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M Davis

Publications and source records attributed to M Davis.

At least 199 records · Page 11Linked to original sources
PubMed1997

Role of the septum in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex.

Intracerebroventricular administration of corticotropin-releasing hormone (CRH) elicits a constellation of behavioral, autonomic, and endocrinological changes typically observed in stress. One of the behavioral changes after intracerebroventricular CRH is a profound increase of startle amplitude (CRH-enhanced startle). The present study examined the role of the septum in CRH-enhanced startle. The septum has direct and indirect connections to the amygdala and inhibits the amygdala. Electrophysiological data show that CRH in the septum is inhibitory. Therefore, it has been hypothesized that intracerebroventricular CRH inhibits the septum, which in turn disinhibits the amygdala, resulting in a constellation of changes via activation of amygdala efferent targets. In testing this hypothesis, it was found that electrolytic lesions of the medial septum, but not the lateral septum, blocked CRH-enhanced startle. However, fiber-sparing chemical lesions of the medial septum did not block CRH-enhanced startle, suggesting that the blockade seen with the electrolytic lesions was caused by damage to fibers of passage. A major fiber bundle passing through the medial septum is the fornix, the primary efferent pathway for the hippocampus. Fimbria transection blocked CRH-enhanced startle almost completely, whereas the large electrolytic lesions of the dorsal hippocampus did not block CRH-enhanced startle. Taken together, these data suggest that perhaps the ventral hippocampus and its efferent target areas, which communicate via the fimbria, may be critically involved in CRH-enhanced startle.

Acoustic Stimulation↗
PubMed1997

Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex.

Previously, we demonstrated that transection of the fimbria/fornix blocked the excitatory effect of corticotropin-releasing hormone (CRH) on startle (CRH-enhanced startle), suggesting that the hippocampus and its efferent target areas that communicate via the fimbria may be critically involved in CRH-enhanced startle. The bed nucleus of the stria terminalis (BNST) receives direct projections from the ventral hippocampus via the fimbria/fornix. Therefore, the role of the ventral hippocampus, the BNST, and the amygdala in CRH-enhanced startle was investigated. NMDA lesions of the BNST completely blocked CRH-enhanced startle, whereas chemical lesions of the ventral hippocampus and the amygdala failed to block CRH-enhanced startle. However, the same amygdala-lesioned animals showed a complete blockade of fear-potentiated startle, a conditioned fear response sensitive to manipulations of the amygdala. In contrast, BNST-lesioned rats had normal fear-potentiated startle. This indicates a double dissociation between the BNST and the amygdala in two different paradigms that enhance startle amplitude. Microinfusions of CRH into the BNST, but not into the ventral hippocampus, mimicked intracerebroventricular CRH effects. Furthermore, infusion of a CRH antagonist into the BNST blocked CRH-enhanced startle in a dose-dependent manner. Control studies showed that this blockade did not result from either leakage of the antagonist into the ventricular system or a local anesthetic effect caused by infusion of the antagonist into the BNST. The present studies strongly suggest that CRH in the CSF can activate the BNST, which could lead to activation of brainstem and hypothalamic BNST target areas involved in anxiety and stress responses.

Acoustic Stimulation↗
PubMed1997

Second-order fear conditioning prevented by blocking NMDA receptors in amygdala.

Antagonists of NMDA (N-methyl-D-aspartate)-type glutamate receptors disrupt several forms of learning. Although this might indicate that NMDA-receptor-mediated processes are critical for synaptic plasticity, there may be other mechanisms by which NMDA-receptor antagonism could interfere with learning. For instance, fear conditioning would be blocked by microinfusion of the NMDA-receptor antagonist AP5 (D,L-2-amino-5-phosphonovalerate) into the basolateral amygdala if AP5 inhibited routine synaptic transmission, thereby reducing the ability of stimuli to activate amygdala neurons. In second-order fear conditioning, the reinforcer is a fear-eliciting conditioned stimulus rather than an unconditioned stimulus. Expression of conditioned fear is amygdala-dependent and so provides a behavioural assessment of the ability of the reinforcer to activate amygdala neurons in the presence of AP5. We report here that intra-amygdala AP5 actually enhances expression of conditioned fear to the conditioned stimulus that provides the reinforcement signal for second-order conditioning. Nevertheless, acquisition of second-order fear conditioning is completely blocked. Our findings strongly support the view that NMDA receptors are critically involved in synaptic plasticity.

2-Amino-5-phosphonovalerate↗
PubMed1997

Empirical free energy calculations: a blind test and further improvements to the method.

Empirical Gibbs functions estimate free energies of non-covalent reactions (deltaG) from atomic coordinates of reaction products (e.g. antibody-antigen complexes). The function previously developed by us has four terms that quantify the effects of hydrophobic, electrostatic and entropy changes (conformational, association) upon complexation. The function was used to calculate delta deltaG of ten lysozyme mutants affecting the stability of the HyHEL-10 antibody-lysozyme complex. The mutants were computer-modeled from the X-ray structure of the wild-type, and free energy calculations produced a correlation coefficient of 0.5 with the experimental delta deltaG data (average absolute error +/-3 kcal). The following changes were then introduced into the Gibbs function: (1) the hydrophobic force was made proportional to the molecular surface, as calculated by the GEPOL93 algorithm, with the scaling constant of 70 cal/mol/A2; (2) calculation of the electrostatics of binding was carried out by the finite difference Poisson-Boltzmann algorithm, which employed uniform grid charging, dielectric boundary smoothing and charge anti-aliasing; and (3) side-chain conformational entropy was estimated from the CONGEN sampling of torsional degrees of freedom. In the new calculations, correlation with experimental data improved to 0.6 or 0.8 if a single outlying mutant, K96M, was neglected. Analysis of the errors remaining in our calculations indicated that molecular mechanics-based modeling of the mutants, rather than the form of our amended Gibbs function, was the main factor limiting the accuracy of the free energy estimates.

Animals↗
PubMed1997

Enhancement by an ampakine of memory encoding in humans.

Acentrally active drug that enhances AMPA receptor-mediated currents was tested for its effects on memory in humans. Evidence for a positive influence on encoding was obtained in four tests: (i) visual associations, (ii) recognition of odors, (iii) acquisition of a visuospatial maze, and (iv) location and identity of playing cards. The drug did not improve scores in a task requiring cued recall of verbal information. The selectivity of drug effects on memory was confirmed using tests of visual recognition, motor performance, and general intellectual functioning. These results suggest that positive modulators of AMPA receptors selectively improve at least some aspects of memory.

Adult↗
PubMed1997

Loss of heterozygosity at the alpha-inhibin locus on chromosome 2q is not a feature of human granulosa cell tumors.

The alpha-inhibin gene has been shown in knockout mouse models to be a suppressor of granulosa tumorigenesis in the mouse. To determine if alpha-inhibin has the same function in humans, we have assessed the frequency of loss of heterozygosity (LOH) of the alpha-inhibin gene locus on chromosome 2q in 17 human granulosa cell tumors and 36 epithelial ovarian cancers. LOH was detected in 12 of 36 (33.3%) epithelial tumors but in only 1 of 17 (6%) granulosa cell tumors. These data suggest that in contrast to the suggestions from the mouse model alpha-inhibin does not function as a granulosa cell tumor suppressor gene in the human. Furthermore, analysis of the TP53 gene in the granulosa cell tumors failed to detect either LOH or point mutations, indicating that they have a developmental pathway distinct from that of epithelial ovarian tumors.

Adult↗
PubMed1997

Selective impairments of mitochondrial respiratory chain activity during aging and ischemic brain damage.

Cumulative oxidative damage to mitochondrial deoxyribonucleic acid (DNA) with subsequent defects in oxidative phosphorylation may reduce the capacity of the aging brain to cope with metabolic stress. This may contribute to the age related increase in cerebral infarct size that has been documented following permanent middle cerebral artery occlusion (MCAO) in the rat. This hypothesis was evaluated by assessing mitochondrial respiratory chain complex activity in both ischemic and non ischemic brain tissue of adult (10 month) and aged (28 month) male Wistar rats, six hours after occlusion of the left middle cerebral artery. Aging was associated with a significant decline in cerebral mitochondrial function with impairment of the activities of complexes I. II and IV. The individual respiratory chain complexes also exhibited selective vulnerability to a focal cerebral ischemic lesion, with significant impairment of complex I activity in the lesioned hemisphere of both age groups. The age related decline in complex I activity may be important in the enhanced susceptibility of the aging brain to ischemic neuronal damage.

Aging↗
PubMed1997

The effect of non-competitive N-methyl-D-aspartate receptor antagonism on cerebral oedema and cerebral infarct size in the aging ischaemic brain.

Although vulnerability to ischemic neuronal injury is enhanced with age, the aging brain may be less amenable to neuroprotection as a result of quantitative and qualitative changes in the NMDA receptor. In addition, the elderly may be less tolerant of adverse effects of neuroprotective drugs and this might ultimately limit therapeutic potential in human stroke. However, antagonism of the excitotoxic effects of glutamate by parenteral administration of the non competitive NMDA antagonist magnesium has been well tolerated and has shown to be neuroprotective in young animal models of stroke and head injury. We therefore evaluated the potential of magnesium chloride to reduce ischemic neuronal injury in aged rodents subjected to permanent occlusion of the middle cerebral artery. Treatment with magnesium chloride induced hypotension and hyperglycaemia in both adult and aged rats and did not reduce ischemic neuronal injury or cerebral edema. However, despite these adverse haemodynamic and biochemical effects, which may augment cerebral infarct size, ischemic damage was not exacerbated in the treated groups, suggesting that magnesium has the potential to salvage penumbral neurons and that inotropic support and maintenance of normoglycaemia may permit realisation of its neuroprotective potential. This may have important implications for future clinical stroke trials.

Aging↗
PubMed1997

The transition to adulthood for youth who have serious emotional disturbance: developmental transition and young adult outcomes.

This article reviews studies that depict the developmental transition from adolescence to young adulthood of persons who have experienced serious emotional disturbance (SED) as children or adolescents. The literature demonstrates that their plight in young adulthood is grave. Youth with SED enter the transition phase delayed in their developmental maturation and face additional challenges relative to their nondisabled peers. As a group, they are undereducated, underemployed, and have limited social supports. Homelessness, criminal activity, and drug use are prevalent. This article defines the transitional youth population, describes the developmental tasks of transition, and summarizes the results of longitudinal studies that have tracked functional outcomes of transitional youth into young adulthood. The discussion focuses on the relevance of these findings to service provision.

Adolescent↗
PubMed1997

Anti-arthritic activity of hydroxamic acid-based pseudopeptide inhibitors of matrix metalloproteinases and TNF alpha processing.

OBJECTIVE AND DESIGN: The effects of two hydroxamate inhibitors of metalloproteinase and tumor necrosis factor alpha (TNF alpha) processing on endotoxin-induced plasma TNF alpha and arthritic lesions in adjuvant-induced arthritic (AA) rats were determined. MATERIAL AND TREATMENT: BB-1101 and BB-1433 were administered orally twice daily to AA Lewis rats with an established disease (days 13 to 22). AA rats (day 16) or normal rats were injected with bacterial endotoxin and plasma levels of TNF alpha were also determined. METHODS: Hindpaw swelling was measured plethysmographically. Bone degradation was determined by radiography and bone mineral densitometry. TNF alpha was quantified using a sandwich ELISA. RESULTS: The hydroxamic-acid pseudopeptides inhibited plasma. TNF alpha levels in vivo and significantly reduced swelling and bone degradation of the tibiotarsal joints of AA rats in the range of 10-50 mg/kg given orally (p < 0.01 by Student's t-test). CONCLUSIONS: Thus, these novel compounds offer a new disease modifying therapy for arthritis and the results also suggest that inhibition of TNF alpha production may contribute, at least in part, to their anti-arthritic activity.

Animals↗
PubMed1997

Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-chlorophenylpiperazine (mCPP).

Preclinical studies suggest that acoustic startle amplitude is increased during ethanol withdrawal. The current study evaluated the effects of intravenous infusion of the alpha 2-adrenergic antagonist, yohimbine (0.4 mg/kg), the serotonin partial agonist m-chlorophenylpiperazine (mCPP, 0.1 mg/kg), and placebo administered to 22 male patients meeting DSM-III-R criteria for alcohol dependence and 13 male healthy subjects. Patients and healthy subjects completed 3 test days under double-blind conditions in a randomized order. Patients were sober for 12-26 days prior to testing. On each test day, participants completed startle testing 80 min following drug infusion. Stimuli with varying intensities (90, 96, 102, 108, 114 dB) were presented in a randomized order balanced across four blocks. Stimuli consisted of 40-ms bursts of white noise administered every 45-60 s for 15-20 min through headphones. Analyses indicated that patients exhibited elevated acoustic startle magnitudes on the placebo day relative to healthy subjects. In patients, the magnitude of startle amplitudes elicited at 90 dB, but not 114 dB, correlated significantly with the number of previous alcohol detoxifications. Yohimbine increased startle magnitudes and reduced startle latencies relative to placebo and mCPP in both patients and healthy subjects. mCPP did not alter startle magnitude in either group. Yohimbine also increased the probability that a 90-dB stimulus produced a startle response in healthy subjects, but not in patients. Blunting of yohimbine effects on startle probability may reflect the baseline elevations in startle probability levels in patients, but may also be consistent with other evidence of reduced postsynaptic, but not presynaptic, noradrenergic function in these same patients. These data replicate and extend previous reports indicating that yohimbine facilitates the acoustic startle response in humans. They also further implicate the number of episodes of ethanol withdrawal as a factor influencing subsequent neurobiological responsivity in chronic alcoholic patients. Based on the current data, future research should explore whether measurement of the acoustic startle response provides an objective quantitative severity measure of ethanol withdrawal.

Acoustic Stimulation↗
PubMed1997

Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle.

The whole-body acoustic startle response is a short-latency reflex mediated by a relatively simple neural circuit in the lower brainstem and spinal cord. The amplitude of this reflex is markedly enhanced by moderate fear levels, and less effectively increased by higher fear levels. Extensive evidence indicates that the amygdala plays a key role in the potentiation of startle by moderate fear. More recent evidence suggests that the periaqueductal gray is involved in the loss of potentiated startle at higher levels of fear. The influence of both structures may be mediated by anatomical connections with the acoustic startle circuit, perhaps at the level of the nucleus reticularis pontis caudalis. The present chapter reviews these data.

Amygdala↗
PubMed1997

Elicitation and reduction of fear: behavioural and neuroendocrine indices and brain induction of the immediate-early gene c-fos.

The elicitation and reduction of fear were indexed with fear-potentiated startle and corticosterone release and induction of the immediate-early gene c-fos as a marker of neural activity in male Sprague-Dawley rats. Conditioning consisted of pairing one stimulus with footshock, which was withheld when the conditioned stimulus was preceded by a different modality stimulus, the conditioned inhibitor. On the test day, approximately 60% of the rats were used for c-fos in situ hybridization, and were presented with either the conditioned stimulus alone, the conditioned inhibitor alone, a compound of the two stimuli, or no stimuli, and killed 30 min following the presentation of 10 such stimuli. The remaining rats were tested with the fear-potentiated startle paradigm. Rats displayed reliable fear-potentiated startle and corticosterone release to the conditioned stimulus, and both measures were reduced when the conditioned stimulus was preceded by the conditioned inhibitor. The ventral bed nucleus of the stria terminalis, septohypothalamic nucleus, some tegmental nuclei, and the locus coeruleus had particularly high c-fos induction in rats that received the conditioned inhibitor, providing one of the first functional indication that these nuclei might be important in behavioural or endocrine inhibition. Conditioning specific c-fos induction in the three groups that received a stimulus on the test day was observed in many hypothalamic areas, the medial geniculate body and the central gray, structures previously involved in fear and anxiety. The cingulate, infralimbic and perirhinal cortex, nucleus accumbens, lateral septum, dorsal endopiriform nucleus, and ventral tegmental area had higher c-fos induction in rats presented with the fearful conditioned stimulus, confirming previous studies. The amygdala and hippocampus of conditioned rats did not show higher c-fos induction than in rats repeatedly exposed to the context. Many regions displayed c-fos messenger RNA induction in the control condition, suggesting that processes other than fear and anxiety participate in c-fos induction.

Animals↗
PubMed1997

Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase I metabolites and glutathione conjugates.

Sulforaphane (SFN) is a naturally occurring isothiocyanate present in cruciferous vegetables, such as broccoli, that has been identified as a potent inducer of glutathione S-transferase activities in laboratory animals. The present studies were carried out to elucidate the metabolic fate of SFN in the rat. Particular emphasis was placed on glutathione (GSH)-dependent pathways because conjugation with GSH is a major route by which many isothiocyanates are eliminated in mammals. Male Sprague-Dawley rats were administered a single dose of SFN (50 mg kg-1 ip), and bile and urine were collected over ascorbic acid. Analysis of biological fluids was carried out by ionspray LC-MS/MS using the neutral loss (129 Da) and precursor ion (m/z 164) scan modes to detect GSH and N-acetylcysteine (NAC) conjugates, respectively. In bile, five thiol conjugates (designated M1-M5) were detected. Metabolites M2 and M4 were identified as the GSH conjugates of SFN and erucin (ERN, the sulfide analog of SFN), respectively, by comparing their LC-MS/MS properties with those of standards obtained by synthesis. M1 was characterized as the GSH conjugate of a desaturated metabolite of SFN (tentatively assigned the structure of delta 1-SFN), suggesting that the parent compound also undergoes oxidative metabolism. Metabolites M3 and M5 were identified as the NAC conjugates of SFN and ERN, respectively, and together with the NAC conjugate of delta 1-SFN, these species also were detected in urine. Quantitative determination of the former two mercapturates in urine indicated that approximately 60% and approximately 12% of a single dose of SFN is eliminated in 24 h as the NAC conjugates of SFN and ERN, respectively. The corresponding figures in rats dosed with ERN were approximately 67% and approximately 29%. When the GSH conjugate of SFN was incubated with phosphate buffer (pH 7.4, 37 degrees C), < 1% of the conjugate dissociated to liberate free SFN. On the other hand, the conjugate underwent a facile thiol exchange reaction (> 70% conversion) when incubated in the presence of excess cysteine, thereby acting as an effective carbamoylating agent. It is concluded that SFN undergoes metabolism by S-oxide reduction and dehydrogenation and that GSH conjugation is the major pathway by which the parent compound and its phase I metabolites are eliminated in the rat.

Animals↗
PubMed1997

Inhibition of fear-potentiated startle can be detected after the offset of a feature trained in a serial feature-negative discrimination.

Using the fear-potentiated startle paradigm in rats, 4 experiments examined whether the inhibitory effect of a feature is evident after its offset following serial feature-negative discrimination training (A+ and X-->A-). When startle probes were presented shortly after the offset of X on X-->A test trials, the inhibitory properties of X were observed immediately after its offset. Furthermore, trace reinforcement of X (X-->+), but not delay reinforcement (X+), disrupted the ability of X to inhibit fear-potentiated startle on X-->A trials. Trace conditioning to X was also retarded after A+ and X-->A- training. These results suggest that the inhibitory properties of the serially trained feature are present after its offset and raise the possibility that either temporal information regarding nonreinforcement or poststimulus attributes of X acquire inhibitory properties.

Animals↗
PubMed1997

Olfactory bulbectomy enhances sensitization of the acoustic startle reflex produced by acute or repeated stress.

The effects of olfactory bulbectomy on the acoustic startle reflex and shock-induced sensitization of the startle reflex were examined in 3 experiments. In Experiment 1, bulbectomized animals showed a modest increase in baseline startle responding following surgery, and normal acquisition of fear-potentiated startle, but a pronounced increase in baseline startle responding during the course of conditioning relative to sham-operated controls. In Experiments 2 and 3, bulbectomized animals showed shock-induced sensitization of the startle reflex to shock intensities that did not produce sensitization in sham and unoperated controls. These data suggest that olfactory bulbectomy results in an increased vulnerability to stressors, which may be mediated by a disinhibition of the amygdala or other structures involved in mediating stress and anxiety. Thus, the olfactory bulbectomy model of depression may share some similarities with other stress-induced models of depression.

Acoustic Stimulation↗