparations, in which the heart was acutely denervated, intravenous administration of prenalterol significantly enhanced contractility (left ventricular max dP/dt) as well as heart rate, and reduced left atrial pressure. Hence the data confirmed that this agent is an effective inotropic as well as a chronotropic agent. Ventricular function curves were determined in these studies to establish the efficacy of the myocardium in handling volume loads at various filling pressures. In order to relate the increased output directly to increases in inotropy, heart rate was kept constant by electrical pacing. Prenalterol significantly shifted these curves upward and to the left, indicating enhanced contractility. In a separate series, it was demonstrated that the inotropic effect of prenalterol persists for longer durations as indicated by the significant shift that occurred in left ventricular function curves 70 min after administration of a single dose of the drug. The data collectively suggest that prenalterol, an orally effective inotropic agent, possesses prolonged duration of action; hence, this drug may be more preferable than dopamine or dobutamine in the treatment of heart failure since the effects of these two agents are transient and are subjected to tolerance during continuous intravenous infusions.
Analgesic effect of acetaminophen‐codeine combination in mice
Authors: Hertz Françoise , Ranson Michèle , Deghenghi Romano
Published: January 2005

The analgesic activity of acetaminophen and codeine phosphate was evaluated in mice (writhing test and hot‐plate test) after oral administration. When the two drugs were administered in combination, a potentiation was obtained; the analgesic effect is 1.8–6.6 times greater than when each drug is given alone. A central component for acetaminophen analgesia was confirmed.
New perspectives for the clinical evaluation of atherosclerosis
Authors: Bond M. Gene , Morley Deborah
Published: January 2005

Title: New perspectives for the clinical evaluation of atherosclerosis. Atherosclerosis is a progressive and degenerative disease of the artery wall that begins relatively early in life but does not become recognized until it is severe enough to result in the development of clinical signs and symptoms. Too often, however, these clinical events are closely associated with morbidity and mortality. Much progress has been made in elucidating those risk factors associated with development of clinical endpoints; however, risk when used in this context is defined as increased chance and, except in unusual circumstances, cannot predict specific individuals who will develop signs and symptoms nor when these events will occur. Several methods have been developed during the last 25 years that have the potential for detecting atherosclerotic plaques in their preclinical stages. High‐resolution, B‐mode ultrasound imaging, particularly, has high sensitivity and specificity in detecting carotid artery plaques and in accurately measuring size characteristics of individual lesions. Reliability studies have demonstrated the possibility of detecting changes in asymptomatic carotid artery atherosclerosis with 95%percnt; confidence, if these changes are greater than ± 0.4 mm. Application of this noninvasive method to identify subjects with asymptomatic lesions, and to monitor plaque changes over time, will aid greatly in determining the efficacy of various therapies and potentially will decrease the mortality and morbidity associated with stroke.