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1.
Behav Brain Res ; 359: 950-957, 2019 02 01.
Article in English | MEDLINE | ID: mdl-29932954

ABSTRACT

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.


Subject(s)
Depression/etiology , Depression/pathology , Helplessness, Learned , Stress, Psychological/etiology , Tegmentum Mesencephali/injuries , Animals , Disease Models, Animal , Electric Stimulation/adverse effects , Electroshock/adverse effects , Habenula/physiology , Male , Phosphopyruvate Hydratase/metabolism , Quinolinic Acid/toxicity , Rats , Rats, Sprague-Dawley , Tegmentum Mesencephali/physiology , Time Factors
2.
Neuroscience ; 148(4): 978-95, 2007 Sep 21.
Article in English | MEDLINE | ID: mdl-17706878

ABSTRACT

Cocaine's (COC) direct interaction with the dopamine (DA) transporter is usually considered the most important action underlying the psychomotor stimulant and reinforcing effects of this drug. However, some physiological, behavioral and psycho-emotional effects of COC are very rapid and brief and they remain intact during DA receptor blockade, suggesting possible involvement of peripheral non-DA neural mechanisms. To assess this issue, single-unit recording with microiontophoresis was used to examine changes in impulse activity of dorsal and ventral striatal neurons to i.v. COC (0.25-0.5 mg/kg) in the same rats under two conditions: awake with DA receptor blockade and anesthetized with urethane. In the awake preparation approximately 70% striatal neurons showed rapid and transient (latency approximately 6 s, duration approximately 15 s) COC-induced excitations. These effects were stronger in ventral than dorsal striatum. During anesthesia, these phasic effects were fully blocked and COC slowly decreased neuronal discharge rate. Cocaine-methiodide (COC-M), a derivative that cannot cross the blood-brain barrier, also caused phasic excitations in the awake, but not anesthetized condition. In contrast to regular COC, COC-M had no tonic effect on discharge rate in either preparation. Most striatal neurons that were phasically excited by both COC forms also showed short-latency excitations during tail-touch and tail-pinch in the awake preparation, an effect strongly attenuated during anesthesia. Finally, most striatal neurons that in awake conditions were phasically excited by somato-sensory stimuli and COC salts were also excited by iontophoretic glutamate (GLU). Although striatal neurons were sensitive to GLU in both preparations, the response magnitude at the same GLU current was higher in awake than anesthetized conditions. These data suggest that in awake animals i.v. COC, like somato-sensory stimuli, transiently excites striatal neurons via its action on peripheral neural elements and rapid neural transmission. While the nature of these neuronal elements needs to be clarified using other analytical techniques, they might involve voltage-gated K(+) and Na(+) channels, which have a high affinity for COC and are located on terminals of visceral sensory nerves that densely innervate peripheral vessels. Therefore, along with direct action on specific brain substrates, central excitatory effects of COC may occur via indirect action, involving afferents of visceral sensory nerves and rapid neural transmission. By providing a rapid sensory signal and triggering transient neural activation, such a peripherally triggered action might play a crucial role in the sensory effects of COC, thus contributing to learning and development of drug-taking behavior.


Subject(s)
Anesthesia , Cocaine/administration & dosage , Corpus Striatum/cytology , Dopamine Uptake Inhibitors/administration & dosage , Neurons/drug effects , Wakefulness/physiology , Action Potentials/drug effects , Analysis of Variance , Animals , Drug Administration Routes , Injections, Intravenous/methods , Iontophoresis/methods , Male , Rats , Rats, Long-Evans
3.
Neuroscience ; 145(1): 335-43, 2007 Mar 02.
Article in English | MEDLINE | ID: mdl-17196751

ABSTRACT

It is well known that the dopamine (DA) system plays an essential role in the organization and regulation of brain activational processes. Various environmental stimuli that induce locomotor activation also increase DA transmission, while DA antagonists decrease spontaneous locomotion. Our previous work supports close relationships between locomotor activation and brain and body temperature increases induced by salient environmental challenges or occurring during motivated behavior. While this correlation was also true for psychomotor stimulant drugs such as methamphetamine and MDMA, more complex relationships or even inverted correlations were found for other drugs that are known to increase DA transmission (i.e. heroin and cocaine). In the present study we examined brain, muscle and skin temperatures together with conventional locomotion during selective interruption of DA transmission induced by a mixture of D1 and D2 antagonists (SCH-23390 and eticlopride at 0.2 mg/kg, s.c.) and its selective activation by apomorphine (APO; 0.05 and 0.25 mg/kg, i.v.) in rats. While full DA receptor blockade decreased spontaneous locomotion, it significantly increased brain, muscle and skin temperatures, suggesting metabolic brain activation under conditions of vasodilatation (or weakening of normal vascular tone). In contrast, APO strongly decreased skin temperature but tended to decrease brain and muscle temperatures despite strong hyperlocomotion and stereotypy. The brain temperature response to APO was strongly dependent on basal brain temperature, with hypothermia at high basal temperatures and weak hyperthermia at low temperatures. While supporting the role of DA in locomotor activation, these data suggest more complex relationships between drug-induced alterations in DA transmission, behavioral activation and metabolic brain activation.


Subject(s)
Body Temperature/physiology , Brain/physiology , Dopamine/metabolism , Motor Activity/physiology , Analysis of Variance , Animals , Apomorphine/pharmacology , Behavior, Animal , Benzazepines/pharmacology , Body Temperature/drug effects , Brain/drug effects , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Drug Interactions , Male , Motor Activity/drug effects , Rats , Rats, Long-Evans , Salicylamides/pharmacology
4.
Eur J Endocrinol ; 155(6): 813-21, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17132750

ABSTRACT

OBJECTIVE: The role of preoperative localisation of abnormal parathyroid glands remains controversial but is particularly relevant to the management of patients with recurrent or persistent hyperparathyroidism and familial syndromes. We report our experience of the use of selective parathyroid venous sampling (PVS) in the localisation of parathyroid disease in such patients. DESIGN: We report a retrospective 10-year experience (n = 27) of the use of PVS in complicated primary hyperparathyroidism and contrast the use of PVS with neck ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and sestamibi imaging modalities. RESULTS: In 14 out of 25 patients who underwent surgery PVS results were completely concordant with surgical and histological findings and 88% of patients achieved post-operative cure. Out of 13 patients referred after previous failed surgery, 12 underwent further surgery which was curative in 9. In total PVS yielded useful positive (n = 13) and/or negative information (n = 6) in 19 out of 25 patients undergoing surgery. Using histology as the gold standard, 59% of PVS studies were entirely consistent with histology, as compared with 39% of ultrasound scans, 36% of sestamibi scans and 17% of MRI/CT scans. CONCLUSIONS: PVS is a valuable adjunct to MRI/CT and sestamibi scanning in selected patients with complicated hyperparathyroidism when performed in an experienced unit.


Subject(s)
Hyperparathyroidism/pathology , Parathyroid Glands/blood supply , Parathyroid Glands/pathology , Vena Cava, Superior , Adult , Aged , Female , Humans , Hyperparathyroidism/diagnostic imaging , Hyperparathyroidism/surgery , Magnetic Resonance Imaging , Male , Middle Aged , Parathyroid Glands/diagnostic imaging , Parathyroid Hormone/blood , Parathyroid Neoplasms/diagnostic imaging , Parathyroid Neoplasms/pathology , Parathyroid Neoplasms/surgery , Preoperative Care , Radionuclide Imaging , Radiopharmaceuticals , Reoperation , Retrospective Studies , Technetium Tc 99m Sestamibi , Tomography, X-Ray Computed
5.
Neuroscience ; 116(2): 525-38, 2003.
Article in English | MEDLINE | ID: mdl-12559108

ABSTRACT

Since metabolic neural activity is accompanied by heat release, measurement of local brain temperature offers a method for assessing alterations in neural activity. This approach, continuous monitoring of local brain (ventral tegmental area, ventral striatum, and hippocampus) and body (temporal muscle) temperature, was used to study intravenous cocaine self-administration in trained rats. The first self-administration of a session was preceded by a strong temperature increase that continued after the drug infusion. After peaking at the time of the second self-administration, temperature plateaued (+0.7 degrees C) with biphasic fluctuations (+/-0.10-0.15 degrees C) around each subsequent self-administration. Temperature gradually increased before and for 30-50 s after the lever-press, but then abruptly decreased to a minimum at 180-240 s, when it began to increase to reach another peak immediately after the next lever-press. Doubling the dose of injected cocaine significantly potentiated the post-cocaine temperature decrease and increased time to the next lever-press. In contrast to drug-reinforced lever-presses, temperatures phasically increased after non-reinforced lever-presses and at the end of a session when the lever was blocked and the rat was hyperactive, trying to reach the inaccessible lever. While temperature changes in each recording location were generally correlative, the initial temperature elevation was stronger in all brain structures than in muscle and ventral striatum was the structure that showed the most pronounced and consistent temperature fluctuations. These data suggest a generalized brain activation associated with cocaine-seeking and cocaine-taking behavior with its phasic fluctuations around individual drug self-injections. While the initial component of brain activation preceding the first lever-press for cocaine is internally determined and closely related to behavioral search, subsequent biphasic fluctuations in neural activity associated with repeated drug intakes appear to be drug-mediated. Cocaine-induced potentiation of monoamine transmission is a possible factor for gradual increases in neural activity that drive cocaine seeking, while a rapid, brain concentration-dependent action on Na(+) transport (local anesthetic action) is the most probable factor determining an abrupt, transient cessation of neural activation associated with cocaine reward.


Subject(s)
Body Temperature/physiology , Brain/drug effects , Brain/physiology , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Animals , Cocaine-Related Disorders/metabolism , Energy Metabolism/physiology , Male , Motivation , Rats , Rats, Long-Evans , Reward , Self Administration
7.
Arch Environ Contam Toxicol ; 45(4): 479-91, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14708664

ABSTRACT

The extended free ion activity model (FIAM) was developed by integrating concepts from the original FIAM into biological receptor theory, to obtain a conceptual model that more precisely quantifies the interaction of chemical species at biological receptor sites. The extended FIAM was tested by determining the acute (48 h) valve movement behavior (VMB) (measured in terms of the duration of valve opening) of the Australian freshwater bivalve, Hyridella depressa, to increasing concentrations of total Cd or Cu, in a standard synthetic water under conditions of varying pH (6.5-7.5) and/or dissolved organic carbon (as model fulvic acid (FA)) concentrations (0-11.2 mg L(-1)). Valve movement behavior, measured using an automated data acquisition system, was shown to be a quantifiable and rapid, real-time endpoint for assessing the toxic effects of Cd and Cu exposures. The VMB of H. depressa to Cd was independent (p > 0.05) of pH and/or model FA concentration. In contrast, the VMB of H. depressa to Cu was highly dependent (p < 0.001) on pH and/or model FA concentration; individuals were more sensitive to Cu at low pH and model FA concentrations. The VMB of H. depressa was directly proportional to the activity of the free metal ion (Cd2+), for the linear region of the concentration-response curves. In contrast, the VMB of H. depressa was a weighted function of the activities of the free metal ion and the 1:1 metal hydroxide species (i.e. 2.02 x Cu2+ + CuOH+), whereby Cu2+ had a two-fold greater binding affinity than CuOH+ at the cell membrane surface. Moreover, the results for Cd and Cu are consistent with the extended FIAM, as opposed to the original FIAM, where the result for Cu would be regarded as an exception. The extended FIAM explained 98% of the variability in VMB, whereas the original FIAM explained only 63% (i.e. an improvement of 35%). The improved predictability of organism response to Cu is relevant to advancing water quality guidelines for protecting aquatic biota.


Subject(s)
Cadmium/toxicity , Carbon/chemistry , Copper/toxicity , Models, Theoretical , Mollusca , Water Pollutants/toxicity , Animals , Cell Membrane/physiology , Hydrogen-Ion Concentration , Ions
8.
Sci Total Environ ; 275(1-3): 27-41, 2001 Jul 25.
Article in English | MEDLINE | ID: mdl-11482401

ABSTRACT

Whole soft tissue concentrations of Mn, Co, Ni, Cu, Zn, Pb, Cd and U were measured in two species of freshwater (unionid) bivalves (Hyridella depressa and Velesunio ambiguus) from a minimally polluted site in the Hawkesbury-Nepean River, south-eastern Australia. Although the mean concentrations of metals in the tissue were similar for each bivalve species, their patterns of accumulation were dissimilar. For each metal, positive linear relationships between tissue concentration and shell length (r2 = 0.37-0.77; P < or = 0.001) and tissue dry weight (r2 = 0.29-0.51; P < or = 0.01) were found in H. depressa, but not in V. ambiguus. However, for both species, positive linear relationships were found between the tissue concentration of each divalent metal and Ca tissue concentration (r2 = 0.59-0.97; P < or = 0.001). For both bivalve species, the normalised rates of accumulation of the metals relative to increasing Ca concentration and/or size, were U approximately = Cd > or = Pb > or = Mn > Co > or = Zn > Cu > Ni. The differential rates of accumulation of divalent metals are interpreted as being predominantly governed by their varying loss rates, which are controlled by the differing solubilities (log Ksp values) of the metals in the phosphatic extracellular granules, the demonstrated major sites of metal deposition in the tissue of H. depressa and V. ambiguus. The rates of accumulation of Mn, Co, Zn, Cu and Ni were linearly and inversely related (r2 = 0.91-0.97; P < or = 0.001) to their solubilities as hydrogen phosphates, a finding consistent with the bioaccumulation model previously developed for the alkaline-earth metals. However, for U, Cd and Pb, this linear inverse relationship did not continue to hold, i.e. their rates of accumulation did not increase with decreasing solubility. However, these results are still consistent with the model if U, Cd and Pb are so insoluble in the granules of H. depressa and V. ambiguus over their lifetime (up to approx. 50 years) that there is effectively no loss of these metals, and hence, no differential between their rates of accumulation. The present results reaffirm the use of Ca tissue concentration to predict the tissue concentrations of other divalent metals by explaining up to 94 and 97% of the variability between individual bivalves of H. depressa and V. ambiguus, respectively. The use of Ca tissue concentration to effectively minimise the inherent variability between individuals in their metal tissue improves the ability of an investigator to discern smaller spatial and/or temporal differences in the metal tissue concentrations of these bivalves, and thus to detect metal pollution.


Subject(s)
Calcium/analysis , Fresh Water/analysis , Mollusca/chemistry , Phosphates/analysis , Water Pollutants, Chemical/analysis , Animals , Australia , Cadmium/analysis , Cobalt/analysis , Copper/analysis , Environmental Monitoring , Environmental Pollution , Lead/analysis , Manganese/analysis , Models, Animal , Nickel/analysis , Tissue Distribution , Trace Elements/analysis , Uranium/analysis , Zinc/analysis
9.
Pharmacol Biochem Behav ; 68(2): 263-72, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11267631

ABSTRACT

Previous animal stress studies have illustrated the marked impact of coping on subsequent behavior and physiology by using shock as the stressor. The current study evaluates the generality of shock stress controllability effects in a new swim stress paradigm on several dependent measures: behavioral despair, analgesia, shuttlebox escape, and alcohol reactivity. In this new paradigm, rats in the escape group are able to learn the behavioral response as evidenced by significant reduction in the acquisition of a lever press response. Both escape and yoked subjects showed "behavioral despair" in comparison to both restrained and home cage controls when tested 24 h later. In the standard shuttlebox escape task 24-h post-stress, no group differences emerged, although a trend for poorer performance in the yoked subjects was evident. No group differences were observed in pain sensitivity after the first or second forced swim exposure. Finally, stress controllability effects were observed in behavioral reactivity to alcohol 2-h post-stress as measured by rotarod performance. This effect is opposite to the previous observations with the tailshock stress controllability paradigm. These results suggest that (1) there are certain similarities, but some fundamental differences between the behavioral endpoints measured following intermittent swim stress in comparison to the well-established effects of the intermittent tailshock stress model and (2) the qualitative nature of a stressor may markedly influence the behavioral and physiological consequences of stress and coping.


Subject(s)
Escape Reaction , Learning , Pain Measurement/methods , Research Design , Stress, Physiological , Analgesia/psychology , Animals , Ataxia/chemically induced , Central Nervous System Depressants/adverse effects , Ethanol/adverse effects , Male , Pain Measurement/psychology , Rats , Rats, Sprague-Dawley , Stress, Physiological/psychology
10.
Aquat Toxicol ; 51(2): 155-75, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11064122

ABSTRACT

The veracity of the free ion activity model (FIAM) was tested by examining the acute (48 h) valve movement responses (VMR) (measured in terms of the duration of valve opening) of the Australian tropical freshwater unionid bivalve, Velesunio angasi to increasing concentrations of total Mn or U, in a standard synthetic water under conditions of varying pH (5.0-6.0) and/or dissolved organic carbon (model fulvic acid, FA) concentrations (0-8.9 mg l(-1)). Valve movement behaviour, measured using an automated data acquisition system, was shown to be a quantifiable and rapid, real-time endpoint for assessing the toxic effects of Mn and U exposures. For Mn, the VMR of V. angasi were independent (P>0.05) of pH and/or model FA concentration. In contrast, VMR to U exposures were highly dependent (P< or =0.05) on pH and/or model FA concentration; individuals were more sensitive to U at low pH and model FA concentrations. Valve movement responses to Mn were directly proportional to the activity of the free metal ion (Mn(2+)), which is consistent with the FIAM. In contrast, VMR to U were regarded as an 'exception' to the FIAM, since they were a weighted function of the activities of the free metal ion and the 1:1 metal hydroxide species (i.e. 1.86 x UO2(2+) + UO2OH(+)). Additionally, the effect of U on V. angasi demonstrates the importance of examining VMR at more than one pH. At a fixed pH, the results for U were consistent with the FIAM (i.e. response was directly proportional to UO2(2+)); only when pH was altered, were the results inconsistent with the FIAM. The inconsistency in the VMR of V. angasi to U exposures in this study, together with similar examples from other studies using different metals (e.g. Al or Zn), raises questions regarding the veracity of the FIAM. A detailed examination of the conceptual development of the FIAM is required to probe its apparent failure to describe several metal-organism interactions.


Subject(s)
Manganese Poisoning/psychology , Manganese/chemistry , Mollusca/physiology , Movement/drug effects , Uranium/toxicity , Algorithms , Animals , Benzopyrans/pharmacology , Chemical Phenomena , Chemistry, Physical , Hydrogen-Ion Concentration , Ions , Models, Biological , Uranium/chemistry
11.
Aquat Toxicol ; 51(2): 177-94, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11064123

ABSTRACT

The present study integrates the concepts of the free ion activity model (FIAM) into biological receptor theory (BRT; i.e. pharmacodynamic principles) to obtain a more rigorous conceptual model; one that more precisely quantifies the interaction of chemical species at biological receptor sites. The developed model, which is viewed as an extended FIAM, explains the conditions under which the FIAM will be effective in explaining biological response (BR). It establishes that BR is directly proportional to the activity of the free metal ion in the linear regions of concentration-response curves only. Additionally, it indicates that [X-cell], the activity of free surface sites on the cell membrane, does not need to be constant in the region of BR, as assumed by the original FIAM. The extended FIAM was tested by re-examining concentration-response data from the literature on aquatic organisms exposed to several ecotoxicologically-relevant trace metals. These data, which would be considered exceptions to the original FIAM, were found to be consistent with the extended FIAM. Due to its more rigorous conceptual basis, the extended FIAM is capable of modelling concentration-response experiments from a wider range of water chemistry conditions (i.e. varying pH, hardness and dissolved organic matter) than the original model and, as such, potentially provides a more useful tool for evaluating metal-organism interactions. This study proposes, for the first time, a quantitative method of uncoupling the biological effects of a metal hydroxide (1:1) complex from that of amelioration of the free metal ion (M(z+)) by H(+). Since the activities of H(+) and metal-hydroxide cannot be independently varied, it has been previously very difficult to evaluate whether metal-hydroxide species contribute to eliciting a BR. Furthermore, the extended FIAM can directly derive fundamental information from concentration-response curves, such as the binding constants of H(+) or the hardness cations (Ca(2+) and/or Mg(2+)) to the cell membrane surface of aquatic organisms.


Subject(s)
Metals/toxicity , Algorithms , Animals , Hydroxides , Metals/chemistry , Minerals/chemistry , Models, Biological , Mollusca/physiology , Organic Chemicals/toxicity , Protons , Receptors, Cell Surface , Water Supply/analysis
12.
J Androl ; 21(2): 328-38, 2000.
Article in English | MEDLINE | ID: mdl-10714828

ABSTRACT

Although the process of glycolysis is highly conserved in eukaryotes, several glycolytic enzymes have unique structural or functional features in spermatogenic cells. We previously identified and characterized the mouse complementary DNA (cDNA) and a gene for 1 of these enzymes, glyceraldehyde 3-phosphate dehydrogenase-s (Gapds). This gene is expressed only in spermatids. The enzyme appears to have an essential role in energy production required for fertilization, and it is reported to be susceptible to inhibition by certain environmental chemicals. We have now cloned and sequenced the cDNA for the human homologue of glyceraldehyde 3-phosphate dehydrogenase (GAPD2) and determined the structure of the gene. The messenger RNA (mRNA) was detected in testis, but not in 15 other human tissues analyzed by Northern blot technique. The deduced GAPD2 protein contains 408 amino acids and is 68% identical with somatic cell GAPD. GAPD2 has a 72-amino acid segment at the amino terminal end that is not present in somatic cell GAPD. This segment is proline-rich but contains smaller stretches of polyproline and is 30 amino acids shorter than the comparable segment of mouse GAPDS. The structure of the human GAPD2 gene was determined by polymerase chain reaction (PCR) to identify exon-intron junctions in a genomic clone and in total genomic DNA. The locations of these junctions in the GAPD2 gene corresponded precisely to those of the 11 exon-intron junctions in the mouse Gapds gene. Immunohistochemical studies found that GAPD2 is located in the principal piece of the flagellum of human spermatozoa, as are GAPDS in mouse and rat spermatozoa. GAPD2 extracted from human spermatozoa and analyzed by Western blot technique migrated with an apparent molecular weight of approximately 56,000, although the calculated molecular weight is 44 501. The conserved nature of the mouse, rat, and human enzymes suggests that they serve similar roles in these and other mammalian species.


Subject(s)
Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Spermatozoa/enzymology , Amino Acid Sequence , Base Sequence , Blotting, Western , Chromosome Mapping , Chromosomes, Human, Pair 19 , DNA, Complementary , Humans , Male , Molecular Sequence Data , Sequence Homology, Amino Acid
14.
J Chem Inf Comput Sci ; 39(6): 1017-26, 1999.
Article in English | MEDLINE | ID: mdl-10614024

ABSTRACT

Combinatorial chemistry and high-throughput screening are revolutionizing the process of lead discovery in the pharmaceutical industry. Large numbers of structures and vast quantities of biological assay data are quickly being accumulated, overwhelming traditional structure/activity relationship (SAR) analysis technologies. Recursive partitioning is a method for statistically determining rules that classify objects into similar categories or, in this case, structures into groups of molecules with similar potencies. SCAM is a computer program implemented to make extremely efficient use of this methodology. Depending on the size of the data set, rules explaining biological data can be determined interactively. An example data set of 1650 monoamine oxidase inhibitors exemplifies the method, yielding substructural rules and leading to general classifications of these inhibitors. The method scales linearly with the number of descriptors, so hundreds of thousands of structures can be analyzed utilizing thousands to millions of molecular descriptors. There are currently no methods to deal with statistical analysis problems of this size. An important aspect of this analysis is the ability to deal with mixtures, i.e., identify SAR rules for classes of compounds in the same data set that might be binding in different ways. Most current quantitative structure/activity relationship methods require that the compounds follow a single mechanism. Advantages and limitations of this methodology are presented.


Subject(s)
Combinatorial Chemistry Techniques/methods , Drug Design , Drug Industry , Structure-Activity Relationship
16.
Pharmacol Biochem Behav ; 62(1): 45-51, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9972844

ABSTRACT

The purpose of this study was to examine whether acute stress exposure would alter the ataxic properties of midazolam or ethanol in rats. Rats were administered either vehicle or FG 7142 (10 mg/kg) and placed back in their home cages, or placed in restraining tubes for 90 min. Three and one-half or 24 h following injection all subjects were then administered an ataxic dose of either ethanol or midazolam and after 10 min, motoric impairment was assessed by rotarod performance. Neither FG 7142 administration nor restraint had an impact on rotarod performance 3-1/2 h later for ethanol nor 24 h later in response to midazolam. However, midazolam-induced ataxia was significantly modified 3-1/2 h following both restraint and FG 7142 exposure. Similarly, at the 24-h time point, both manipulations had a significant effect on ethanol-induced motor incoordination. Importantly, prior exposure to FG 7142 and restraint was without effect on rotarod performance in saline-treated subjects. Functional alterations in behavioral reactivity to low doses of two classes of CNS depressants by the acute stress of restraint and/or FG 7142 administration suggest the anxiogenic nature of these stressors may be the critical factor.


Subject(s)
Ataxia/physiopathology , Carbolines/pharmacology , Ethanol/toxicity , GABA Modulators/toxicity , Midazolam/toxicity , Animals , Ataxia/chemically induced , GABA Antagonists/pharmacology , Male , Motor Activity/drug effects , Motor Activity/physiology , Rats , Rats, Sprague-Dawley , Restraint, Physical , Time Factors
17.
Invert Neurosci ; 4(1): 41-53, 1999.
Article in English | MEDLINE | ID: mdl-12491073

ABSTRACT

The medicinal leech possesses FMRFamide-like immunoreactivity in neural processes and somata associated with the pharynx and pharyngeal ganglia. The pharynx possessed about 25 immunoreactive somata; about half of the approximately 20 neurons of the pharyngeal ganglia were immunoreactive. We provide brief descriptions of several neurons located in the first neuromere of the subesophageal ganglion involved in controlling pharyngeal motility. Double-labeling experiments indicate that one of these cells, named Swallow neuron 1 (SW1), contains a FMRFamide-like peptide. Stimulation of SW1 caused the mouth to open and the pharynx to dilate. Upon termination of SW1 stimulation, the mouth closed, and a peristaltic wave progressed from the mouth down the length of the pharynx. Stimulation of SW1 did not produce 1:1 postsynaptic potentials in pharyngeal muscle cells. Thus, SW1 is apparently not a motor neuron. The pharynx responded to application of FMRFamide and related peptides by producing a series of 20- to 35-s phasic contractions superimposed upon an increase in basal tonus. The peptide-induced response was quantified by measuring increases in basal tonus, peak tension, and integrated area. Although there were some differences in the order of potency depending upon which parameter was considered, the approximate order of potency of RFamide peptides tested was: pQDPFLRFamide > or = FMRFamide approximately YGGFMRFamide > or = YMRFamide approximately FLRFamide approximately GGKYMRFamide approximately YLRFamide > leucomyosuppressin approximately perisulfakinin. Except for differences in potency, each of the RFamide peptides produced similar contractile waveforms. FMRFamide-induced responses were reduced by the protein kinase C inhibitor bisindolylmaleimide I (10 microM), the nonspecific protein kinase inhibitor H-7 (50 microM), and were increased by the protein phosphatase inhibitor okadaic acid (1 microM). However, the FMRFamide-induced response was unaffected by the protein kinase A inhibitor H-89 (1 microM), the phosphodiesterase inhibitor theophylline (1 mM), the phospholipase A(2) inhibitor OBAA (0.1 microM) or the cation channel blocker amiloride (100 microM).


Subject(s)
FMRFamide/pharmacology , Leeches/physiology , Neurons/physiology , Pharynx/drug effects , Pharynx/innervation , Animals , Electrophysiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Immunohistochemistry , Leeches/cytology , Neurons/cytology , Neurons/drug effects , Neuropeptides/pharmacology , Organ Culture Techniques , Peristalsis/drug effects , Peristalsis/physiology , Pharyngeal Muscles/drug effects , Pharyngeal Muscles/physiology , Pharynx/cytology
18.
Sci Total Environ ; 217(3): 201-30, 1998 Jul 03.
Article in English | MEDLINE | ID: mdl-9703695

ABSTRACT

Fresh surface waters from the Hawkesbury-Nepean River, the major river supplying water to the Sydney region in south-eastern Australia, were sampled monthly during 1991 and analysed for major ions (Na, K, Ca, Mg, Cl, SO4 and HCO3), nutrients (NO3 and PO4), organic carbon and trace metals (Al, Fe, Cu, Zn, Pb, Cd, Ni, Co and Mn). The chemical composition of the river during 1991 was consistent with other studies of the river from 1977 to 1996. The major ion composition in the river is predominantly influenced by sea-salt aerosols in rainwater (headwaters) and connate sea-salt in groundwater (mid-lower reaches), with a cationic dominance order of Na >> Mg > Ca > K (equivalents) and an anionic order of Cl >> HCO3 > SO4. This is typical of the headwaters of other permanent coastal rivers (freshwater) in south-eastern Australia with a similar catchment lithology. These results differ markedly from the most common natural major ion assemblages established for world rivers (i.e. Ca > Mg > Na > K and HCO3 > SO4 > Cl), which tend to be predominantly influenced by chemical weathering of rocks and minerals. The mean concentrations of major ions, nutrients, organic carbon and trace metals in the freshwater reaches of the Hawkesbury-Nepean River increased by factors of 2.5-4.4, 14-18, 2.2 and 1.6-11, respectively, with increasing distance from the headwaters. Increases in major ion concentrations are attributed mainly to the increasing influence of saline groundwater inflows from regions of Wianamatta shale. Conversely, concentrations of nutrients, organic carbon and trace metals (except Fe and Al) increased as a consequence of anthropogenic inputs, particularly point discharges from sewage treatment plants (i.e. showing distinct, but variable, concentration peaks), as well as diffuse urban and/or agricultural runoff during storm events. The temporal variability of the mean concentrations of all measured parameters in this study was related to variability in water discharge. The mean concentrations of the major ions decreased by a factor of 1.5-3.0 with increasing water discharge, whereas the concentrations of nutrients, organic carbon and trace metals increased by a factor of 2.0-3.0, 1.6 and 1.3-2.0, respectively. This study provides the first survey of trace metal concentrations in the freshwater reaches of a permanent coastal river in Australia using 'clean' sampling and handling techniques. The concentrations of Cu, Zn, Pb, Cd and Ni measured in the headwaters of the Hawkesbury-Nepean River were amongst the lowest reported in the literature for riverine (freshwater) systems, and will form a benchmark for assessing the effects of increasing urbanisation in the catchment.


Subject(s)
Environmental Monitoring , Fresh Water/analysis , Water Pollutants, Chemical/analysis , Australia , Carbonates/analysis , Chlorides/analysis , Metals/analysis , Nitrates/analysis , Organic Chemicals/analysis , Phosphates/analysis , Trace Elements/analysis
19.
Work ; 8(2): 189-96, 1997.
Article in English | MEDLINE | ID: mdl-24441857

ABSTRACT

High unemployment rates for people with multiple sclerosis are frequently attributed to decreases in self-efficacy and outcome expectations with respect to job seeking and retaining tasks. Hence, return-to-work interventions must enable people with MS to develop positive expectations. They must believe (a) that they possess the abilities needed to respond effectively in the job interview and request reasonable job accommodations (self-efficacy) and (b) that they will secure employment as a result of their efforts (outcome expectations). Based on social cognitive strategies, the Accommodations Planning Team (APT) Seminar offers the skill training required for increasing employment-related efficacy and outcome expectations.

20.
Int J Sport Nutr ; 5(4): 315-28, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8605518

ABSTRACT

This study was undertaken to determine whether high-level training alters food choice behavior with regard to meat and dairy products because of their high fat content. Twenty male collegiate swimmers were compared to 20 male sedentary students for dietary fat intake, nutrition knowledge, and liking of meat and dairy products. There was no significant difference between the two groups for restraint, energy intake, dietary fat intake, and energy derived from fat. Nutrition knowledge, energy derived from saturated fat, and cholesterol intake, however, were significantly higher in the athletes. The two groups did not differ in their hedonic ratings of flavor or in their overall degree of liking of the meat and dairy products, and the athletes actually liked the appearance and texture of the products significantly more than did the sedentary students. This study shows that the sensory appeal of fat-containing animal products is not affected in male swimmers by a high level of exercise.


Subject(s)
Dairy Products , Dietary Fats , Exercise/physiology , Food Preferences , Meat , Swimming , Adult , Attitude , Dietary Fats/administration & dosage , Energy Intake , Humans , Male , Nutritional Physiological Phenomena , Sensation
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