bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosing the decline of major pharmaceutical research laboratories: A prescription for drug companies
Authors: Weisbach Jerry A. , Moos Walter H.
Published: January 2005

Despite dramatically increasing expenditures for in‐house pharmaceutical research and development (R&D) at major drug companies, few internally discovered, breakthrough products are on the horizon. In contrast, and for significantly less private funding, biotechnology companies are playing an ever more significant role in generating promising biomedical product candidates. For a variety of factors, ranging from financial and management to scientific in nature, we suggest that the twentieth century has encompassed the rise and decline of major pharmaceutical discovery research laboratories. Herein, we provide a concise background to the industry and its current predicament. Having diagnosed some of the problems inherent to the existing organizations, we provide a prescription for change, which places pharmaceutical companies at the center of constellations of alliances with biotech ventures. We posit that, for the same or even fewer dollars, pharmaceutical companies could significantly enhance existing research productivity, with less risk, and with potentially higher rewards. Where this approach to be adopted broadly and successfully, the effect on patients, the healthcare industry, numerous major corporations, their employees and stockholders, and the economy in general, could be “just what the doctor ordered”! These lessons and proposals may also have merit in other research‐based industries. © 1995 Wiley‐Liss, Inc.
General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A1 receptor agonist
Authors: Wagner Heribert , Milavec‐Krizman Maria , Gadient Fulvio , Menninger Klaus , Schoeffter Philippe , Tapparelli Carlo , Pfannkuche Hans‐Jürgen , Fozard John R.
Published: January 2005

The pharmacological properties of 6‐cyclohexyl‐2′‐0‐methyladenosine (SDZ WAG 994)—a potent, selective, and orally active adenosine A1 receptor agonist—are described. SDZ WAG 994 is a potent (KD 23 ± 2 nM, n = 5) and selective (1,090‐fold vs. A2A receptors) displacer of binding to pig striatal A1 receptors and behaves as a full agonist at the A1 receptors coupled negatively to adenylate cyclase in rat adipocytes (pEC50 6.4 ± 0.2, n = 3), those which induce contraction of rat spleen (pEC50 7.1 ± 0.1, n = 13) and those which suppress the response to autonomic nerve stimulation in guinea‐pig ileum (pIC50 6.6 ± 0.1, n = 4) and rat kidney (pIC50 6.0 ± 0.1, n = 6). The compound has negligible affinity (pEC50 < 4, n = 5) for the A2B receptor which mediates relaxation of guinea‐pig aorta. In spontaneously hypertensive (SH) rats SDZ WAG 994, 0.05–0.5 mg/kg (0.14–1.4 μmol/kg) po, caused dose‐related and sustained (> 5 h) falls in blood pressure (BP) and heart rate (HR) and suppressed plasma renin activity (PRA); the cardiovascular effects could be immediately and fully reversed by an intravenous injection of 8‐(p‐sulphophenyl)theophylline, 20 mg/kg (56.4 μmol/kg). SDZ WAG 994 given via the food at 0.4 and 1.2 mg/kg/day (1.1 and 3.3 μmol/kg/day) for 7 or 14 days, respectively, induced dose‐related hypotension and bradycardia which were well maintained throughout the treatment periods. In the conscious, normotensive dog, SDZ WAG 994, 1 and 3 mg/kg (2.8 and 8.3 μmol/kg) po, induced substantial, sustained falls in BP which were accompanied by tachycardia. In salt depleted squirrel monkeys, SDZ WAG 994, 0.1–0.3 mg/kg (0.28–0.83 m̈mol/kg) iv or 0.2–0.6 mg/kg (0.56–1.7 μmol/kg) po caused dose‐related and sustained (> 5 h) bradycardia and suppression of PRA but no change in BP. In rhesus monkeys, SDZ WAG 994, 0.1–1.2 mg/kg (0.28–3.3 μmol/kg) po induced sustained bradycardia and suppression of PRA and the plasma free fatty acid and triglyceride concentrations. The data establish SDZ WAG 994 as a potent, selective, and orally active adenosine A1 receptor agonist with therapeutic potential in certain cardiovascular and/or metabolic disease states. © 1995 Wiley‐Liss, Inc.
Antiarrhythmic and electrophysiologic effects of sublingual ibutilide fumarate
Authors: Buchanan Lewis V. , Thompson Dwayne D. , Hsu Chang‐Yuan L. , Walters Rodney R. , Gibson John K.
Published: January 2005

Ibutilide fumarate is a class III antiarrhythmic agent in phase III clinical trials. Due to rapid hepatic metabolism, ibutilide has a low oral bioavailability (< 10%). To assess alternate routes of administration, we performed repeated studies of the electrophysiologic effects of sublingual ibutilide (0.03, 0.1, and 0.3 mg/kg; 0.07, 0.2, and 0.7 m̈mol/kg) in pentobarbital anesthetized dogs. Peak significant increases in QTc interval, ventricular effective refractory period (VERP), and right ventricular monophasic action potential duration (MAPD90) were achieved 30 min following 0.1 or 0.3 mg/kg (0.2 and 0.7 m̈mol/kg) ibutilide and were coincident with peak plasma ibutilide levels. The duration of significant effects ranged from 2 to 5 h. Peak effects were: QTc + 121 msec, MAPD90 + 71 msec, and VERP + 53 msec. The 0.3 mg/kg (0.7 m̈mol) dose significantly decreased heart rate 10 min post dosage through 5 h. The 0.03 mg/kg (0.07 m̈mol) dose increased MAPD90 at 1 to 2 h but was otherwise ineffective. The plasma half life of ibutilide was 2.8 h, with a 72% bioavailability relative to an equivalent intravenous dose. Based on the electrophysiologic results, we chose to test the 0.1 mg/kg (0.2 m̈mol) sublingual ibutilide dose for termination of sustained atrial flutter in anesthetized dogs with y‐shaped right atrial incisions. The administration of 0.1 mg/kg (0.2 m̈mol) sublingual ibutilide during sustained atrial flutter resulted in termination of atrial flutter in all cases (n = 4) after a mean time interval of 11.4 ± 0.8 min. Termination of atrial flutter was associated with ibutilide plasma levels of 19.6 ± 6.3 ng/ml, and 30 and 18 msec increases in atrial and ventricular effective refractory periods. Atrial flutter could be reinduced in 2 dogs, on at 3 h and one at 4 h post ibutilide administration. The ability to reinduce atrial flutter was associated with a reduction in ibutilide plasma levels to 2.3 ± 0.7 ng/ml. We conclude that sublingual ibutilide is rapidly absorbed and produces significant electrophysiologic and antiarrhythmic effects, and is a potential alternative to intravenous and oral therapy. ©1995 Wiley‐Liss, Inc.
Autoradiographic distribution of [3H]‐suriclone binding sites in the rat brain
Authors: Malgouris Christiane , Perrot Fabienne , Dupuis Marion , Kiosseff Thérèse , Daniel Marc , Blanchard Jean‐Charles , Doble Adam
Published: January 2005

Suriclone is a potent non‐benzodiazepine anxiolytic belonging to the cyclopyrrolone family. This study examines the distribution and properties of [3H]‐suriclone binding sites in rat brain by autoradiography. The binding of [3H]‐suriclone to rat brain sections was displaced completely by 1 m̈M flumazenil; saturation experiments revealed a single class of binding sites with a KD value of 1.19 nM and a Bmax of 1.05 pmol/mg protein. The pharmacological specificity of [3H]‐suriclone binding was close to that of the benzodiazepine binding site on the GABAA receptor. Unlike benzodiazepine (BZ) agonists, [3H]‐suriclone binding to rat brain sections was not increased in the presence of GABA, and unlike imidazopyridines such as alpidem, suriclone was unable to discriminate between the BZ1 and BZ2 phenotype of the GABAA receptor. The autoradiographic distribution of [3H]‐suriclone binding sites in the rat brain was heterogeneous and relatively similar to that previously described for GABAA receptors labelled by benzodiazepines; some regions, however, such as certain cortical areas, displayed a different labelling.

The highest densities were found in frontal, occipital, parietal, and cingulate cortices (layers I, II, III, IV), in the molecular layer of the cerebellum, in the superior colliculus and in the hippocampus. Moderate binding densities appeared in numerous areas such as the inferior colliculus, the central grey, the dorsal raphé, and the hypothalamus whereas caudate putamen, globus pallidus, and thalamic nuclei displayed a low density of [3H]‐suriclone binding sites. ©1995 Wiley‐Liss, Inc.
Evidence for multiple antiarrhythmic binding sites on the cardiac rapidly activating delayed rectifier K+ channel
Authors: Chadwick Christopher C. , Krafte Douglas S. , O'Connor Bernard , Volberg Walter A. , Ezrin Alan M. , Johnson Rober E. , Silver Paul J.
Published: January 2005

We have previously shown that [3H]dofetilide binds with high affinity to sites associated with the guinea pig cardiac rapidly activating delayed rectifier K+ (IKr) channel and that class III antiarrhythmic agents, including dofetilide, clofilium, quinidine, sotalol, and sematilide, competitively displace [3H]dofetilide with IC50 values that correlate with those for blockade of the IKr channel. In this report, we show that other class III antiarrhythmic agents, namely, E‐4031 (1‐[2‐(6‐methyl‐2‐pyridyl)ethyl]‐4‐(4‐methylsulfonylamidobenzoyl)piperidine) and L‐691, 121 (3,4‐dihydro‐1′‐[2‐(benzofurazan‐5‐yl)ethyl]‐6‐methanesfulonamidospiro[(2H)‐1‐benzopyran‐2,4′‐piperidin]‐4‐one), potently block guinea pig IKr channels with respective IC50 values of 29 and 8 nM, yet have a low potency for displacement of [3H]dofetilide. Moreover, WIN 61773‐2 [(R)(+)‐4,5‐dihydro‐4‐methyl‐1‐phenyl‐3(2‐phenylethyl)‐(1H)‐2,4‐benzodiazepine monohydrochloride] biphasically displaces [3H]dofetilide according to a two site competitive binding model (site 1 = 21% displacement, IC50 = 116 nM; site 2 = 79% displacement, IC50 = 50 m̈M) with correlation to IKr block in the first phase (IC50 = 92 nM). These findings suggest that E‐‐4031, L‐691, 121, and WIN 61773‐2 inhibit IKr channels by interacting at sites distinct from the high affinity [3H]dofetilide binding site. The partial displacement of [3H]dofetilide by low concentrations of WIN 61773‐2, correlated with complete block of IKr, suggests allosteric modulation of the dofetilide binding site by this agent. ©1995 Wiley‐Liss, Inc.
Antidiabetic agent pioglitazone increases insulin receptors on 3T3‐L1 adipocytes
Authors: Swanson Michael L. , Bleasdale John E.
Published: January 2005

Pioglitazone and other antidiabetic thiazolidinediones appear to overcome insulin resistance by affecting an unidentified early event in insulin action. Because attempts to determine changes in insulin receptors in tissues from thiazolidinedione‐treated diabetic animals are complicated by drug‐induced reduction of hyperinsulinemia and consequent receptor up‐regulation, 3T3‐L1 cells were utilized here as an in vitro model system. After the excess insulin required for optimal differentiation of 3T3‐L1 adipocytes was removed from the culture medium, there was an increase in specific binding of insulin to the cell surface that was further augmented 25 and 47% in cells treated with pioglitazone for 12 and 24 h, respectively (EC50 about 0.6 μM, maximal at 5–25 μM). Pioglitazone increased the number of insulin receptors without changing binding affinity. Specific IGF‐I binding was not affected by pioglitazone in the 3T3‐L1 cells. Glycerol 3‐phosphate dehydrogenase activity, a marker of adipocyte differentiation, was also increased in a dose‐dependent manner by pioglitazone (maximal at 10–25 μM). Tunicamycin, which inhibits the N‐linked glycosylation of newly synthesized insulin receptors that is required for their translocation to the cell surface, decreased specific insulin binding by about 50% after 24 h, and this decrease remained unchanged when pioglitazone was simultaneously present. Pioglitazone increased not only cell surface insulin receptors, but also total cellular insulin receptors (quantitated either by specific insulin binding or by immunoblotting) and insulin receptors mRNA. In addition, among several structurally related thiazolidinediones there was a positive correlation between in vivo antihyperglycemic activity and their ability to increase insulin binding in vitro, suggesting a possible common molecular mechanism for these actions. © 1995 Wiley‐Liss, Inc.
Canine plasma concentration‐cardiovascular effect relationships for bidisomide, a new antiarrhythmic drug, and disopyramide, cibenzoline, and propafenone
Authors: Garthwaite Susan M. , Schmidt Jennifer J. , Hatley Frida R. , Cook Chyung , Frederick Leo G.
Published: January 2005

Bidisomide (SC‐40230) is a unique new antiarrhythmic agent. In this study the canine intravenous (i.v.) antiarrhythmic doses of bidisomide (9 ± 1 mg/kg), disopyramide (8 ± 1 mg/kg), cibenzoline (8 ± 2 mg/kg), and propafenone (6 ± 0.5 mg/kg) were established in a 24 h coronary ligation ventricular arrhythmia model. Based on the canine therapeutic doses of the four agents, three cumulative i.v. doses (load/maintenance infusions) of each of these drugs and placebo were then studied in normal anesthetized dogs to evaluate their general cardiovascular effects. Propafenone (0.7–3.0 μg/ml plasma concentration) caused potent reductions in cardiac output and increases in QRS duration relative to the other agents. Cibenzoline (0.9–7.0 μg/ml) and disopyramide (1.4–12.9 μg/ml), at matched plasma concentrations, caused very similar cardiac output reductions, but cibenzoline caused nearly double the QRS increase. Bidisomide (1.9–16.1 μg/ml) had the least potent effects on cardiac output and QRS duration. All four drugs increased PR and QT in addition to QRS, but only disopyramide and propafenone increased JT (QT‐QRS). These experiments suggest that the antiarrhythmic plasma concentrations of bidisomide, in contrast to those of selected reference agents, do not cause prominent ventricular conduction slowing or prolongation of ventricular repolarization, and in addition, cause only modest hemodynamic effects in normal dogs. © 1995 Wiley‐Liss, Inc.
Esterification improves antiarthritic effectiveness of lupeol
Authors: Kweifio‐Okai George , Field Barry , Rumble Baden A. , Macrides Theodore A. , De Munk Fred
Published: January 2005

Adult male Wistar rats were made arthritic by the subplantar injection of complete Freund's adjuvant. Oral treatment with the triterpenes lupeol, luepol palmitate, or lupeol linoleate (66 mg/kg BW every 2 days) from days 24 to 32 reduced synovial granulomatous growth (proximal interphalangeal foot joints) and its invasion of the synovial cavity and reduced the destruction of articular cartilage and subchondral bone (lupeol linoleate > lupeol palmitate > lupeol). Rats treated with the lupeol esters showed reduced periosteal bone erosion with bone repair in the form of periosteal new bone formation. Arthritic rat blood lymphocytes and serum levels of the joint degradative product, hyaluronate, which increased by 73% and 51%, respectively, were reduced by the triterpenes (lupeol linoleate > lupeol palmitate > lupeol) with lupeol linoleate restoring them to normal values. The antiarthritic effectiveness of lupeol was therefore increased by esterification with the long‐chain fatty acids. © 1995 Wiley‐Liss, Inc.
Caffeic acid prevents liver damage and ameliorates liver fibrosis induced by CCI4 in the rat
Authors: Reyes Maria T. , Mourelle Marisabel , Hong Enrique , Muriel Pablo
Published: January 2005

It has been postulated that during liver damage there is an arachidonic acid metabolism deflection toward lipoxygenase products and a simultaneous decrement of the synthesis of cytoprotective prostaglandins. Accordingly, we have demonstrated that leukotriene synthesis inhibition protects the liver from acute damage induced by CCI4. Thus, the aim of the present work was to study the effect of caffeic acid (a specific 5‐lipoxygenase inhibitor) on liver cirrhosis induced by CCI4 administration in the rat. Caffeic acid prevented significantly the increment of serum markers of liver damage, as well as lipid peroxidation and the depletion in glycogen content of the liver induced by chronic CCI4 intoxication. Collagen content increased fivefold in the CCI4‐treated rats. The group treated with the lipoxygenase inhibitor, in addition to CCI4, showed less collagen content than the group receiving only CCI4 (P ⩽ .05). Caffeic acid prevented liver damage significantly. The hepatoprotective effect of this compound could be attributed to its ability to inhibit 5‐lipoxygenase activity, and thus leukotriene production. © 1995 Wiley‐Liss, Inc.
Inhibition of 36CI− influx and [35S]TBPS binding in the rat brain by leumedins: A novel class of anti‐inflammatory agents
Authors: Jarvis Michael F. , Gant Daniel B. , Gessner George W. , Pendley Charles , Sutherland Charles , Martin Gregory E.
Published: January 2005

The leumedins, a series of N‐(fluorenyl‐9‐methoxycarbonyl) amino acids, are putative anti‐inflammatory agents that have been shown to inhibit leukocyte recruitment into inflammed tissue. While the exact mechanism of action of these agents is unknown, there are some reports suggesting that leumedins selectively block transmembrane ion flux in neutrophils. In order to examine the possibility that the leumedins may interact with chloride transport mechanisms, we evaluated representative leumedins for their ability to interact with the GABA/benzodiazepine chloride ionophore in rat brain. NPC 17923, at micromolar concentrations, was found to compete for 2 nM [35S]TBPS binding (IC50 = 16 μM) and inhibit 36CI— influx (IC50 = 133 μM) in rat brain. Saturation studies indicated that NPC 17923 inhibited [35S]TBPS binding in a noncompetitive fashion. Other less potent leumedins also inhibited [35S]TBPS binding in a concentration‐dependent fashion. The leumedins had no significant activity at other GABA/benzodiazepine recognition sites labeled by [3H]muscimol, [3H]flunitrazepam, or [3H]RO15‐4513. The two most potent leumedins effectively attenuated 36CI— influx into rat brain, while all of the leumedins examined blocked 36CI— influx into guinea pig neutrophils at moderate micromolar concentrations. The present data offer the first demonstration that the leumedins can block chloride flux at the rat brain GABA/benzodiazepine chloride ionophore and in guinea pig neutrophils at similar concentrations required to produce anti‐inflammatory actions on human neutrophils. These results show that while the leumedins can block chloride flux in both neurons and neutrophils, the relative low affinity of the leumedins to produce this effect suggests an apparent nonselective interaction at a number of different chloride transporters similar to that found with the disulfonic stilbene derivative chloride channel blockers. © 1995 Wiley‐Liss, Inc.
Comparative efficacy and safety of intravenous non‐steroidal anti‐inflammatory drugs in two animal models of pain
Authors: Rodriguez Rodolfo , Medina Martha , Rojas Yolanda
Published: January 2005

In this study, the antinociceptive activity of five non‐steroidal anti‐inflammatory drugs (NSAIDs) was determined in two animal models of different pain intensity and compared with their capacity to produce motor incoordination and death. Intravenous clonixine, diclofenac, dipyrone (metamizole), ketorolac, and piroxicam produced dose‐dependent antinociception in the acetylcholine‐induced writhing test with ED50 values ranging from 14 (clonixine) to 205 (dipyrone) μmol/kg. The behavioral responses in the 55°C hot plate assay were also inhibited in a dosedependent manner, but significantly higher doses were required to display antinociceptive activity, the ED50 values ranging from 116 (clonixine) to 2, 263 (dipyrone) μmol/kg. In the writhing test, the antinociceptive effects of NSAIDs were present at doses far below those producing toxic effects. In contrast, their ED50 values against a more intense nociceptive stimulus approached those producing lethal effects so that the therapeutic ratios were very small, ranging from 1.3 (diclofenac) to 3.0 (dipyrone). The antinociceptive activity of the reference drug morphine is striking, since both types of nociceptive responses were eliminated at doses substantially lower than those producing death (therapeutic ratios of 502 and 121). Morphine exhibited the highest antinociceptive efficacy, followed by dipyrone, ketorolac, clonixine, and piroxicam. Diclofenac showed a more limited efficacy. These findings imply potential risks for patients treated iv with this class of drugs and suggest caution in the use of high doses of NSAIDs. Future development of injectable NSAID formulations should include a detailed analysis of adverse reactions following iv administration of high doses. © 1995 Wiley‐Liss, Inc.
Performance of baby monkeys on the Hebb‐Williams closed field maze learning task
Authors: Zimmermann Robert R.
Published: January 2005

Infant monkeys, 15 to 120 days of age, were tested in a Hebb‐Williams maze. Age was a significant variable affecting error scores, and the relationship between age and performance on this test might best be described as U‐shaped. The operation of changing motor and motivational systems appears to be a crucial factor in determining performance of infant monkeys in this task, rather than learning abilities.
The effect of criterion level on the acquisition and retention of a 1‐way avoidance response in young and old rats
Authors: Potash Marc , Ferguson H. Bruce
Published: January 2005

Young (23–25 days old) and adult (80–84 days old (rats) n = 8, per group) were trained on an active‐avoidance task to a criterion of 0, 5, or 15 consecutive correct trials and then tested for retention 30 days later. In original training, both age groups acquired the response in about the same number of trials when the criterion was set at 5/5 but young subjects required significantly more trials than older subjects to learn the response under the 15/15 criterion. In retraining, both age groups performed equally well when original training was to the 15/15 criterion although adults retained significantly better than weanlings when original training was to 5/5 correct responses.
Alleviation of separation distress in 3 breeds of young dogs
Authors: Pettijohn T. F. , Wong T. W. , Ebert P. D. , Scott J. P.
Published: January 2005

Twenty‐four puppies (8 each of Shetland sheepdogs, Telomians, and beagles) served as subjects in this experiment which was designed to examine the effectiveness of 12 stimulus conditions (food, toys, canine contact, and human contact) on alleviation of separation‐induced distress vocalization. Testing consisted of a prestimulus trial, stimulus trial, and post‐stimulus trial each session 3 times a week from 4 to 8 weeks after birth. Overall results showed human contact to be the most effective, followed by canine contact, toys, and food. Breed differences were significant in only 2 of the stimulus conditions. In the typical case of effective treatment, the vocalization rate declined from the prestimulus trial to a low point in the stimulus trial and then increased again in the post‐stimulus trial.
“Impoverished” rats weigh more than “Enriched” rats because they eat more
Authors: Fiala Beverly , Snow Frederick M. , Greenough William T.
Published: January 2005

Net consumption measures indicated that rats reared individually in standard laboratory cages consume more food and water and gain weight more rapidly than do their littermates reared in groups in large toy‐filled cages.
The effect of visual deprivation in the rat on transfer effects after form discrimination training
Authors: Tees Richard C. , Bruinsma Yvonne , Midgley Glenda
Published: January 2005

In 3 experiments the performances of light‐reared (LR) and dark‐reared (DR) 90‐day‐old rats were compared on a variety of transfer tests following acquisition of 3 discriminations involving patterns of small squares (dots). Though no significant difference due to rearing condition was found in acquisition of those discriminations consisting of single lines of dots in various orientations, transfer tests did reveal subtle differences in the way LR and DR rats analyze contour information. Significant differences due to rearing were also observed on the acquisition of a complex dot pattern (∇ vs X) and, in spite of overtraining, on subsequent stimulus equivalence tests. Anomalous transfer effects were not observed in any of these test situations.
Behavioral effects of unilateral basal gangliar lesions in neonatal rats
Authors: Van Hartesveldt Carol , Lindquist David
Published: January 2005

Two‐day‐old rats were given unilateral lesions of the caudate‐putamen, globus pallidus, or hippocampus and their postural orientation was observed for 30 min immediately after surgery. All groups with damage to the caudate‐putamen and/or globus pallidus showed a significant postural deviation toward the side ipsilateral to the lesion. At this age, neurogenesis in the basal ganglia is complete but synapses, neurotransmitters, and enzymes for neurotransmitter synthesis are far below adult levels. These results indicate that the basal ganglia have a role in motor function prior to their full maturation as measured by neuroanatomical and biochemical techniques.
Effects of undernutrition and litter size on material variables and pup development
Authors: Jen Kai‐Lin Catherine , Wehmer Francine , Morofski Jan
Published: January 2005

Differential effects of maternal nutrition and litter size variation were examined in a 2 × 2 factorial design in which undernourished or ad lib fed mothers nursed litters of 4 or 12. Litter size accounted for a greater proportion of pup body weight at weaning than did maternal nutrition. When the mother was fed ad lib, birth weight of individual pups and later body weight were correlated regardless of litter size. When the mother was undernourished, these correlations were not found. Enlargement of litter size increased the pup weight coefficient of variability only when the mother was fed ad lib. Size of the litter did not influence the maternal variables under study: open field behavior, adrenal weight, and body weight.
The ontogeny of exploration in the rat: Habituation and effects of handling
Authors: File Sandra E.
Published: January 2005

Exploration, measured by head‐dipping in a holeboard, was tested in male rats at 16, 21, 28, 56, and 84 days of age. Headdipping increased with increasing age from Day 16 to Day 84, and so did the number of rears made. At all ages handled rats showed more head‐dipping and made more rears than did their unhandled litter‐mates. The age differences in exploration cannot be explained by different patterns of habituation: rats showed significant within‐session habituation of head‐dipping at all ages tested (Days 16, 21, and 28). Day 16 rats also showed significant between‐session habituation.
The interstimulus interval in classical autonomic conditioning of young infants
Authors: Ingram Eben M.
Published: January 2005

Conditioned auditory discrimination and extinction of the skin potential response were attempted in 4‐month‐old infants using interstimulus intervals of 1500, 3500, 5500, and 7500 msec. Half of the infants in each of the interstimulus interval groups were defined as high magnitude orienters and half were low magnitude orienters. Conditioning was successful with the 5500‐ and 7500‐msec interstimulus intervals, but not with the 1500‐ and 3500‐msec intervals. Analysis of individual subject data indicated that individual differences in conditionability were related to interstimulus interval and orienting response magnitude. Also, those subjects discriminating at the longer intervals tended to be high magnitude orienters. In other words, longer interstimulus intervals interacted with a high magnitude of orienting to facilitate conditioning. The results were taken as evidence that individual differences in the magnitude of the orienting response reflect different individual needs in stimulus information processing time.
Directional responses by kittens to an auditory stimulus
Authors: Clements Maureen , Kelly Jack B.
Published: January 2005

Six kittens were tested in a 2‐choice maze to determine if they would execute directional approach responses to an auditory stimulus. Tests were done at various postnatal ages (4–10, 11–17, 18–24, and 25–31 days) and comparison was made with responses of 5 kittens tested without auditory stimulation. At the earliest ages no evidence was seen for auditory approach responses but by 18–24 days consistent approach responses were found.
Vocalization in the cat and kitten
Authors: Brown Kenneth A. , Buchwald Jennifer S. , Johnson Judith R. , Mikolich Dennis J.
Published: January 2005

Vocal responses of kittens and mature cats were recorded in a variety of standard behavioral situations. Sonographic analysis of these responses showed similarities of responses obtained repeatedly from different cats within each recording situation. Marked differences in responses patterns were noted in different recording situations. The kitten and cat vocal repertoires thus include a variety of specific responses to particular motivational or behavioral circumstances.
Sensory regulation of maternal behavior in rats: Effects of pup age
Authors: Stern Judith M. , Mackinnon Diane A.
Published: January 2005

Maternal behavior (retrieving, crouching, and licking) was induced in Sprague‐Dawley virgin female rats by constant exposure to pups aged 1‐2, 3‐4, 5‐6, 7‐8, 9‐10, 11‐12, 13‐14, or 15‐16 days. The incidence of spontaneous components of maternal behavior, notably retrieving, was geater towards pups 1‐8 days of age than towards older pups, whereas the occurrence of cannibalism did not differ as a function of pup age. With pups 1‐2 through 13‐14 days, the latency to onset of full maternal behavior was shortest with 1‐2‐day‐old pups (2‐day median) and longest with 13‐14‐day‐old pups (7‐day median). Females exposed to pups aged 3‐4 through 11‐12 days did not differ significantly in their latencies, the medians of which ranged from 4.0 to 5.5 days. Only 1 female out of 8 exposed to pups aged 15‐16 days became fully maternal, but 5 more displayed components of maternal responsiveness. The optimal nature of neonates and the general attractiveness of a wider range of pup ages as stimuli for the elicitation of maternal behavior in rats, as well as comparisons to mice and hamsters, were discussed.
Effects of rearing in different environments on subsequent environmental preference in rats
Authors: Will Bruno , Pallaud Berthille , Ungerer Arielle , Ropartz Philippe
Published: January 2005

Environmental preference of male rats reared during 2 months after weaning either in a complex and changing environment (EC) or in empty laboratory cages (SC) was assessed in 4 different experiments. For 2 weeks after differential rearing, rats were placed in groups of 6 in testing cages which were divided into 2 compartments with communicating holes. One of these compartments was empty; the other contained 6 objects (complex compartment). Daily, 3 objects were moved from 1 compartment to the other and replaced by new ones. The preference for any of the compartments was chiefly assessed by the localization of feces (Experiments I and II) and directly by the localization of the animals through videorecording (Experiments III and II) and directly by the localization of the animals through videorecording (Experiments III and IV). Both EC and SC rats showed a significant preference for the empty compartment during both light and dark portions of the daily cycle, but particularly during the light portion. Moreover, EC and SC animals differed from one another in that the SC rats showed a stronger preference for the empty compartment than the EC rats, especially when active. General preference for the empty compartment seemed to diminish slowly, but EC and SC rats tended to remain distinct in habitat selection, at least during the period tested. This behavioral difference, tentatively interpreted in terms of neophobia, might constitute a possible mechanism for automaintenance of differential rearing effects.
Long‐term effects of propylthiouracil‐induced neonatal hypothyroidism
Authors: Schalock R. L. , Brown W. J. , Smith R. L.
Published: January 2005

Hypothyroidism was induced in neonatal Sprague‐Dawley rats by adding propylthiouracil to the lactating female's food and water. Behavioral evaluation on a 6‐item battery occurred from 70 to 114 days of age. Results indicated long‐lasting behavioral changes in the neonatal hypothyroid animals characterized by increased activity and decreased performance on avoidance and escape learning. Serum thyroxine levels were reduced in the hypothyroid animals throughout the 120‐day period. Experimental animals also had fewer synaptic contacts in the cerebellar cortex when analyzed at 90 days of age.
Role of the nursing order in social development of mountain lion kittens
Authors: Pfeifer Sharon
Published: January 2005

Early patterns of social interaction, including fighting while nursing, social grooming, and social play, were analyzed in a litter of mountain lion kittens to determine if interactive patterns formed during nursing persist into subsequent social stages (i.e., social grooming and social play). The data suggest that the nursing order established by mountain lion kittens has an important role in early social development by initially directing interactive patterns among littermates.
The ontogenesis of defensive reactions to shock in preweanling rats
Authors: Collier Alexis C. , Bolles Robert C.
Published: January 2005

Behavioral observations were made on the reaction to tailshock and footshock in 5‐ to 20‐day‐old hooded rats. For detection thresholds, age differences were found for footshock but not for tailshock. During intershock intervals, more generalized activity and freezing were elicited by footshock, whereas more responding directed to the shock source was elicited by tailshock. The unconditional responding to shock indicated that the older animals had a larger behavioral repertoire of defensive reactions and responded differentially to different shock intensities. The younger animals appeared to have a more limited and stereotyped repertoire of defensive reactions and to be more sensitive to the same nominal shock level. These normative data should prove useful in evaluating motivational and response repertoire problems when assessing learning processes developmentally.
A model for development of social behavior in vervet monkeys
Authors: Bramblett Claud A.
Published: January 2005

Polynomial regression was used to construct linear descriptive models for age‐related behavioral changes among socially‐living, captive vervet monkeys. Seventeen social acts were divided by gender into performer (director) and recipient to produce 68 predictive equations. The aptness of these models was examined by an analysis of residuals, including a lack‐of‐fit F test. Consistency was further validated by a sign test comparison of predicted and observed means. A log10 (Y + 1) transformation produced satisfactory fits for 51 of the 68 parameters. Only 1 behavior (male gape D) had a nonsignificant cumulative F value and low coefficient of multiple determination. Although the remaining 16 acts did show age relationships, they exhibited a significant lack of fit to the proposed model. A table of predictive equations is presented as a mathematical model of behavioral development in vervet monkeys.
The effects of social isolation on the behavior of juvenile domestic cats
Authors: Guyot Gary W. , Bennett Thomas L. , Cross Henry A.
Published: January 2005

The effects of social isolation on the behavior of juvenile domestic cats were assessed by rearing 4 male and 4 female infant kittens in each of the following rearing conditions: (1) mother‐littermate; (2) mother‐only; (3) brooder‐littermate; and (4) brooder‐only. They were then tested twice a week individually and twice a week socially from 2 to 6 1/2 months of age in a playroom, utilizing multiple categories of behavior. The mother‐only‐reared juveniles were hyperactive in both object play (when tested individually) and social play. The brooder‐only‐reared kittens displayed enhanced socially directed behavior and were generally hypergregarious, whereas the brooder‐littermate‐reared kittens displayed retarded social behavior. Observations indicated that littermate‐deprived kittens did not learn social communication skills and that some prolonged separation effects existed for littermate‐reared kittens. The results suggest that the determinants of social play are more complex than the determinants of object play.
Gender differences in visual discrimination by rats in response to malnutrition of varying durations
Authors: Galler Janina R. , Manes Michael
Published: January 2005

Visual discrimination of hooded rats was tested at 3 months of age by a Lashley procedure. Three groups of rats were used: those with histories of protein deprivation for up to 20 generations, those with protein deprivation for a single generation, and well‐nourished controls. Growth retardation was present to a similar degree in both genders of the 2 malnourished groups. Deficits in visual discrimination were observed in female animals with intergenerational malnutrition, but not in females with single‐generation malnutrition. Males with intergenerational and single‐generation malnutrition showed equal deficits in visual discrimination. These findings demonstrate that the performance of female rats is impaired only after prolonged exposure to malnutrition, whereas males are vulnerable after shorter periods.
Early perceptual selectivity in the swamp sparrow
Authors: Dooling Robert , Searcy Margaret
Published: January 2005

The cardiac orienting response to species‐specific songs was measured in young swamp sparrows and song sparrows. Swamp sparrows respond with significantly greater deceleration to conspecific songs than to songs of the sympatric song sparrow. This discriminatory ability is operating during the sensitive period for song learning and is evident upon initial exposures to conspecific song. These results are the 1st direct evidence for a sensory component in the process of selective vocal learning in birds.
Gender and early environmental influences on activity, overresponsiveness, and exploration
Authors: Joseph Rhawn , Gallagher R. E.
Published: January 2005

One hundred eighty‐five rats reared in either an enriched or restricted environment were tested during adulthood to determine the influence of gender and rearing environment on 3 related response characteristics, activity, overresponsiveness, and exploratory behavior. Eight experiments were performed. It was found that although females are more active than males, rearing environment does not influence behavior in the running wheel or open field. When tested in a complex compartmentalized open field, females in general and restricted rats are significantly more active than enriched males. In addition, over subsequent testing, restricted animals are increasingly responsive and fail to habituate to the testing stimuli. When tested and retested for maze learning ability, males excel over females; enriched rats maintain their ability to outperform restricted rats, although both groups had previously learned the problem. Moreover, enriched rats demonstrate a greater tendency to explore and make irrelevant section entries on a maze that is problem free. Restricted rats, specifically, and females generally, have difficulty suppressing a learned repetitious pattern of rewarded responding when it is subsequently punished; restricted rats were deficient in the ability to passively avoid or escape noxious stimuli. These experiments, as well as supporting evidence in the literature, indicate that rats reared in a restricted environment develop a limited behavioral repertoire which is characterized by a generalized tendency to overrespond, a propensity towards perseverating in repetitious patterns of limited and circumscribed responding, and a failure to habituate to repeated contact with novel stimuli.
Peer and maternal influences on the expression of foot‐clasp mounting by juvenile male rhesus monkeys
Authors: Wallen Kim , Goldfoot David A. , Goy Robert W.
Published: January 2005

The display of adultlike foot‐clasp mounts by male rhesus monkeys occurs during the 1st year of life in animals reared with their mothers in social groups where peer interaction is possible 24 hr per day. In contrast, this form of mount is rarely displayed if infants are separated from their mothers at 3 months of age and allowed daily. 5‐hr periods for peer interaction. To distinguish between maternal and peer access‐time influences upon the development of this response, we housed rhesus monkeys with their mothers and allowed either. 5‐hr or 24‐hr daily access to peers in the presence of their mothers during the 1st year of life. Male infants restricted to .5‐hr periods with peers rarely or never foot‐clasp‐mounted peers, although 3 of 6 males foot‐clasp‐mounted their mothers. In contrast, males given 24‐hr access to peers regularly mounted peers using the foot‐clasp mount. Males from the 2 groups did not differ in total frequencies of all mount types displayed, only in the display of foot‐clasp mounts. After maternal separation at the end of the 1st year, rearing effects on the display of mounting persisted into the 2nd year. Males that received 24‐hr daily peer access during the 1st year continued to foot‐clasp‐mount peers whereas .5‐hr males failed to do so, indicating that the experience of mounting one's mother with the adult posture was not sufficient to support peer‐oriented foot‐clasp mounting at a later age. In addition to deficits in peer‐oriented foot‐clasp mounting, .5‐hr infants displayed higher frequencies of threat and withdrawal behaviors to peers and presented to peers less frequently than did infants from the 24‐hr rearing condition. These results contradict a motor deficiency hypothesis to account for the rare display of foot‐clasp mounts to peers by males receiving .5‐hr daily access to peers during the 1st year of life. Instead, data support the view that .5‐hr animals either failed to develop positive response patterns necessary for the execution of the foot‐clasp mount, or learned negative patterns of social interaction that prevented the display of this cooperative behavior.
Home‐orienting behavior in rat pups: The effect of 2 and 3 generations of rehabilitation following intergenerational malnutrition
Authors: Galler Janina R. , Seelig Cheryl
Published: January 2005

In an earlier study in this laboratory, we examined home‐orienting ability in rats with histories of intergenerational malnutrition that were rehabilitated postnatally with an adequate protein diet (Galler, 1979). Despite increased size and activity, 1st‐generation rehabilitated pups showed no improvement in homing ability when compared to malnourished pups. In the current study, offspring of rats with intergenerational malnutrition were rehabilitated for 2 additional generations and tested for homing ability from postnatal Day 4 through Day 12. The pups rehabilitated for 2 and 3 generations did not perform as well as control pups, even though growth and activity returned to normal levels. Furthermore, the rehabilitated pups failed to demonstrate any preference for the nest on all days of testing; in contrast, control pups favored the nest quadrant by Day 8 of life. No significant improvement was evident on any measure from the 2nd to the 3rd generation of rehabilitation.
Effect of cross‐rearing on species identification in zebra fish and pearl danios
Authors: McCann Lee I. , Carlson Canute C.
Published: January 2005

Zebra fish and pearl danios were either cross‐reared or raised with conspecifics and tested as adults for species preference over 4 days. Subjects were then placed with conspecifics by group for 30 days and retested over 2 days. Initial testing showed less preference (species identification) for conspecifics by cross‐reared subjects and less conspecific preference by pearls than zebras. At retesting pearls showed a great increase in preference for conspecifics whereas zebras showed little change.
Brainstem‐evoked responses of guinea pigs exposed to high noise levels in utero
Authors: Cook Reginald O. , Konishi T. , Salt A. N. , Hamm C. W. , Lebetkin E. H. , Koo J.
Published: January 2005

Pregnant guinea pigs were exposed to loom room noise at 115 dB A for 7.5 hr/day for various periods during the last one‐third of pregnancy. When the hearing of their offspring was tested by auditory brain stem‐evoked response techniques at 6‐dB intervals, peak IV latencies of exposed pups were found to be significantly longer than those of otherwise similar control pups. The latency differences corresponded to a 5‐dB increase in stimulus at medium stimulus levels and 10–12 dB near threshold. The results indicate that it is possible for noise‐induced hearing loss to occur in utero in mammals whose auditory maturation process is complete, or nearly so, before birth.
Generalization after form discrimination in light‐reared and dark‐reared rats
Authors: Tees Richard C. , Midgley Glenda , Nesbit John C.
Published: January 2005

In 2 experiments the performance of 90‐ and 150‐day‐old light‐reared and dark‐reared rats was compared under appetitive reinforcement conditions on rigorous tests of form discriminative abilities. Although early stimulatory history had little impact on either the ability to discriminate shapes on the basis of contour orientation or to generalize from that initial experience to lines in other orientations, lack of visual experience did have significant consequences with respect to a comparable task in which the relationship between lines was the significant feature. Little change in the initial deficits was observed with exposure to a normal light environment for 60 days following the period of early visual deprivation in the case of this 2nd complex pattern discrimination task.
Differential effects of upper gastrointestinal fill on milk ingestion and nipple attachment in the suckling rat
Authors: Lorenz Dennis N. , Ellis Susan B. , Epstein Alan N.
Published: January 2005

Milk intake and nipple attachment behaviors were studied in the natural suckling situation after gastrointestinal preloading. Rat pups, deprived of their dam for 9 hr at 1, 10, or 20 days of age, were preloaded by gavage with volumes ranging from 2 to 16% of their body weight and returned to suckle. Preloads of artificial bitch's milk decreased the intake of mother's milk in a volume‐related manner at all ages. At 1 and 10 days 4% preloads decreased milk intake without affecting attachment behaviors; larger prelods of 8 and 16% decreased intake and reduced the incidence of attachment. At 20 days of age small and large preloads decreased both incidence of attachment and milk intake. Preloads up to 8% of body weight had no effect on latency to attach at any age.

Complete subdiaphragmatic bilateral vagotomy increased milk intake of 7–9–day‐old pups fed automatically through an anterior mouth cannula in a nonsuckling situation. Vagotomy combined with spinal cordotomy (T2‐T3) resulted in a synergistic hyperphagia and massive distension of the upper GI tract.

The results indicate that suckling rats can control their intake of mother's milk while remaining attached to a nipple as early as 1 day of age. The suppression of ingestion in response to GI filling appears to be mediated by visceral afferent activity. Conversely, attachment behaviors are less affected by GI fill. This suggests that ingestive behaviors and attachment behaviors have different controls during the 1st 10 days of postnatal development.
Effects of body build and arousal on newborn infant stepping
Authors: Thelen Esther , Fisher Donna M. , Ridley‐Johnson Robyn , Griffin Nora J.
Published: January 2005

Newborn stepping is widely believed to be a “primitive reflex” whose disappearance signals cortical maturation. Observations of normal newborns showed that the number of steps was directly related to generalized behavioral arousal. In less highly distressed infants, those who were relatively heavier for their length stepped less. These results challenge the view that stepping is reflexively released by the upright posture and support the hypothesis that the movements disappear because infants' muscle strength may not be sufficient to lift their increasingly heavy legs.