Insensitive Sites Research Articles

Mechanisms That Underlie μ-Opioid Receptor Agonist–Induced Constipation: Differential Involvement of μ-Opioid Receptor Sites and Responsible Regions

Reducing the side effects of pain treatment is one of the most important strategies for improving the quality of life of cancer patients. However, little is known about the mechanisms that underlie these side effects, especially constipation induced by opioid receptor agonists; i.e., do they involve naloxonazine-sensitive versus -insensitive sites or central-versus-peripheral μ-opioid receptors? The present study was designed to investigate the mechanisms of μ-opioid receptor agonist-induced constipation (i.e., the inhibition of gastrointestinal transit and colonic expulsion) that are antagonized by the peripherally restricted opioid receptor antagonist naloxone methiodide and naloxonazine in mice. Naloxonazine attenuated the fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine or oxycodone. Naloxone methiodide suppressed the oxycodone-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine, indicating that μ-opioid receptor agonists induce the inhibition of gastrointestinal transit through different mechanisms. Furthermore, we found that the route of administration (intracerebroventricular, intrathecally, and/or intraperitoneally) of naloxone methiodide differentially influenced the suppressive effect on the inhibition of colorectal transit induced by morphine, oxycodone, and fentanyl. These results suggest that morphine, oxycodone, and fentanyl induce constipation through different mechanisms (naloxonazine-sensitive versus naloxonazine-insensitive sites and central versus peripheral opioid receptors), and these findings may help us to understand the characteristics of the constipation induced by each μ-opioid receptor agonist and improve the quality of life by reducing constipation in patients being treated for pain.

Aging and long-term caloric restriction regulate neuropeptide Y receptor subtype densities in the rat brain

The effects of aging and long-term caloric restriction (LTCR), on the regulation of neuropeptide Y (NPY) Y1, Y2 and Y5 receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12months. [125I]GR231118, a Y1 antagonist was used as Y1 receptor radioligand. [125I][Leu31, Pro34]PYY, a high affinity agonist of Y1 and Y5 subtypes was used in the absence or presence of 100nM BIBO3304 (a highly selective Y1 receptor antagonist) to assess the apparent levels of [125I][Leu31, Pro34]PYY/BIBO3304 insensitive sites (Y5-like) from [125I][Leu31, Pro34]PYY/BIBO3304 sensitive sites (Y1). [125I]PYY(3–36) was used to label the Y2 receptor. In the brain of 3-month-old AL rats, the distribution and densities of Y1, Y2 and Y5 receptors were in agreement with previous reports. In the brain of 20AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed. In contrast, LTCR had multiple effects. It induced specific decreases of Y1-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y2-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y1-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y2-receptor densities in the CA2 subfield of the hippocampus. These results indicate that LTCR not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions.

NF‐κB p52:RelB heterodimer recognizes two classes of κB sites with two distinct modes

The X‐ray structure of the nuclear factor‐κB (NF‐κB) p52:RelB:κB DNA complex reveals a new recognition feature not previously seen in other NF‐κB:κB DNA complexes. Arg 125 of RelB is in contact with an additional DNA base pair. Surprisingly, the p52:RelB R125A mutant heterodimer shows defects both in DNA binding and in transcriptional activity only to a subclass of κB sites. We found that the Arg 125‐sensitive κB sites contain more contiguous and centrally located A:T base pairs than do the insensitive sites. A protein‐induced kink observed in this complex, which used an AT‐rich κB site, might allow the DNA contact by Arg 125; such a kink might not be possible in complexes with non‐AT‐rich κB sites. Furthermore, we show that the p52:RelB heterodimer binds to a broader spectrum of κB sites when compared with the p50:RelA heterodimer. We suggest that the p52:RelB heterodimer is more adaptable to complement sequence and structural variations in κB sites when compared with other NF‐κB dimers.

Comment on "Seismomagnetic Effects from the Long-Awaited 28 September 2004 M 6.0 Parkfield Earthquake" by M. J. S. Johnston, Y. Sasai, G. D. Egbert, and R. J. Mueller

We present some comments on two issues dealt with in Johnston et al. (2006), which reported that there were no electric and magnetic (EM) precursors for the 28 September 2004 M 6.0 Parkfield earthquake (EQ). The first comment is on their introduction, which, while raising critical comments on seismic electric signals (SESs) in Greece and Japan, concluded that useful prediction of EQs seems unlikely using electromagnetic data. We show point by point that their criticism is unfounded. The second comment is on their assertion of the nonexistence of SESs at Parkfield. We point out that this assertion may be premature as their efforts to identify signals appear insufficient. They show, in a timescale too coarse to recognize SESs, only band-passed magnetic and electric data for the five day period before the Parkfield EQ, which is much too short. Even if the claimed nonexistence of an electric precursor is demonstrated by further data analysis, the probability will remain that their single observation site was insensitive to SESs. They apparently have made no search effort for SES sensitive sites. Our experiences show that SES insensitive sites are not uncommon even near epicenters. On these grounds, their overall negative attitude on electromagnetic methods seems much too premature and inappropriate. Even if no EM precursors were generated for the Parkfield EQ, we suggest it would be more scientifically sound to seek the physical reason for it before negating SESs in general, which have been well observed elsewhere. Johnston et al. (2006) (J2006, hereafter), in their introduction, list four reasons for doubting the observations of SESs in Greece and Japan. Although this portion seems to have rather little to do with their own work, it demonstrates their basic negative stance against the VAN method (which is a method for short term earthquake prediction by monitoring …

Influence of composition and annealing conditions on the site-occupation in the σ-phase of Fe–Cr and Fe–V systems

Neutron diffraction technique was used to study the site-occupation in the σ-phase in the Fe–Cr and Fe–V systems. It was found that all five sites A, B, C, D and E are “mixed”, i.e. occupied by both elements. The occupation is neither random – the degree of randomness increases with Fe content – nor regular, i.e. sites A and D are predominantly occupied by Fe atoms while B, C and E sites are occupied preferentially by Cr or V atoms. For all five sites the increase of Cr(V) concentration results in an irregular decrease of the number of Fe atoms on each site, the rate of decrease being the smallest for the sites A and D. In the Fe–Cr system the population of A with Fe atoms, N A, is similar to that of D, N D, while for the system Fe–V N D > N A and the difference increases with V content. The lowest Fe population in both investigated systems has B, but N B(V) < N B(Cr). N C = N E for Fe–V, while N C > N E for Fe–Cr. The influence of sample preparation conditions (plastic deformation prior to phase transformation, annealing time, t a, and temperature of annealing, T a) were also tested on a σ-Fe 53.8Cr 46.2 sample. In general the influence of these conditions on the site population is small. The largest effect had the plastic deformation, and the smallest one the annealing time in case of non-deformed samples. The most insensitive sites were revealed to be D and E, and the most sensitive ones were B and A.

Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat

The central actions of oxytocin on reproduction-related functions and behaviors are strongly steroid-dependent and gender specific. This study characterizes sexual differences in the oxytocin binding site expression in forebrain and spinal cord of the rat. Using film autoradiography, we quantified the density of oxytocin binding sites in the ventromedial hypothalamic nucleus, the medial and central nuclei of the amygdala, the medial bed nucleus of the stria terminalis and the spinal cord dorsal horns both in adult male and female rats, and during development. In addition, neonatal castrated males and intact neonatal females treated with a single injection of testosterone (1 mg) were examined. Data showed a sexual dimorphism in the expression of oxytocin binding sites in the spinal cord dorsal horns and in restricted areas of the forebrain that are sensitive to gonadal steroids such as the ventromedial hypothalamic nucleus, but not in gonadal steroid insensitive sites such as the central nucleus of the amygdala. Adult males had higher oxytocin binding site densities in the ventromedial hypothalamic nucleus and dorsal horns than females. In the forebrain, but not in the dorsal horn, this sexual difference required a perinatal exposure to testosterone. Neonatal castration only abolished the sexual difference in the ventromedial hypothalamic nucleus of adults, but not in the dorsal horn. Furthermore, females that received a single injection of testosterone 1 day after birth showed significant increases in the density of oxytocin binding sites in the ventromedial hypothalamic nucleus, medial nucleus of the amygdala and medial bed nucleus of the stria terminalis. In addition, the findings suggest that the sexual difference in the ventromedial hypothalamic nucleus also requires gonadal hormones in adulthood. Our data support the hypothesis that sexually dimorphic oxytocin binding sites may contribute to the regulatory central actions of oxytocin in gender specific functions and behaviors such as nociception and reproduction.

The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase.

CLIP-170/Restin belongs to a family of conserved microtubule (MT)-associated proteins, which are important for MT organization and functions. CLIP-170 is a phosphoprotein and phosphorylation is thought to regulate the binding of CLIP-170 to MTs. However, little is known about the kinase(s) involved. In this study, we show that FKBP12-rapamycin-associated protein (FRAP, also called mTOR/RAFT) interacts with CLIP-170. CLIP-170 is phosphorylated in vivo at multiple sites, including rapamycin-sensitive and -insensitive sites, and is phosphorylated by FRAP in vitro at the rapamycin-sensitive sites. In addition, rapamycin inhibited the ability of CLIP-170 to bind to MTs. Our observations suggest that multiple CLIP-170 kinases are involved in positive and negative control of CLIP-170, and FRAP is a CLIP-170 kinase positively regulating the MT-binding behavior of CLIP-170.

The selectivity of the Ioannina VAN station

Two peculiar characteristics of the VAN method of short-term earthquake prediction are: (1) the existence of sensitive and insensitive sites to seismic electric signal (SES) and (2) the selective sensitivity of a sensitive station to SES from specific focal area(s). The process of their discovery, which so far has not been published adequately, is examined for the Ioannina (IOA) station. The sensitive site was discovered simply through repeatedly moving the temporary observation network. The selectivity map of the IOA station was made by first identifying the earthquake source areas with SESs which were considered to have been detected at IOA, and second by examining the direction of SESs from different such source areas. For the latter purpose, information from long dipoles appears to have been helpful. The selectivity map is empirically constructed and is updated regularly. We have independently tried to construct a selectivity map of IOA by examining VAN's raw SES records and by using the same criteria as VAN. The selectivity map we obtained was not exactly, but roughly similar to that of VAN.

Does neuropeptide Y contribute to the modulation of brain stimulation reward by chronic food restriction?

The rewarding effect produced by electrically stimulating particular sites in the lateral hypothalamus (LH) can be enhanced by chronic food restriction and body weight loss. The impact on brain stimulation reward (BSR) of certain hormones involved in the regulation of energy balance, such as leptin and corticotropin-releasing hormone, depends upon the sensitivity of BSR to food restriction. The present investigation assessed the influence of neuropeptide Y (NPY), a potent orexigenic peptide, on BSR generated by stimulating restriction-sensitive and -insensitive sites in the LH. Twelve male Long Evans rats were trained to press a lever for a rewarding train of stimulation. Rate–frequency curves, reflecting the number of rewards earned as a function of the stimulation frequency, were collected during free-feeding and then again following a period of food restriction and 20–25% body weight loss. NPY (4 μg) was administered intraventriculary during the food restriction condition. Alterations in the rewarding effect of the stimulation were assessed by measuring changes in the frequency required to maintain half-maximal rewards earned (M-50). In half of the subjects, food restriction produced significant decreases in M-50 values, indicating that the reward effectiveness of the stimulation was potentiated. In contrast, M-50 values were unaltered by food restriction in the remaining six animals. In most of the subjects in which M-50 values decreased following chronic food restriction, NPY failed to alter BSR. Similarly, BSR was unchanged by NPY administration in most of the rats with restriction-insensitive stimulation sites. These findings suggest that NPY does not take part in the process whereby food restriction and leptin modulate reward circuitry activated by stimulating restriction-sensitive sites.

Evidence for the Differential Distribution of at Least Two Adrenomedullin Receptor Subtypes in the Rat Brain

We recently reported that specific [I]human Adrenomedullin13-52 (hADM13-52) binding sites are very discretely distributed in the rat brain[1]. Furthermore, in rat brain membrane homogenates, we suggested the existence of at least two populations of [I]hADM13-52 receptor binding sites[2]. In the present study, we investigated the differential distribution of specific [I]hADM1352 sites that are sensitive and insensitive to hADM22-52 in the rat brain. Adjacent coronal rat brain sections were incubated with 35 pM [I]hADM13-52 in the presence of increasing concentrations of hADM22-52. As previously reported, specific [I]hADM13-52 sites were observed in the choroid and linings of ventricles, basal amygdaloid nucleus, neuronal lobe of the pituitary gland, trigeminal nucleus, and cerebellum. Specific [I]hADM13-52 binding is fully inhibited by 1 μM hADM22-52 in all these brain regions except in the cerebellum. In fact, hADM22-52 was able to inhibit only 70% of specific [I]hADM13-52 binding sites in the rat cerebellum. These data suggest for the first time that the rat cerebellum contains at least two populations of ADM receptors, one that is sensitive to hADM22-52 while the other is resistant. This characterization of cerebellar [I]hADM13-52 / hADM22-52 -insensitive sites is currently under investigation. Supported by grant from the CIHR to RQ.

Discussion of “Optimal Allocation of Water Withdrawals in River Basin” by Jennifer M. Jacobs and Richard M. Vogel

The authors present an objective methodology using flow duration curves and a chance-constrained mathematical programming technique to determine the optimal allocation of streamflow to competing multiple users in a river basin. The discusser feels that the methodology presented by the authors is very interesting and valuable to field engineers and policymakers involved in water allocation decisions. The methodology has merits because of its simplicity, its ease in implementation, and its ability to help in understanding the impact of streamflow availability and user requirements on the streamflow allocation. However, the discusser feels that a few points associated with the formulation and application of the proposed general chance-constrained model for maximizing water allocation in a river basin for productive use must be addressed and clarified before the proposed model can be advocated for implementation in solving real-life problems. STREAMFLOW ALLOCATION MODELS The inequality constraints defined by (2) and (3) in the proposed general chance-constrained model for maximizing water allocation in a river basin for productive use place restrictions on the permitted withdrawal quantity to ensure that water allocation at a site does not exceed its demand and in no case is it less than the existing permitted quantity. In fact, these inequality constraints represent the upper and lower bounds placed upon the amount of permitted withdrawals by users at various sites. Solutions are being sought to optimize total water withdrawals in a river basin to meet demands at various sites with its acceptable streamflow reliabilities. Taking this cognizance, the inequality constraints defined by (6) and (7) become redundant. The constraint set defined by (3) and (4) itself ensures that the decision variables q i and ri are nonnegative, where qi is the permitted withdrawal quantity for site i, and ri is the streamflow reliability for withdrawal i. If allocation is desired on the basis of only flow duration curves (FDCs) and demands at various sites, without putting any restriction of minimum withdrawal permit, solution can be obtained by assigning zero values to pi for all values of i, where pi is the existing permitted withdrawal at site i. The second issue is associated with the range within which the water allocation at a particular site is allowed to take any value during the optimization search process to maximize the total water allocation in a river basin. The constraint set defined by (3) is nothing but the demands requested by various users estimated currently or previously. The constraint set defined by (2) is basically the projected demand by various users in the coming future. This conceptualization has a flavor of scheduling the permitted withdrawals at various sites. Thus, it may be appropriate even to cut down water allocation at some insensitive sites to values less than their existing permits in order to maximize the production function. This is relevant when the reductions are likely to occur in streamflow availability. In such cases, the optimal solution will be primarily based on the FDCs. The sensitivity herein is with respect to production function. In fact, the lower limit on the variable q i

Characterization of the myosin light chain kinase from smooth muscle as an actin-binding protein that assembles actin filaments in vitro

In addition to its kinase activity, myosin light chain kinase has an actin-binding activity, which results in bundling of actin filaments [Hayakawa et al., Biochem. Biophys. Res. Commun. 199, 786–791, 1994]. There are two actin-binding sites on the kinase: calcium- and calmodulin-sensitive and insensitive sites [Ye et al., J. Biol. Chem. 272, 32182–32189, 1997]. The calcium/calmodulin-sensitive, actin-binding site is located at Asp 2–Pro 41 and the insensitive site is at Ser 138–Met 213. The cyanogen bromide fragment, consisting of Asp 2–Met 213, is furnished with both sites and is the actin-binding core of myosin light chain kinase. Cross-linking between the two sites assembles actin filaments into bundles. Breaking of actin-binding at the calcium/calmodulin-sensitive site by calcium/calmodulin disassembles the bundles.

Recondensation of sperm nucleus during male pronuclear formation in bovine oocytes following in vitro fertilization: Light microscopic observation

In addition to its kinase activity, myosin light chain kinase has an actin-binding activity, which results in bundling of actin filaments [Hayakawa et al., Biochem. Biophys. Res. Commun. 199, 786–791, 1994]. There are two actin-binding sites on the kinase: calcium- and calmodulin-sensitive and insensitive sites [Ye et al., J. Biol. Chem. 272, 32182–32189, 1997]. The calcium/calmodulin-sensitive, actin-binding site is located at Asp2–Pro41 and the insensitive site is at Ser138–Met213. The cyanogen bromide fragment, consisting of Asp2–Met213, is furnished with both sites and is the actin-binding core of myosin light chain kinase. Cross-linking between the two sites assembles actin filaments into bundles. Breaking of actin-binding at the calcium/calmodulin-sensitive site by calcium/calmodulin disassembles the bundles.

Expression and Characterization of the Neuropeptide Y Y5Receptor Subtype in the Rat Brain

The neuropeptide Y Y5 receptor subtype has generated great interest, especially regarding its possible involvement in feeding behaviors. However, its distribution and sites of expression in the mammalian brain are, in large part, unknown because of the lack of selective tools. We demonstrate in this study that specific [125I][Leu31, Pro34]PYY binding is competed in a biphasic manner by BIBP3226, a Y1 receptor antagonist, demonstrating the existence of sensitive and insensitive sites to BIBP3226. Assays performed by using [125I][Leu31,Pro34]PYY in the presence of 1 microM BIBP3226 to block the Y1 receptor subtype revealed a pharmacological profile highly similar to the cloned Y5 receptor. Moreover, results obtained with GW1229 suggest that the Y4 subtype represents only a very small proportion of the total population of NPY receptors in the rat brain. Quantitative receptor autoradiographic data revealed the discrete distribution of [125I][Leu31,Pro34]PYY/BIBP3226-insensitive Y5 sites in the rat brain, with the external plexiform layer of the olfactory bulb, the lateral septum, the anteroventral thalamic nucleus, the CA3 subfield of the ventral hippocampus, the nucleus tractus solitarius, and the area postrema being most enriched. Rather surprisingly, in the hypothalamus, a key structure modulating food intake, only low densities of Y5 binding sites were detected as well as in most other regions of the rat brain. These data suggest that the Y5 receptor protein is expressed and translated by a small percentage of hypothalamic neurons and that the effect of NPY on feeding behaviors likely is mediated by more than one class of NPY receptors. It also indicates that the Y5 receptor may be involved in other biological actions induced by NPY. Taken together, these data represent the first pharmacological demonstration of the expression and discrete localization of the Y5 receptor protein in the rat brain.

Alterations in Calcium Metabolism in Murine Macrophages by the Benzene Metabolite 1,4-Benzoquinone

Exposure of murine peritoneal macrophages to very low concentrations of 1,4-benzoquinone (BQ) induced immediate increases in intracellular Ca2+concentrations ([Ca2+]i). Increases in [Ca2+]iwere induced by concentrations as low as 5 nM and the response was dose dependent and linear up to 1 μM. The sources of Ca2+were from both internal inositol triphosphate (IP3)-sensitive and -insensitive sites and from the external medium. BQ did not induce IP3formation and did not affect binding to its receptors. 1,4-Hydroquinone had no effect on [Ca2+]i. Catechol did elicit some increases in [Ca2+]i, but did so only at much higher concentrations (5 μM). The action of BQ was almost identical to that of the established Ca2+–ATPase inhibitor thapsigargin except that there were some intracellular stores of Ca2+released by thapsigargin that were not released by BQ. BQ also was mitogenic for macrophages in conjunction with phorbol myristate acetate. These data suggest that BQ raises [Ca2+]iby inhibition of Ca2+–ATPases, is a comitogen, and does so at concentrations that could be achievedin vivoin the general urban population.

Amiloride high- and low-sensitivity, as well as insensitive sites in the blowfly: implications for sugar, water and anion taste reception mechanisms

Among chemoreceptor cells of the blowfly ( Protophormia terraenovae , the so-called 'sugar' and 'water' cells respond to bovine serum albumin (BSA) and L -alanine (the C-terminal amino acid of the BSA molecule) with the highest spike frequency. In both cell types the response to either BSA or L -alanine was unaffected by 0.1 mM amiloride. However, 0.5 mM amiloride decreased the response of the 'water' cell to both BSA and L-alanine significantly, and similarly inhibited the response of the 'sugar' cell to L -alanine, but in contrast to the 'water' cell, 0.5 mM amiloride did not affect the 'sugar' cell response to BSA. The 'sugar' cell responses to both BSA and L-alanine were unaffected by the putative cell second messengers, cAMP and cGMP. The so-called 'anion' cell unexpectedly gave responses to BSA and L-alanine that were enhanced by amiloride at both concentrations. However, like the 'sugar' cell, the 'anion' cell was also unaffected by cAMP and cGMP.We conclude that the 'sugar' cell must have at least three types of receptor sites: the previously described 'F' (amiloride sensitive) and the 'P' (amiloride insensitive) sites, and a low-sensitivity 'T' site that mediates, at least in part, the response to BSA and L -alanine. The effects of amiloride on the responses of the 'water' and 'anion' cells are more difficult to interpret because fundamental information on their chemoreception mechanisms is still lacking.

Effects of stimulation of alpha 1-adrenergic and NMDA/glycine-B receptors on learning defects in aged rats.

The present study was designed to investigate the efficacy of stimulation of alpha1-adrenoceptors and the strychnine insensitive glycine-B binding sites of the N-methyl-D-aspartate (NMDA) receptor complex to alleviate the age-related defect in water maze (WM) spatial (hidden platform) navigation. We found that daily pretraining IP treatment with 2-(2-chloro-5-trifluoromethylphenylamino) imidazole nitrate (ST 587), an alpha1-adrenoceptor agonist, at 3000 micrograms/kg, but not at 1000 micrograms/kg, facilitated acquisition of water maze spatial navigation in aged rats. However, ST 587 3000 micrograms/kg (IP) did not stimulate WM spatial reversal learning or cue navigation to a visible platform in aged rats. A partial strychnine insensitive glycine-B binding site agonist, D-cycloserine (DCS) at 10000 micrograms/kg stimulated acquisition of WM navigation, but had no effect on reversal learning or cue navigation. DCS at 1000 or 3000 micrograms/kg (IP) had no marked effect on WM spatial navigation, and did not enhance the WM performance improving effect of ST 587 in aged rats. A subthreshold dose of ST 587 1000 micrograms/kg did not enhance the therapeutic effect of DCS 1000 micrograms/kg. The present results indicate that activation of alpha1-adrenoceptors and glycine binding sites of NMDA receptor may to some extent alleviate the age-related defect in spatial navigation. DCS treatment does not enhance the therapeutic effects of ST 587 and vice versa.

Autoradiographic Localization of 5-HT1E and 5-HT1F Binding Sites in Rat Brain: Effect of Serotonergic Lesioning

5-carboxamidotryptamine (5-CT)-insensitive binding sites labelled by [3H]5-hydroxytryptamine (5-HT) in the presence of 100 nM 5-CT and 100 nM mesulergine, were examined by semi-quantitative autoradiography in rat brain. Under these conditions most of the labelled sites correspond to 5-HT1E and 5-HT1F sites. The 5-CT-insensitive binding is located mainly in cortical layer V, caudate-putamen, interpeduncular nucleus and claustrum. In cortex and caudate-putamen, a large proportion of 5-CT-insensitive sites is displaced by 250 nM sumatriptan and can be attributed to the presence of 5-HT1F receptors. A low, but significant, level of displacement by sumatriptan was observed in the choroid plexus. Lesions of serotonergic neurones by intracerebroventricular 5,7-dihydroxytryptamine injection does not significantly modify the densities of 5-HT1E or 5-HT1F binding sites. Our findings suggest that the 5-HT1F receptor has a limited distribution in rat brain, mainly located on non-serotonergic neurones.

On the sensitivity of Holocene talus‐derived rock glaciers to climate change in the Ben Ohau Range, New Zealand

AbstractThe morphology and surface ages of talus‐derived rock glaciers are investigated to establish the timing of rock glacier formation in the central Southern Alps. Samples of rock weathering rinds show that all rock glaciers studied were formed during the Neoglacial period, but differences exist between sites in the number of new rock glacier lobes formed by Holocene climatic fluctuations. A qualitative conceptual model is proposed to explain rock glacier formation in terms of two thresholds. An external threshold relates to the presence of a cool climate capable of allowing internal ice to form within talus slopes. An internal threshold relates to the presence of sufficiently thick talus at a site to generate a shear stress capable of overcoming internal friction within the talus/ice mass. The model produces a non‐steady‐state response to explain why unmodified talus, single‐lobed and double‐lobed rock glaciers developed at adjacent sites under the same climatic regime. Individual landforms have different sensitivities to formation, which depend partly on the previous history of talus accumulation and rock glacier activity at a site. The model demonstrates how successive cool climate periods may be fully represented by rock glacier lobes at sensitive sites but under‐represented at insensitive sites. Sensitivity (and therefore climatic representativeness) is favoured by high rates of debris supply. By implication, the timing of formation of rock glacier lobes in regions of prolonged cool climate and low debris production is less likely to correspond to the timing of climatic cooling and more likely to follow the ‘rules’ of deterministic chaos.

Interaction of abecarnil, bretazenil, and Ro 19-8022 with diazepam-sensitive and -insensitive benzodiazepine sites in the rat cerebellum and cerebral cortex

Abecarnil, bretazenil, and Ro 19-8022 inhibited the binding of [ 3H]Ro 15-4513 to diazepamsensitive and -insensitive sites in the rat cerebellum and cerebral cortex, but all three had a much higher affinity for the diazepam-sensitive sites in both tissues. The GABA-shift for bretazenil and Ro 19-8022 was low (< 2) for all sites studied, consistent with their partial agonistic profile. The GABA-shift for abecarnil was appreciably higher for diazepam-sensitive binding in the cerebellum than in the cerebral cortex (1.97 vs 1.18). Furthermore, the GABA-shift for abecarnil was markedly different for the diazepam-sensitive and -insensitive sites in the cerebellum (1.97 vs 0.71). All three compounds inhibited [ 3H]Ro 15-4513 binding to the diazepam-sensitive sites with a slope factor >1, suggestive of positive cooperativity in their binding to GABA A receptors. Abecarnil only partially inhibited diazepam-insensitive binding of [ 3H]Ro 15-4513 in the cerebellum, indicating that this site can be differentiated into abecarnil-sensitive and -insensitive components.