bluuebunny/crossref_metadata_2025 huggingface dataset:
Nicotinic potentiation of glutamatergic synapses in the prefrontal cortex: New insight into the analysis of the role of nicotinic receptors in cognitive functions
Authors: Vidal Catherine
Published: January 2005

In contrast with the now well‐recognized effects of nicotine in promoting learning and memory, little is known about the functional and pharmacological properties of putative nicotinic acetylcholine receptors located in neocortical areas involved in cognitive functions. Recent electrophysiological experiments using intracellular recordings in the rat prefrontal cortex in vitro have revealed that nicotine selectively enhances the amplitude of excitatory postsynaptic potentials mediated by glutamate in pyramidal cells. The effect was blocked by the specific nicotinic antagonists neuronal bungarotoxin and dihydro‐β‐erythroidine. Several arguments suggest that the potentiation of excitatory potentials by nicotine is due to the activation of presynaptic nicotinic receptors located on glutamatergic afferent terminals. Thus the control by nicotinic receptors of the effectiveness of excitatory inputs to the prefrontal cortex might influence significantly the processing of information in this area. The possibility of a functional cooperation between nicotinic and glutamatergic systems in the neocortex provides an integrative mechanism for the involvement of both neurotransmitter systems in synaptic plasticity underlying memory processes. © 1994 Wiley‐Liss, Inc.
Structure activity relationships for derivatives of adenosine‐5′‐triphosphate as agonists at P2 purinoceptors: Heterogeneity within P2x and P2y subtypes
Authors: Burnstock Geoffrey , Fischer Bilha , Hoyle Charles H. V. , Maillard Michel , Ziganshin Airat U. , Brizzolara Antonia L. , von Isakovics Amy , Boyer José L. , Harden T. Kendall , Jacobson Kenneth A.
Published: January 2005

The structure‐activity relationships for a variety of adenine nucleotide analogues at P2X and P2Y‐purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N6‐substituents, and a uridine base instead of adenine), the ribose moiety (2′ and 3′‐positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P2Y‐purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P2X‐purinoceptors was assayed in the rabbit saphenous artery and the guinea‐pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P2X‐ or the P2Y‐purinoceptors. Certain analogues displayed selectivity or specificity within the P2X‐ or P2Y‐purinoceptor superfamilies, giving hints about possible subclasses. For example, 8‐(6‐aminohexylamino)ATP and 2′,3′‐isopropylidene‐AMP were selective for endothelial P2Y‐purinoceptors over P2Y‐purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P2X‐purinoceptors. The potent agonist N6‐methyl ATP and the somewhat less potent agonist 2′‐deoxy‐ATP were selective for P2Y‐purinoceptors in the guinea pig taenia coli, but were inactive at P2X‐purinoceptors and the vascular P2Y‐purinoceptors. 3′‐Benzylamino‐3′‐deoxyATP was very potent at the P2X‐purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P2X‐ and P2Y‐purinoceptor classes. © 1994 Wiley‐Liss, Inc.
Cardiovascular effects of nicorandil and nitroprusside in furosemide plus digoxin pretreated dogs
Authors: Humphrey Stephen J.
Published: January 2005

In support of human congestive heart failure (CHF) trials, the cardiovascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG). In anesthetized control dogs, iv NP (2–19 μg/kg/min) and NIC (24–105 μg/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) BY 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DIG's plasma concentrations were unaffected by adjunctive NIC infused for 2.5 h at a mean 17 μg/kg/min iv. No untoward interactions were seen with any combination. In conscious dogs, the hypotension and tachycardia seen with iv NP (2–20 μg/kg/min) and NIC (20–160 μg/kg/min) were also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0.0125 mg/kg/day), with no intolerance. Repeated oral NIC (7.5 mg/kg/day × 3 days) in these chronic FURO + DIG dogs ws consistently hypotensive but steadily more tachycardiac. This study offers a prototype of 3‐way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC and NP in dogs.
Status of safety pharmacology in the pharmaceutical industry, 1993
Authors: Kinter Lewis B. , Gossett Kent A. , Kerns William D.
Published: January 2005

General pharmacology and safety pharmacology studies are of considerable value in drug discovery and safety assessment. The knowledge gained from these studies adds mechanistic perspectives and functional dimensions to contemporary animal pharmacology and toxicology studies. If conducted prior to initiation of drug development activities, general pharmacology and safety pharmacology studies can assist in the selection of drug classes and specific candidates for drug development, and contribute to selection of rational high doses for chronic toxicity studies. If conducted prior to initiation of clinical safety studies, these studies can influence the design of clinical protocols so that appropriate strategies are put in place to ensure appropriate patient management and care. Finally, general pharmacology and safety pharmacology studies can provide an important communication pathway between the non‐clinical and clinical segments of a drug development program.
Estimating protein function from combinatorial sequence data using decision algorithms and neural networks
Authors: Goldman Ellen R. , Füllen Georg , Youvan Douglas C.
Published: January 2005

Correlations between protein sequences and phenotypes were explored using databases of combinatorial cassette mutants of pigment‐protein complexes. Heuristically formulated decision algorithms and computer implemented neural networks were compared to determine their accuracy in classification of phenotypic categories. For the databases examined, decision algorithms employing very simple rules were able to properly classify mutants 80–84% of the time, based only on the amino acid sequence of the mutagenized region. Such decision algorithms did not require the formulation of any rules that involved site‐to‐site interactions, but rather, performed well based on the stringency of specific critical sites in the protein that accept only a restricted set of amino acids. In some cases, neural networks scored almost 10% higher than decision algorithms on the same databases (i.e., 94%). However, the success of the primitive decision algorithms and perceptrons at sorting sequences into categories suggests that linear effects predominate in the classification of a mutant's phenotype. Such methods should be generally applicable to the broad spectrum of databases that are currently being generated in combinatorial chemistry and biology experiments. © 1994 Wiley‐Less, Inc.
Ca2+ channel toxins: Tools to study channel structure and function
Authors: Saccomano Nicholas A. , Ahlijanian Michael K.
Published: January 2005

A remarkable diversity of voltage‐dependent Ca2+ channels exists in the mammalian nervous system to subserve the broad and complicated roles that impulse‐generated changes in intracellular Ca2+ play in neuronal functions such as synaptic transmission, cell firing, gene expression, and related functional sequelae. A detailed understanding of how such temporally and subcellularly restricted changes in intracellular Ca2+ affect cellular and synaptic function requires selective pharmacological tools that can specifically dissect one channel apart from the operating neuron or neuronal system. A set of selective reagents currently available to the Ca2+ channel pharmacologist or physiologist has been provided by a variety of predatory animals from disparate phylogenetic origins. It is fortunate that these creatures invested in countless years of toxin engineering providing essential implements which otherwise might have been obtained only through an enormous effort on the part of current‐day scientists. This review will offer a discussion of the current understanding of the pharmacology and chemistry of important Ca2+ channel toxins in the context of the growing field of neuronal Ca2+ channel structure and function. © 1994 Wiley‐Liss, Inc.
Lifibrol increases hepatic cholesterol 7α‐hydroxylase activity in sprague‐dawley rats
Authors: Dinh Dac M. , Michael Funk G. , Vidmar Thomas J. , Spilman Charles H.
Published: January 2005

The hypocholesterolemic drug lifibrol was administered orally to Sprague‐Dawley rats to determine its effects on lipoprotein cholesterol distribution and hepatic HMG‐CoA reductase and cholesterol 7α‐hydroxylase activities. The effects of lifibrol on those endpoints were compared with the effects of gemfibrozil and lovastatin. When administered to either chow‐fed or cholesterol‐fed rats, lifibrol (25 or 50 mg/kg/day) caused a redistribution of lipoprotein cholesterol such that HDL increased and VLDL + LDL decreased significantly. Gemfibrozil (30 or 50 mg/kg/day) caused similar changes in lipoprotein cholesterol distribution. In contrast, lovastatin (10 mg/kg/day) decreased both HDL and VLDL + LDL in chow‐fed animals, but had no effect in cholesterol‐fed animals. Hepatic HMG‐CoA reductase activity was increased in rats treated with lifibrol (50 mg/kg/day), gemfibrozil (50 mg/kg/day), and lovastatin (10 mg/kg/day). The most significant finding is that lifibrol was the only drug that increased hepatic cholesterol 7α‐hydroxylase activity. This observation in rats separates the mechanism of action of lifibrol from those of the HMG‐CoA reductase inhibitors and the fibrates, and suggests that one mechanism of action of lifibrol is to enhance cholesterol elimination through conversion to bile acids. © 1994 Wiley‐Liss, Inc.
Expression and characerization of human kainate receptor subunits in Escherichia coli and mammalian cells
Authors: Foldes Robert L. , Fantaske Robert P. , Korczak Bozena , Hoo Ken H. , Nutt Stephen L. , Kamboj Rajender K.
Published: January 2005

Cellular expression systems for human kainate receptor subunits (EAA1 and EAA2) have been developed as tools to support drug screening and rational drug design. EAA1 and EAA2 sequence‐specific polyclonal antibodies were generated to characterize polypeptide expression on introduction of appropriate plasmid expression constructs to Escherichia coli (E. Coli), chinese hamster ovary (CHO) and human embryonic kidney (HEK‐293) cells. A polypeptide with an apparent molecular mass of ∼ 120 kilodaltons (kDa) was identified by Western blot analysis in CHO and HEK‐293 cells expressing EAA2. Three major immunoreactive bands of 116, 110, and 90 kDa were identified in HEK‐293 cells expressing EAA1. The polyclonal antibodies will allow the direct determination of EAA1 and EAA2 expression in human brain. Pharmacological characterization of a stable CHO cell line expressing EAA2 revealed a dissociation constant for kainate (KD) of 1.92 ± 0.28 nM (n = 3). This is the first report describing a stable cell line expressing EAA2 and the third report describing a stable cell line expressing a human glutamate receptor subunit. These studies are an important prelude to discovery of EAA1 and/or EAA2 specific drugs. © 1995 Wiley‐Liss, Inc.
Pharmacological antagonism of α‐adrenergic agonist induced increases in canine intraurethral pressure in vivo
Authors: Brune Michael E. , Buckner Steven A. , Polakowski James , Kerwin James F. , Hancock Arthur A.
Published: January 2005

Treatment with α1 antagonists represents a pharmacological alternative to surgery for the treatment of urinary obstruction associated with benign prostatic hyperplasia (BPH). A minimally invasive method to measure elevation of prostatic urethral tone through a urethral catheter was used to study the effects of α‐adrenoceptor agonists and antagonists on canine intraurethral pressure (IUP). α1‐adrenoceptor agonists, but not α2 agonists, elicited elevations in IUP. The contractile response was primarily the result of prostatic smooth muscle contraction, since it was of smaller magnitude in female dogs or in male dogs outside of the prostatic urethra. The contractile responses to epinephrine obtained in the absence of antagonist on the same or different test dates were highly reproducible in dogs greater than 2 years of age. The increase in IUP caused by epinephrine was specifically antagonized by α1‐adrenoceptor antagonists, in direct proportion to their potency in isolated canine prostatic strips in vitro and in proportion to their affinity at receptors determined in radioligand binding assays in vitro. These data confirm the role of α1‐adrenoceptors in canine prostatic smooth muscle contraction and this relatively non‐invasive in vivo model will allow the study of novel compounds for their effects on canine prostatic tone. © 1995 Wiley‐Liss, Inc.
Intranasal delivery of human growth hormone: Optimization of formulation
Authors: Albertsson‐Wikland Kerstin , Hedin Lars , Jansson Peter , Rosberg Sten , Wikström Conny
Published: January 2005

Ten different formulations of recombinant human growth hormone (hGH) and a permeation enhancer of the nasal mucosa, sodium tauro‐24,25‐dihydrofusidate (STDHF) were administered intranasally (i.n.) to ten patients with classical GH deficiency. The formulations contained three variables: the hGH content (2, 4.1, or 6.3 mg = 4, 8.25, or 12.5 IU), the concentration of STDHF (0.75, 1, or 1.25%) and the spray volume (2 × 35, 2 × 53, or 2 × 70 m̈l). The influence of these variables on the bioavailability of hGH after i.n. administration and the local (nasal) irritation were assessed. The bioavailability was measured as the plasma concentration of hGH obtained by blood sampling, prior to and at frequent intervals for up to 5 h after administration. The effects on the nasal mucosa were evaluated by nasal inspections before and after each administration and also by using a self‐rating protocol to estimate the nasal sensations for each dose. The influences of the three variables (hGH content, STDHF concentration, and spray volume) on the bioavailability of hGH were analyzed by analysis of variance and multivariate statistical analysis being a useful way to evaluate multiple factors in pharmaceutical preparations with a limited number of observations in early clinical trials. This study demonstrates that formulations with low spray volumes (2 × 35 m̈l) resulted in a lower uptake of hGH and somewhat less inter‐individual variability compared to larger volumes (2 × 53, 2 × 70 m̈l) and that the concentrations of STDHF (0.75, 1, or 1.25%) had no significant effect on the bioavailability. The higher concentrations of STDHF were accompanied by more intense nasal sensations even if none of the formulations resulted in any damage of the nasal mucosa as determined by nasal inspections.
OHM3597: A novel fentanyl derivative with morphine‐like behavioral effects in rhesus monkeys
Authors: France Charles P. , Carr Daniel J. J. , Brockunier Linda L. , Bagley Jerome R.
Published: January 2005

OHM3597, a fentanyl‐like piperidine with a thalidomide‐like moiety, was studied in rhesus monkeys for its behavioral effects and for its effects on lipopolysaccharide (LPS)‐induced production of tumor necrosis factor (TNF)‐α, OHM3597 had morphine‐like discriminative stimulus effects that were antagonized by naltrexone in a manner that was consistent with μ receptor mediation. OHM3597 also had antinociceptive effects, producing a maximal (20 sec) antinociceptive effect in a tail withdrawal procedure with a 50°C stimulus. This effect of OHM3597 also was antagonized by naltrexone in a dose‐related manner. Behavioral effects of this fentanyl derivative had a rapid onset and a relatively short duration of action; discriminative stimulus effects were evident 3 min after subcutaneous (sc) administration of 0.32 mg (0.58 μM)/kg of OHM3597 and the duration of antinociceptive effects produced by 1.0 mg (1.6 μM)/kg (sc) was less than 90 min. OHM3597 also was compared to thalidomide for its effects on LPS‐induced TNF‐α production in peripheral blood mononuclear cells that were obtained from drug‐naive rhesus monkeys. Thalidomide suppressed the production of TNF‐α in a concentration‐dependent manner with concentrations of 10 nM and 1 μM of thalidomide decreasing TNF‐α levels to 81 and 65%, respectively, of control (saline) values. In contrast, up to a concentration of 1 μM, OHM3597 failed to suppress LPS‐induced TNF‐α production. These results demonstrate OHM3597 to be a potent, morphine‐like opioid with a relatively short duration of action. Although OHM3597 did not alter TNF‐α production, a compound with both antinociceptive and immunomodulatory effects might be available within this chemical series and could provide a unique approach to the concurrent treatment of pain and infectious disease. © 1995 Wiley‐Liss, Inc.
Facilitating effects of SR 57746A on short‐term memory in an operant delayed alternation task in aged rats
Authors: Roux Sylvain , Hubert Isabelle , Wettstein Joseph G. , Soubrié Philippe , Le Fur Gérard , Porsolt Roger D.
Published: January 2005

The effects of SR 57746A during acquisition and on stabilized performance of a delayed alternation task in a Skinner Box (Model E 10.10, Coulbourn Instruments, Lehigh Valley, PA) were investigated in aged rats (22–26 months old). Test sessions consisted of repeated trials during which animals were first presented with a single lever (left or right) followed several seconds later by two levers. A press on the lever opposite to that presented previously (delayed alternation) was rewarded. The number of correct responses and the reaction times to the one‐ and two‐lever presentations were recorded. SR 57746A (0.3 and 3 mg/kg p.o.) was first evaluated during the acquisition of the delayed alternation, given before each of 10 daily acquisition sessions to different groups of aged animals. The imposed delay was 5 sec. Afterward, training continued without drug until asymptotic performance was reached. Rats were then given repeated drug test sessions during which different intervals (5, 10, and 20 sec) were presented in a random order. During this phase, both young and aged animals received all the different treatments (SR 57746A at 0.3, 1, and 3 mg/kg and vehicle p.o.). Aged animals showed clear deficits during both acquisition and stabilized performance phases. SR 57746A, particularly at the highest dose tested (3 mg/kg p.o.), clearly increased response accuracy of aged animals both during acquisition of the delayed alternation and during stabilized performance. In the latter phase, the facilitation of response accuracy was observed only in conditions (10 sec retention delay) where aged animals showed a deficit compared with young animals. SR 57746A did not affect response accuracy during stabilized performance in young animals at any delay. The drug‐induced increase in response accuracy in aged animals occurred at a dose of SR 57746A (3 mg/kg p.o.) that lengthened reaction times, particularly simple reaction times, during both acquisition and stabilized performance and also lengthened reaction times in young animals during the stabilized performance phase. These results suggest that SR 57746A specifically attenuates age‐related short‐term memory impairment in rats. © 1995 Wiley‐Liss, Inc.
Adenosine A1 receptors in rat brain synaptosomes: Transductional mechanisms, effects on glutamate release, and preservation after metabolic inhibition
Authors: Abbracchio Maria P. , Brambilla Roberta , Camisa Manuela , Rovati G. Enrico , Ferrari Rosaria , Canevari Laura , Dagani Fiorenzo , Cattabeni Flaminio
Published: January 2005

Synaptosomes from various rat brain areas show saturable and specific binding to an adenosine A1 receptor ligand [Dagani et al. (1993): Drug Dev Res 28:359–363]. In this study, the functional correlates of these receptors were characterized in rat hippocampal synaptosomes by evaluating the ability of the adenosine analogue cyclo‐pentyl‐adenosine (CPA) to modulate KCI‐ and veratridine‐induced glutamate outflow. CPA concentration‐dependently reduced both depolarization‐induced glutamate release and the associated increases of intrasynaptosomal Ca2+ concentrations. Maximal reduction by 100 μM CPA (30% and 40% with respect to control for veratridine‐ and KCI‐induced release, respectively) was completely antagonized by the xanthine adenosine receptor blocker bamyfilline, confirming the involvement of adenosine A1 receptors. CPA selectively affected outflow of glutamate, with no significant influence on release of aspartate or GABA. Experiments performed in the absence of extrasynaptosomal Ca2+ ions suggested that adenosine selectively modulates glutamate Ca2+ ‐dependent vesicular pool. Transductional studies showed that mobilization of Ca2+ from intrasynaptosomal inositol‐phosphate‐sensitive stores does not contribute to adenosine effects on release, therefore implying that CPA reduction of Ca2+ influx is due to direct effects on membrane Ca2+ conductance. Conversely, activation of A1 receptors resulted in inhibition of forskolin‐stimulated cAMP production in the same agonist concentration range effective on modulation of release, suggesting that this second messenger may play a role in the presynaptic effects of adenosine analogues. Finally, CPA reduced both glutamate efflux and the increases of internal Ca2+ concentrations associated with block of synaptosomal energy metabolism with rotenone and iodoacetic acid, suggesting that presynaptic A1 receptors represent a strategic site of action for adenosine also under experimental conditions resembling brain ischemia and hypoxia. © 1995 Wiley‐Liss, Inc.
A‐80426, a potent and selective α2‐adrenoceptor antagonist with serotonin uptake‐blocking activity and putative antidepressant‐like effects: II. Pharmacology profile
Authors: Giardina William J. , Buckner Steven A. , Brune Michael E. , Hancock Arthur A. , Wismer Carol T. , Milicic Ivan , Rattin Anthony J. , Roux Sylvain , Wettstein Joseph G. , Meyer Michael D. , Porsolt Roger D. , Kerwin James F. , Williams Michael
Published: January 2005

A‐80426 N‐[2‐(benzofuran‐6‐yl)ethyl]‐N‐[(R)−( + (‐5‐methoxy‐1,2,3,4‐tetrahydronaphthalen‐1‐yl methyl]‐N‐methylamine) is a compound that combines in vitro selective inhibition of serotonin synaptosomal uptake and α2‐adrenoceptor antagonism. In the present studies, A‐80426 was evaluated in vivo for its ability to block serotonin uptake and α2‐adrenoceptors. The antidepressant potential of the compound was also assessed.

In rats, A‐80426 significantly reduced p‐chloroamphetamine (PCA)‐induced hyperactivity, a measure of the in vivo blockade of serotonin uptake, after acute (ED50 = 13 μmoles/kg, po) and chronic (14 day) (ED50 = 4.1 μmoles/kg, po) dosing. At doses of 6.7 and 22 μmoles/kg, po, A‐80426 was effective in this test procedure for at least 12 h following administration. Doses of 6.7 to 224 μmoles/kg, ip, of A‐80426, however, failed to block hypothermia and hypoactivity produced by the α2‐adrenoceptor agonist clonidine, and doses of 100 and 300 μmoles/kg, po, were required to blocked clonidine‐induced mydriasis. Thus, the in vitro α2 receptor binding and blocking effects observed with A‐80426 did not translate into the in vivo situation.

A‐80426 was able to reverse the step‐down passive avoidance deficit seen in olfactory bulbectomized rats (ED70 = 7.1 μmoles/kg, po), a finding suggesting that the compound has antidepressant potential. The compound was, however, inactive in the tail suspension and forced swim tests of antidepressant activity in mice at doses up to 72 μmoles/kg, ip. In contrast, fluoxetine was active in all three paradigms.

Despite its favorable in vitro profile, A‐80426 is not an effective α2 blocker in vivo and is inactive in the behavioral dispair models of depression. It is unlikely that A‐80426 would have antidepressant activity equivalent to existing selective serotonin reuptake inhibitors. α2 blockade as a potential approach to eliciting antidepressant activity is discussed. © 1995 Wiley‐Liss, Inc.
Structure‐activity studies of analogs of β, γ‐methylene‐ATP at P2X‐purinoceptors in the rabbit ear central artery
Authors: Martin Pauline L. , Gero Thomas W. , Potts Alice Anne , Cusack Noel J.
Published: January 2005

Structure‐activity studies using naphthylmethyl analogs of β, γ‐methylene‐ATP were conducted at the P2X‐purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α, β‐m‐ATP. On the adenine base, substitution at the C2‐position (WRC‐0440) increased the agonist potency 2‐fold and substitution at the C8‐position (WRC‐0431) did not change agonist potency, and both compounds had the same maximal response as β, γ‐m‐ATP, whereas substitution at the N6‐position (WRC‐0416) abolished activity. On the D‐ribose sugar, substitution on the 2′‐hydroxyl generated a partial agonist (WRC‐0479), which had a maximal effect of only 39% of that of β‐γ‐m‐ATP. Attempts to substitute the 3′‐hydroxyls by naphthylmethyl failed, but substitution by p‐methoxybenzyl (WRC‐0617) did not change potency or the maximal response. Cyclic substitution of both the 2′‐ and 3′‐hydroxyls by naphthylmethylidine (WRC‐0498) had no effect on the agonist potency or the maximal response relative to β‐γ‐m‐ATP. On the β, γ‐methylenetriphosphonate chain, substitution on the methylene linkage by naphthylmethyl (WRC‐0433) had no effect on agonist potency, but the maximal response increased to 122% that of β‐γ‐ATP. However, the contractile response to WRC‐0433 was not desensitized by α, β‐γ‐ATP (contractile responses to all other agonists were abolished by α‐β‐γ‐ATP pretreatment), but was blocked by the α1 antagonist prazosin (10−6 M). WRC‐0433 appears to act at a prejunctional site that mediates ATP‐induced release of norepinephrine. Purine nucleotides with substituents at the 2′‐position of the ribose sugar could provide a lead to the generation of P2X‐purinoceptor antagonists. © 1995 Wiley‐Liss, Inc.
Development of postural asymmetry in premature human infants
Authors: Gardner Judith , Lewkowicz David , Turkewitz Gerald
Published: January 2005

The head position of 95 infants, born between 30 and 37 weeks gestational age, was observed every 15 min for 2 hr weekly from birth until 39 weeks conceptional age. At 35 weeks and increasingly thereafter, significantly more time was spent with the head to the right than to the left. By 39 weeks the infants were similar to term infants: almost 90% spent 80% or more time with their heads to the right. The increase appeared independent of intra‐ or extrauterine experience; neither age at birth nor time since birth was consistently related to head position. Unlike term infants, prematures were equally likely to turn left as right and have their heads left as right 15 min after release from a midline position. These findings suggest complex determinants of asymmetry including factors intrinsic to the fetus and those contributed by the uterine environment.
Diurnal cortisol and temperature variation of normal and autistic children
Authors: Hill Suzanne D. , Wagner Emily A. , Shedlarski Joseph G. , Sears Suzanne P.
Published: January 2005

Blood samples and temperature measurements were taken over a 24‐hr period for 6 children with autistic features and 3 normal control children of approximately the same age. The normal children showed relatively adult diurnal rhythmicity in cortisol and temperature. In contrast, 4 of 6 autistic children showed abnormal patterns in both measures.
Patterns of behavioral development in spontaneously hypertensive rats and Wistar‐Kyoto normotensive controls
Authors: McCarty Richard , Kopin Irwin J.
Published: January 2005

We have examined the behavior of spontaneously hypertensive (SHR) rats and stroke‐prone hypertensive (SP‐SHR) male rats during the development and maintenance of elevated blood pressure and compared this pattern with age‐ and gender‐matched normotensive (WKY) rats of the same Wistar‐Kyoto strain as controls. Rats of each strain (n = 10/age group) were isolated in individual cages and observed for 60 min at 3,4,6,8,10, or 20 weeks of age using a scan sampling technique. At all ages SHR rats were significantly more active than WKY rats whereas SP‐SHR rats were intermediate in level of activity. In a 2nd series, activity of male rats of each strain was monitored continuously for 24 hr in the home cage. No strain differences in amount or pattern of total daily activity were evident at either 4–6 or 16–18 weeks of age. These results indicate that SHR rats are more reactive to environmental change, but the intermediate level of activity of SP‐SHR rats suggests that this response is not related to the degree of blood pressure elevation.
Ontogeny of maternal behavior in the laboratory rat: Early origins in 18‐ to 27‐day‐old young
Authors: Mayer Anne D. , Rosenblatt J. S.
Published: January 2005

The responses of unweaned juveniles, 18 to 27 days of age, in brief tests with pups younger than 10 days were observed during initial exposure and at 4–6‐day intervals. They showed no aversive responses and actively sought contact with the pups until 24 days when contact‐seeking declined sharply. Young exposed to pups before 24 days continued to seek contact with them after 24 days showing an effect of the prior experience. Juveniles given a choice between young pups and a warm bowl chose the pups; given a choice between young pups and age mates, they chose the young pups until day 23, but chose the age mates after then. When housed continuously with young pups at 22 days of age, 5 of 9 retrieved and grouped pups with a latency of 1 day. Our results indicate that timidity or fear of novelty develops in rats in this situation about Day 24 and thereafter is a factor inhibiting the expression of positive social behavior toward pups.
Infant responsiveness to maternal cues in mice of 2 inbred lines
Authors: Hennessy Michael B. , Li Julia , Levine Seymour
Published: January 2005

The present study examined the responsiveness of 19‐ to 20‐day‐old C57BL/6J (C) and A/J (A) mouse pups to maternal cues. The C pups were found to spend more time near their C or A foster mother than they did near a virgin female. The A pups showed no such preference. Attempts to increase the motivation of A pups to approach the mother did not produce any preference for maternal cues. However, when the bedding on which odorous substances had been permitted to accumulate for an extended period of time was used as choice stimuli, pups of both lines showed a preference for the bedding of the mother as opposed to that of a virgin female. These results support findings with other rodents of a change in the female's odor during lactation which increases her attractiveness to her pups; and they demonstrate a genetic difference between pups of 2 inbred strains in their approach to maternal cues.
The first foray: Maternal influences in nest egression in the weanling rat
Authors: Alberts Jeffrey R. , Leimbach Michael P.
Published: January 2005

A series of experiments was performed to examine the determinants of the rat pups' 1st excursions from the maternal nest into the novel environment outside the burrow. A standardized, nidic environment consisting of a maternal nest and adjoining open field was studied under a variety of structured test conditions. When the mother was outside the nest, pups readily ventured into the field. The early excursions were not stimulated by the mother's absence from the nest because when the mother was removed from the nest but not placed in the field the pups remained nestbound. Anesthetized dams elicited few excursions, suggesting that olfactory cues are less potent in this situation than behaviorally transmitted signals. Nonlactating adults were not attractive to pups but after induction of “maternal responsiveness” concaveated males facilitated egression. The data from a final experiment suggest that when in the nest, the dam stimulates egression by providing additional “permissive” stimuli that render the weanling more responsive to approach cues outside the nest.
Neonatal stress in lambs: Behavioral and physiological responses
Authors: Moberg Gary P. , Wood Valeria A.
Published: January 2005

For the 1st 5 weeks after birth, experimental lambs reared in small flocks under conditions that approximated the normal social environment for sheep were subjected 3 times a week to an experimental procedure that was designed to expose the lambs to neonatal stress. The experimental procedure consisted of maternal separation, handling, and exposure to a Pavlovian conditioning paradigm. Each lamb responded to this experimental procedure with elevated plasma corticosteroid levels and intense vocalization. In contrast to the experimental (or neonatal stressed) lambs, the control lambs remained undisturbed with their mothers during the time the experimental lambs were being stressed.

When both groups of lambs were subsequently exposed to open‐field testing, the 2 groups did not differ in their behavioral responses (e.g., vocalization, latency to 1st movement, or locomotion) even though each of these behaviors has been found to be sensitive to the effects of neonatal social experience. Also no difference existed between the 2 groups in their initial adrenocortical response to open‐field testing; however, the plasma concentration of corticosteroids of the experimental lambs took longer to return to pretest levels.

At 5 months of age, the lambs were subjected to brief restraint in a dark chamber, and the effect of this brief stress on heart rate and plasma corticosteroids was measured. No differences were found between the 2 groups in either the heart rate or adrenocortical response to this stress. Thus, we have no evidence from these studies that neonatal stress had any effect on the lambs' subsequent ability to respond to brief behavioral stress.
The ontogeny of play in rats
Authors: Panksepp Jaak
Published: January 2005

Play behavior, as indicated by frequency and duration of pinning behavior, was studied in young rats between 18 and 64 days of age. The incidence of play was markedly increased by social isolation. Play increased from 18–28 days of age, peaked between 32 and 40 days of age, and gradually declined thereafter. Animals developed stable “dominance hierarchies” during the course of testing so that one animal pinned the other on the average 70% of the time. Also, “dominant” animals exhibited the longer pin durations. The data indicate that social play can be efficiently studied in the laboratory rat and, further, that one function of play may be to establish stable social relationships.
Developmental aspects of 2‐way shuttlebox avoidance in the spontaneously hypertensive and normotensive rat
Authors: Sutterer James R. , DeVito William J. , Rykaszewski Irene
Published: January 2005

In Experiment I, male and female rats from the spontaneously hypertensive (SHR) and Wistar‐Kyoto (WKYN) normotensive strains were given 1 session of 2‐way shuttlebox avoidance training at 25–26, 35–36, or 45–46 days of age. The avoidance training was preceded by a pretest which consisted of 10 presentations of the compound conditioned stimulus alone in order to assess any differential tendency of the 2 strains to respond to the presentation of novel stimuli. The WKYN rats made a significantly higher number of pretest avoidance responses and achieved a higher level of avoidance performance than SHR rats. In addition, during the pretest, WKYN rats were more active and had a shorter 1st trial latency. In Experiment II, the pretest phase was replicated with a manipulation of the intensity of the auditory cue. Although the WKYN rats had a higher rate of pretest avoidance than SHR rats, the rate of pretest avoidances increased with intensity in both strains. The WKYN rats had a shorter 1st trial latency and a shorter median latency for the 10 trials and were more active than SHR rats during the pretest. These results relate to age‐independent behavioral characteristics of these strains and the question of reactivity to environmental stimulation.
Maternal touch at 1st contact with the newborn infant
Authors: Trevathan Wenda R.
Published: January 2005

Human mothers have been reported to exhibit a species‐characteristic pattern of tactile contact with their newborn infants that begins with fingertip touch of infant extremities and progresses to palmar massaging of the infant trunk. This study presents data on maternal tactile interaction during 10 min of contact following each of 66 deliveries. Most of the women in the study were of Hispanic origin and delivered with midwives in an El Paso, Texas maternity center. Time‐sampling techniques were used with tactile behaviors recorded every 10 sec. Most observations began less than 10 min after birth. The statistical analysis revealed that maternal tactile behavior in the 1st 10 min of active interaction is more variable than previously reported. No evidence was offered of a pattern of touch progression: active tactile exploration appeared to vary with the gender of the infant and parity and socioeconomic or sociocultural background of the mother.
Effects of early environmental enrichment upon open‐field behavior and timidity in the domestic chick
Authors: Jones R. Bryan
Published: January 2005

Early environmental enrichment was evaluated by its effect on the behavior of 7‐day‐old male and female domestic chicks in an open field or novel environment and in a hole‐in‐the‐wall test of timidity. The chicks were housed in same‐sex groups of 10. The bare environments contained wood litter, food, and water, whereas the enriched boxes also contained various objects. In the open field, immobility was lower while feeding, walking, jumping and vocalization were higher in the enriched birds than in those reared in the bare environment. Enrichment also decreased emergence latencies in the hole‐in‐the‐wall box. The increased stimulation provided by environmental enrichment may decrease fearfulness in subsequent fear‐inducing situations and may enhance the ability of animals to adapt to novelty.
Temporal organization of ultrasonic vocalizations in infant mice
Authors: Elwood Robert W. , Keeling Fergus
Published: January 2005

The number of ultrasonic calls produced per minute by infant mice in response to room temperature increases during the 1st week after birth and decreases during the 2nd. These vocalizations show a distinct bout organization that changes with age. The initial increase in call production is due to an increase in the number of bouts whereas the subsequent decline is primarily due to bouts of fewer calls. The rate of calling within bouts, however, increases steadily with age. These findings are discussed in terms of maturational and motivational changes.
Prenatal and postnatal determinants of the 1st suckling episode in albino rats
Authors: Pedersen Patricia E. , Blass Elliott M.
Published: January 2005

Conditions under which an odor could elicit the 1st nipple attachment in albino rats were investigated. In Experiment I rats exposed prenatally and immediately after birth to citral, a lemon scent, suckled the washed nipples of an anesthetized, parturient dam when the nipples had been scented with citral. Moreover, these rats did not suckle the normal, unwashed nipples of these dams. In Experiment II rats were exposed to citral either (a) in utero, (b) immediately after birth, (c) both pre‐ and post‐natally, or (d) not at all. Only rats in Group (c) attached to washed, citral‐scented nipples and did not suckle the normal unwashed nipples that elicited suckling in control rats. These findings suggest that prenatal and postnatal events can determine which olfactory stimuli elicit the newborn rat's 1st nipple attachment.
Limitations on input as a basis for neural organization and perceptual development: A preliminary theoretical statement
Authors: Turkewitz Gerald , Kenny Patricia A.
Published: January 2005

We propose an alternative to the conventional view that limitations on infant functioning are handicaps to be overcome. According to our view, limitations, particularly of the sensory systems, produce adaptive advantages for infants by facilitating perceptual organization. During embryogenesis, developmental rates of sensory systems are unequal so that onset of functioning is sequential. We argue that such differential onset results in relative independence among emerging systems, thereby reducing competition which helps regulate subsequent neurogenesis and functioning. In addition to prenatal effects, neonatal sensory limitations are discussed as a major source of perceptual organization. Limitations reduce the amount of information with which the infant must contend and promote temporal contiguity between multimodal attributes of a stimulus. Although we focus on human perceptual development, our view is a broadly based comparative one. Thus, other organisms have evolved means of restricting sensory input, and evidence is cited suggesting the importance of this reduced input in regulating normal perceptual development.
Developmental overproduction and selective attrition: New processes in the epigenesis of birdsong
Authors: Marler Peter , Peters Susan
Published: January 2005

All phases of song development from infancy to adulthood were studied intensively in a group of laboratory‐reared birds. Male swamp sparrows, Melospiza georgiana, trained with tape‐recorded songs in infancy, developed song some 8 months later, averaging 2.2 song types per bird. Analysis of the intermediate stage of plastic song revealed that the birds generated 4 to 5 times more song material than was needed for the species‐specific song repertoire. The excess was discarded at the time of full song crystallization. Indications that the attrition process is selective include tendencies to retain imitated rather than nonimitated elements, and the rejection of heterospecific elements. Attrition may also be influenced by vocal stimulation at the time of song crystallization, providing an opportunity for behavioral adjustment even though new themes can no longer be learned. Attrition has been described in the transition in human infants from babbling to speech.
Effects of nutrition and environment on brain biochemistry and behavior
Authors: Crnic Linda S.
Published: January 2005

A factorial design was used to explore the influence of malnutrition and environmental enrichment on brain development and adult behavior. Malnutrition in suckling rats was produced by restricting the intake of their dams to 40% of normal food consumption. Environment was enriched using combined preweaning handling and a postweaning complex environment treatment. Malnutrition produced lasting effects upon brain biochemical composition and behavior. The environmental manipulation had no ameliorative effect on the brain parameters measured but it had pronounced effects on behavior, decreasing latency to move in the open field and increasing some measures of activity while it enhanced passive‐avoidance performance. There was little evidence for any interaction between the nutritional and environmental variables, but all trends were in the direction of the environmental treatment having more effect on the well‐nourished rats.
Determinants of suckling versus drinking in weanling albino rats: Influence of hydrational state and maternal contact
Authors: Bruno John P. , Blass Elliott M. , Amin Farid
Published: January 2005

Preferences of weanling albino rats (15, 20, and 25 days of age) for nonnutritive suckling or drinking were determined using a Y‐maze. Age, hydrational state, and the opportunity to contact the mother all influenced choice behavior. When tested in a maze that allowed continuous maternal contact in the “drinking‐goal box,” dehydrated rats chose to drink, while nondehydrated rats chose to suckle. Testing dehydrated rats in a maze that precluded maternal contact in the “drinking‐goal box” eliminated drinking preference at all ages. These observations identify maternal presence as an important condition for the expression of drinking behavior during the weaning period and confirm our previous demonstration of dehydration's inhibition of suckling behavior.
Alarm call responsivity of mallard ducklings: II. Perceptual specificity along an acoustical dimension affecting behavioral inhibition
Authors: Miller David B.
Published: January 2005

Mallard ducklings (Anas platyrhynchos) inhibit their vocal and locomotor behavior upon hearing the maternal alarm call. An important acoustic feature of the call that affects such inhibition is the slow repetition rate of the notes. This study assesses the range of repetition rates that affect behavioral inhibition in 1‐day‐old domestic mallard (Peking) ducklings. Four hundred and fifty maternally naive ducklings were tested in groups of 30 to repetition rates ranging from 2 to 3.0 notes/sec in 2/10‐sec increments. Various behavioral measures (i.e., incidence of inhibition, latency and duration of inhibition) revealed that the optimal range of repetition rates affecting inhibition extends from.8 to 1.8 notes/sec. Within this range, 1.0 and 1.6 notes/sec are particularly effective. The efficacy of these particular 2 rates may reflect their correspondence with the rates of the modal alarm call and certain kinds of self‐produced embryonic vocalizations, respectively. Unexpectedly, very slow repetition rates (.2 and.4 notes/sec) are not as effective as faster rates in promoting inhibition. Thus, the inhibitory response exhibited by ducklings upon hearing the alarm call reflects auditory perceptual specificity to a range of moderately slow repetition rates that are characteristic of normally occurring sounds of the perinatal environment.
Forty minutes of experience increase the weight and RNA content of cerebral cortex in periadolescent rats
Authors: Ferchmin P. A. , Eterovic Vesna A.
Published: January 2005

The goal of this work was to determine the shortest period of exposure to environmental complexity (EC) that would produce measurable changes in brain weight or RNA content. This period varied with the age of subjects. In young adult rats, 3 months old, 4 days of exposure to EC increased the RNA concentration in the occipital cortex above the level of littermates kept in impoverished condition (IC). Cortical weight was not affected. Seven or one daily hrs of exposure to EC did not produce significant differences between rats in EC and IC. In periadolescent rats, 30‐ to 40‐day‐old, 1 daily hr of enrichment for 4 days increased both the weight of occipital cortex and its RNA content. Exposures of 7 or 24 hrs/day produced similar results. In another experiment with periadolescent rats 1 hr or even 10 min of exposure to EC per day, for 4 days, increased total cortical weight and RNA content. Thus, periadolescent rat brain display remarkably high plasticity. These very short exposure periods are comparable to the duration of learning sessions in simple formal trainings.