Search PubMed⌕ Search

Biomedical subjects

A J Dunn

Publications and source records attributed to A J Dunn.

At least 19 recordsLinked to original sources
PubMed1992

Apparent inter-channel interference in dual-electrode electrochemical detection.

During the course of routine high-performance liquid chromatographic analyses of brain catecholamines using dual-electrode electrochemical detection, we encountered an unusual negative peak in the lower-voltage channel. Subsequent investigations suggested that this peak was caused by tyrosine which produced a positive peak in the higher-voltage channel. Our investigations indicate that compounds that generate a peak in one channel appear to be responsible for complex peaks in a second channel set at a lower voltage, close to or below that necessary for oxidation. The complex peaks are biphasic; a sharp negative peak coinciding with the positive peak on the higher-voltage channel, followed by a positive peak. This effect was not specific for tyrosine, but was observed on the lower-voltage channel with all compounds tested that produced signals on the high-voltage channel. The cause of the problem is unknown, but it appears to be an artifact of the electrical coupling of the two electrode channels in a dual-channel system.

Animals↗
PubMed1992

Non-glycosylated recombinant pro-concanavalin A is active without polypeptide cleavage.

The complex post-translational processing of concanavalin A (Con A) in maturing jackbeans is unique because the non-glycosylated mature active protein is circularly permuted in primary sequence relative to its own inactive precursor (glycosylated pro-Con A) and to other legume lectins. We show here that non-glycosylated pro-Con A expressed in bacteria from recombinant cDNA (rec-pro-Con A) folds in vivo and in vitro to a stable form which is active without further processing. N-glycosylation alone must therefore be sufficient to inactivate pro-Con A--a novel role for glycosylation in regulating activity during protein maturation.

Base Sequence↗
PubMed1992

Nucleus basalis lesions in neonate rats induce a selective cortical cholinergic hypofunction and cognitive deficits during adulthood.

Ibotenic acid was infused into the nucleus basalis magnocellularis (nBM) of 2-day old rats to eliminate immature cholinergic neurons before they develop functional synaptic connections in the neocortex. For bilaterally lesioned neonates, cognitive testing was initiated 2 months after lesioning and animals were sacrificed at 8 or 12 months of age. Lesioned animals exhibited a marked deficit in the retention of passive avoidance behavior, as well as in the acquisition of 2-way active avoidance behavior. Lesioned animals also made significantly more alternation errors than control animals in the Lashley III spatial maze and showed severe impairments in general learning, reference memory and working memory during 17-arm radial maze testing. For all 4 tasks, neonatally lesioned animals did not show any recovery to the performance level of control animals. Histological analysis of the subcortex from lesioned animals during adulthood revealed: (1) a substantial reduction in acetylcholinesterase-positive cells (presumably cholinergic) within the nucleus basalis, (2) decreased acetylcholinesterase staining in neocortex and (3) a gliosis essentially restricted to the globus pallidus. Surrounding brain regions were apparently not damaged as a direct result of excitotoxin infusion. Neurochemically, neonate nBM lesioning produced a long term cholinergic hypofunction as evidenced by significant reductions of 25% and 18% in frontal cortex choline acetyltransferase (CAT) activity at 12 and 8 months of age, respectively. By contrast, prefrontal cortical concentrations of biogenic amines and their metabolites were unaffected, thus indicating a degree of neurochemical specificity for these neonatal nBM lesions. The persistent cortical cholinergic hypofunction in lesioned animals may be related to the long term deficits in learning/memory abilities that were also observed. It is suggested that neonatal nBM lesioning could provide a useful animal model for elucidating the plasticity of the developing brain after cortical anervation.

Acetylcholinesterase↗
PubMed1992

The role of cyclo-oxygenase and lipoxygenase in the interleukin-1-induced activation of the HPA axis: dependence on the route of injection.

Interleukin-1 (IL-1) has been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis, and to elevate cerebral concentrations of tryptophan and the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG). Eicosanoids have been shown to be involved in a number of the effects of IL-1, but their role in the activation of the HPA axis is controversial. We studied the effects of various cyclo- and lipoxygenase inhibitors on the neurochemical and HPA responses to IL-1. Pretreatment of mice with the cyclo-oxygenase inhibitors, indomethacin (10-25 mg/kg) or ibuprofen (10 mg/kg) failed to prevent the elevations of plasma corticosterone, or hypothalamic MHPG or tryptophan that followed intraperitoneally (IP) administered IL-1. Similar results were obtained with the nonspecific oxygenase inhibitor, BW 755C, and the lipoxygenase inhibitor, BW A4C. However, the cyclo-oxygenase inhibitor, diclofenac, did attenuate the IL-1-induced elevation of plasma corticosterone and the neurochemical changes. To resolve the conflicting data on the effect of indomethacin on the IL-1-induced elevation of plasma concentration, we studied the effects of indomethacin on the response to IL-1 injected intravenously (IV). By contrast with the response to IP IL-1, that to IV IL-1 was attenuated by indomethacin. Time course of the HPA response to IL-1 is more rapid following IP injections than IV, therefore we assessed the effects of IV IL-1, earlier than that to IP IL-1. Forty min following IP IL-1, the corticosterone response to IL-1 was markedly attenuated. This suggests that more than one mechanism is involved in the HPA response to IL-1. The more rapid one, predominant in the case of IV injections, is sensitive to cyclo-oxygenase inhibitors, whereas the slower one is not.

Animals↗
PubMed1992

Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies.

The effects of cocaine on defensive withdrawal behavior in rats and elevated plus-maze behavior in mice were investigated. Cocaine (20 mg/kg IP) injected daily for 7 or 14 days induced defensive withdrawal; that is, the latency to emerge from a small chamber in an open field and the mean time in the chamber were both significantly increased. Acute cocaine administration also induced defensive withdrawal, and this effect was prevented by prior treatment with chlordiazepoxide (5 mg/kg IP). Both acute and chronic cocaine treatments significantly increased plasma concentrations of corticosterone and reduced the ratios of 3,4-dihydroxyphenylacetic acid to dopamine and 5-hydroxyindoleacetic acid to serotonin in several brain regions. Further evidence for an acute anxiogenic effect of cocaine was obtained from mice studied in the elevated plus-maze. Acute cocaine administration decreased both the number of entries into and the time spent in the open arms of the maze. These results taken together strongly support an anxiogenic action of acute and chronic cocaine administration.

Animals↗
PubMed1992

Iron induces degeneration of nigrostriatal neurons.

Parkinson's-diseased (PD) brains have been reported to contain increased quantities of iron within the zona compacta of the substantia nigra (SN). To test whether excess iron in the SN could cause a PD-like loss of dopaminergic neurons, various concentrations of iron were infused unilaterally within the SN of adult male rats. At 1-2 months post-infusion, examination of thionine and iron stained brain sections from animals infused with low concentration iron revealed: (1) iron diffusion limited to and concentrated within the infused SN and (2) a selective degeneration of neurons within zona compacta of SN. Infusion of higher iron concentrations induced near complete neuronal losses in zona compacta, as well as neuronal degeneration within zona reticularis and areas immediately adjacent to the SN. Striatal dopamine and its catabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced in a dose-dependent fashion, with over 80% depletions observed at the highest iron concentration infused. These data indicated that neurons within zona compacta of SN are sensitive to infusions of low iron concentrations. The data support the notion that iron in zona compacta of the SN could act as an endotoxin in the pathogenesis of PD.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

The role of interleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin.

Both interleukin-1 (IL-1) and endotoxin (lipopolysaccharide, LPS) are potent activators of the hypothalamo-pituitary-adrenal (HPA) axis, and they also increase cerebral norepinephrine metabolism and tryptophan. Injections of cause macrophages to synthesize and release various cytokines, including IL-1 and tumor necrosis factor alpha (TNF alpha). The hypothesis that macrophage production of IL-1 mediates the HPA-activating effect of LPS was tested in mice using the IL-1-receptor antagonist protein (IRAP). Administration of IRAP largely prevented the effects of IL-1 alpha or IL-1 beta on the elevation of plasma corticosterone and the concomitant increase in hypothalamic norepinephrine metabolism, but failed to alter the responses to LPS. IRAP did not prevent the increases in brain tryptophan that occurred after treatment with IL-1 or LPS. Recombinant human TNF alpha, TNF beta, IL-6, and interferon-alpha injected intraperitoneally failed to activate the HPA axis, but mouse TNF alpha was effective by this route, and human TNF alpha, TNF beta, and IL-6 were effective intravenously. None of these cytokines was as potent as IL-1. Pretreatment with an antibody specific for mouse TNF alpha, either alone or in combination with IRAP, also failed to prevent the elevation of plasma corticosterone by LPS. Thus, either IL-1 and TNF alpha are not involved in the HPA and noradrenergic responses to LPS, or there are alternative (redundant) pathways by which LPS can activate the HPA axis.

Animals↗
PubMed1992

Noradrenergic innervation of the hypothalamus participates in adrenocortical responses to interleukin-1.

Stress and immune activation are associated with increases in plasma concentrations of corticosterone (CS). To determine whether the catecholaminergic innervation of neurons in the hypothalamic paraventricular nucleus (PVN) is involved in these responses, selective lesions were made using 6-hydroxydopamine (6-OHDA). Injection of 6-OHDA into the PVN depleted its norepinephrine (NE) content by 85% and reduced by 80-82% the increase in plasma CS concentrations following intraperitoneal injection of recombinant human interleukin-1 alpha (IL-1), but did not affect the adrenocortical response to 20 min restraint. Injection of 6-OHDA into the ventral noradrenergic ascending bundle depleted PVN NE content by 77%. This lesion reduced the CS response to human IL-1 alpha by 82-86%, but did not alter that to 20 min restraint, although there was a nonsignificant decrease in the CS response following 3 min of restraint. These results suggest that the noradrenergic innervation of the PVN mediates the activation of the hypothalamic-pituitary-adrenal (HPA) axis by intraperitoneally injected IL-1. There may be a noradrenergic contribution to the HPA response to restraint, but other neural pathways probably also participate in this response.

Adrenal Cortex↗
PubMed1992

Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1.

Administration of either endotoxin (lipopolysaccharide, LPS) or interleukin-1 (IL-1) activates the hypothalamic-pituitary-adrenal axis and cerebral catecholamine systems. Because LPS can stimulate IL-1 production in vivo, it is possible that the effects of LPS are mediated by IL-1. This hypothesis was evaluated by comparing the neurochemical and corticosterone responses to i.p. LPS and IL-1. In addition, the possibility that LPS acts by penetrating the brain was examined by comparing the neurochemical responses to i.p. and i.c.v. administration. Intraperitoneal injection of LPS increased mouse brain concentrations of the norepinephrine catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the dopamine catabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), and the 5-hydroxytryptamine catabolite, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan in all brain regions examined. By contrast, i.p. IL-1 alpha and IL-1 beta increased cerebral concentrations of MHPG, 5-HIAA and tryptophan, but not DOPAC. The MHPG responses to IL-1 were substantially greater in hypothalamus than in other brain regions, whereas those to LPS were less regionally specific. The minimum effective doses of LPS and IL-1 were around 1 microgram and 10 ng, respectively. After i.p. LPS, plasma concentrations of corticosterone, DOPAC and MHPG peaked around 2 hr, whereas peak concentrations of tryptophan and 5-HIAA occurred around 8 hr. Intracerebroventricular LPS also elevated plasma corticosterone and cerebral concentrations of MHPG and 5-HIAA, but DOPAC was unchanged. LPS was not substantially more potent i.c.v. than i.p.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Reduction of exploratory behavior by intraperitoneal injection of interleukin-1 involves brain corticotropin-releasing factor.

The behavior of mice was scored in a multicompartment chamber one hour following intraperitoneal injection of recombinant human interleukin-1 (IL-1). Both IL-1 alpha and IL-1 beta dose-dependently reduced the mean duration for which mice were in contact with novel stimuli without altering measures of locomotor activity, such as movements between the compartments or rears. These behavioral changes resemble those previously observed with prior restraint or intracerebroventricular (ICV) injection of corticotropin-releasing factor (CRF). Effective doses were in the range 0.1-10 ng for IL-1 alpha, and 1-10 ng for IL-1 beta. The reduction in stimulus-contact times induced by 1 ng of IL-1 beta was reversed by prior ICV injection of the CRF antagonist, alpha-helical CRF9-41, suggesting that IL-1 causes secretion of brain CRF which in turn elicits the behavioral changes. These results indicate that peripheral administration of IL-1 alpha or IL-1 beta in low doses can alter behavior. They provide additional evidence that IL-1 administration stimulates brain CRF secretion, and that brain CRF can modulate exploratory behavior, and thus reinforces the concept that IL-1 administration can induce stress.

Analysis of Variance↗
PubMed1991

Stress- and endotoxin-induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity.

Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock- and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on beta- as opposed to alpha-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to 5-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.

Animals↗
PubMed1990

Effects of nucleus basalis lesions on cerebral cortical concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity in the rat.

The present study was designed to determine the effects of partial cholinergic denervation on parietal cortical corticotropin-releasing hormone-like immunoreactivity (CRH-LI) in the rat at different ages. Young adult rats received either unilateral or bilateral ibotenic acid infusions into their nucleus basalis, destroying most of the acetylcholinesterase-positive neurons in that region. Parietal cortical levels of CRH-LI were assayed 2.5, 10, 14 and 19 months after placement of nucleus basalis lesions. Parietal CRH-LI was elevated at 10, 14 and 19 months in bilaterally lesioned animals, while unilateral lesions had no effect on CRH-LI.

Aging↗
PubMed1990

DSP-4-induced depletion of brain norepinephrine produces opposite effects on exploratory behavior 3 and 14 days after treatment.

Exploratory behavior of a complex novel environment was examined 3 and 14 days following treatment with the noradrenergic-selective neurotoxin, DSP-4. This toxin significantly decreased norepinephrine concentrations in neocortex and hippocampus but not hypothalamus. DSP-4 significantly increased exploratory behavior in animals tested 3 days after treatment. In contrast, exploratory behavior was decreased in animals tested 14 days after treatment. The effect of DSP-4 at 3 days is similar to treatments that act to inhibit noradrenergic function such as administration of the alpha 1-antagonist, prazosin, or the alpha 2-agonist, clonidine. The effect of DSP-4 at 14 days resembles that observed following treatment with the alpha 1-agonist, phenylephrine, or the alpha 2-antagonist, idazoxan. These data provide additional support for a role of noradrenergic systems in exploratory behavior. The simplest explanation for the time dependent effects of DSP-4 on exploratory behavior is the occurrence of the slow development of a supersensitivity of cerebral systems affected by norepinephrine.

Animals↗
PubMed1990

Central beta 1-adrenergic receptors are involved in CRF-induced defensive withdrawal.

Previous studies indicated that peripheral administration of propranolol, a nonselective beta-adrenergic antagonist, attenuated ICV CRF-induced suppression of a conditioned emotional response and defensive withdrawal behavior in rats, suggesting the involvement of a beta-adrenergic receptor in the CRF-induced behavioral changes. The present study was carried out to determine whether central or peripheral beta-adrenergic receptors are involved in CRF-induced defensive withdrawal behavior, and which subtype of beta-adrenergic receptor is involved. l-Propranolol (2.5 mg/kg IP) significantly reversed CRF-induced defensive withdrawal behavior. CGP-12177 (1 mg/kg IP), a beta-adrenergic antagonist with predominant effects on peripheral beta-adrenergic receptors, and ICI 118,551 (0.5 mg/kg IP), a selective beta 2-adrenergic antagonist, had no significant effects on CRF-induced defensive withdrawal. When administered ICV, two selective beta 1-adrenergic antagonists, CGP-20712A (10 micrograms) and atenolol (100 micrograms), significantly antagonized CRF-induced defensive withdrawal. Our results suggest that a central beta 1-adrenergic receptor is involved in CRF-induced defensive withdrawal in rats.

Animals↗
PubMed1990

Corticotropin-releasing factor acts via a third ventricle site to reduce exploratory behavior in rats.

Corticotropin-releasing factor (CRF, 20-25 ng) injected into the lateral or fourth ventricles of rats decreased exploratory behavior in the multicompartment testing chamber (MCC), as assessed by decreased mean contact times with novel stimuli. This result extends similar observations made previously in mice. To investigate the site of this action of CRF, cold cream plugs injected into the cerebral ventricles of rats were used to prevent access of the CRF to specific periventricular sites. When the cerebral aqueduct was blocked with cold cream, CRF injected into the lateral ventricle, but not the fourth ventricle, decreased exploratory behavior in the MCC. These results suggest that CRF does not act in the fourth ventricle to alter behavior in the MCC, and most likely acts in the lateral or third ventricles. Cold cream blocks within the third ventricle prevented the effect of lateral ventricle administration of CRF. The clearest effects were obtained when the anteroventral portion of the third ventricle (AV3V) had been coated with cold cream. This region, which contains the organum vasculosum laminae terminalis (OVLT), was the only region blocked that showed a significant statistical interaction between the cold cream block and the effect of CRF. This result suggests that the OVLT, or regions close to it, is the primary site of the behavioral action of CRF in the MCC. It is possible that the peptide could be taken up in this region and transported to another brain site.

Animals↗
PubMed1990

Intracerebroventricular administration of interleukin-1 to mice alters investigation of stimuli in a novel environment.

The behavior of mice administered recombinant interleukin-1 (IL-1) was observed in a novel multicompartment chamber. Doses of human IL-1 alpha (4 pg to 40 ng) injected intracerebroventricularly (ICV) 20 min before testing significantly reduced the mean time mice spent in contact with novel stimuli. No other behavior scored (locomotor activity, grooming, scratching) was significantly affected. Similar results were obtained with murine IL-1 alpha (770 pg or 77 ng) and hIL-1 beta (1 pg to 10 ng). This behavioral change resembled that induced following restraint or ICV injection of corticotropin-releasing factor (CRF). The behavioral effect of ICV IL-1 was lost after it was heated for 10 min at 100 degrees C. Neither the CRF antagonist, alpha-helical CRF9-41 (10 or 20 micrograms ICV) nor the prostaglandin synthesis inhibitor indomethacin (50 mg/kg IP) significantly altered the hIL-1 alpha-induced behavioral changes, but naloxone (0.7 mg/kg SC) or sulpiride (5 mg/kg IP) completely prevented them. Our results suggest that intracerebral administration of IL-1 reduces the exploratory behavior of mice. This effect does not apparently involve CRF or prostaglandins, but may involve opioid and dopaminergic systems. This behavioral response to IL-1 administration is consistent with the behavioral effects of IL-1 reported previously, and strengthens the hypothesis that IL-1 secretion may be responsible for behavioral changes associated with immune activation.

Animals↗
PubMed1990

The involvement of central noradrenergic systems and corticotropin-releasing factor in defensive-withdrawal behavior in rats.

The role of the central noradrenergic systems and corticotropin-releasing factor (CRF) in modulating defensive withdrawal behavior was studied in rats. The apparatus consisted of a small chamber set on one side of a one-meter open field, into which the rat was placed to start the test. When rats were unfamiliar with the apparatus, they displayed species typical defensive withdrawal behavior with long latencies to emerge from and a high proportion of time spent in the small chamber. Intraperitoneal administration of clonidine (0.03 mg/kg), l-propranolol (2.5 micrograms/kg), prazosin (0.1 mg/kg) or chlordiazepoxide (CDP, 5 mg/kg) each significantly decreased the latency to emerge from and the mean time spent in the small chamber (MTIC) and increased the number of chamber entries. When rats were familiar with the apparatus, prior restraint for 20 min significantly increased the latency and MTIC, and decreased the number of chamber entries and rears, but did not alter locomotor activity. Prazosin, clonidine, CDP, l-propranolol and the CRF-antagonist, alpha-helical CRF9-41 (25 micrograms i.c.v.), reversed the restraint-induced increase in the latency and MTIC. CRF (10-100 ng i.c.v.) dose-dependently induced defensive withdrawal behavior in rats familiar with the apparatus; the minimum statistically significant dose was 50 ng. dl-Propranolol (5 mg/kg) and CDP blocked the CRF-induced changes in the latency to emerge and the MTIC; whereas clonidine and prazosin significantly reduced the latency, but had no statistically significant effects on the MTIC. Phenylephrine (25-200 ng i.c.v.) dose-dependently induced defensive withdrawal behavior. This effect of phenylephrine (200 ng) was significantly antagonized by prazosin or alpha-helical CRF9-41 (25 or 50 mg i.c.v.), but not by CDP. Our results suggest that the hyperactivity of the central noradrenergic systems caused by exposure to the novel environment may stimulate the release of CRF, which through some unknown mechanism induces defensive withdrawal behavior in rats. Activation of beta adrenergic receptors may also induce defensive withdrawal.

Animals↗