Biomedical subjects

H A Baldwin

Publications and source records attributed to H A Baldwin.

At least 19 recordsLinked to original sources

PubMed1996

Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury.

Hepatic cytochromes P450 are known to be down-regulated by cytokines, lipopolysaccharide, Gram-positive bacteria, and viruses. Little is known, however, about the regulation by inflammation of cytochromes P450 in other tissues. We have found that lipopolysaccharide and interleukin-1 beta stimulate the expression of catalytically active CYP2E1 (but not CYP1A1 or CYP2B) up to 7-fold in rat brain primary cortical glial cultures. The induction reached a maximum after 24 hr and was accompanied by an increase in CYP2E1 mRNA. Chlormethiazole, a specific inhibitor of hepatic CYP2E1 transcription, completely inhibited the induction of CYP2E1 at the mRNA and enzyme levels. Immunofluorescence studies showed CYP2E1 to be expressed in a subset of astrocytes in the lipopolysaccharide-stimulated cortical glial cultures. Using a model of global ischemic injury in the gerbil, we found CYP2E1 to be induced in vivo in astrocytes in the inflammatory phase, 1-3 weeks after the lesion. Likewise, CYP2E1 was induced in the rat cortex 1 week after a focal ischemic injury. Our results suggest tissue-specific regulation of CYP2E1 by inflammatory factors and that CYP2E1 may play a role in astrocytes during inflammation in the brain.

Animals↗

PubMed1994

Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity.

Central administration of a Corticotropin-Releasing Factor (CRF) antagonist is well documented to attenuate a variety of behavioral responses to several distinct stressors; however, it is not yet clear whether the activation of CRF neurons is dependent on the type or intensity of the experimental stressor, or rather on the particular behavioral response to stress under study. To test the generality of the stress-protective effect of the CRF antagonist, alpha-helical CRF9-41, (1, 5 or 25 micrograms intracerebroventricularly), the present experiments employed a sensitive index of anxiogenic-like behavior by measuring suppression in exploration on the elevated plus-maze following exposure to social, swim, or restraint stressors. A 1 but not 5 or 25 micrograms dose of the CRF antagonist administered just prior to social, swim, or restraint stress reversed the stress-induced inhibition of exploratory behavior. Chlordiazepoxide and the steroid anesthetic, alphaxalone, also attenuated the anxiogenic-like effect of restraint stress and elevated the baseline exploratory behavior of nonstressed control groups. Although the stressors produced a graded secretion of adrenocorticotropin (ACTH) with the ranking restraint > swim > social, the relative amplitude of behavioral reactivity to social, swim, and restraint stress was comparable. The relative efficacy of the CRF antagonist to reverse the stressor effects was also comparable. These results suggest that antagonism of activated brain CRF systems attenuates the behavioral response to stress regardless of the type or intensity of the stressor as measured by ACTH secretion.

Adrenocorticotropic Hormone↗

PubMed1994

Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat.

1. In vivo microdialysis has been used to investigate the concentration of various amino acids and lactate in the extracellular fluid of the rat cortex following focal ischaemia, the probe being placed in the core of the infarct area. 2. An ischaemic infarct was produced in the cortex by use of a photochemical dye (Rose Bengal) and light irradiation. There was a marked increase in lactate concentration (300%) over the next 4 h. Substantial increases were also seen in the concentration of the excitatory (glutamate and aspartate), inhibitory (GABA and taurine) and other amino acids (serine, alanine, asparagine). 3. Administration of chlormethiazole (200 mg kg-1, i.p.) 5 min after the onset of ischaemia reduced the ischaemia-induced neurodegeneration by approximately 30%, measured histologically 24 h later. 4. Chlormethiazole (200 mg kg-1, i.p.) administration also reduced the rise in the concentration of lactate and all the amino acids by between 30-60% during the first 4 h after the onset of ischaemia. 5. Analysis of the time course of the amino acid changes suggested that chlormethiazole is not neuroprotective because of the inhibition of excitatory amino acid release but rather that the attenuated rise in the concentration of all the amino acids is reflective of neuroprotection and therefore decreased cell death. 6. This conclusion was supported by the observation that the enhanced efflux of glutamate from slices of cerebral cortex which had been induced by incubation of the slices in an hypoxic medium was unaltered by the presence of a high concentration of chlormethiazole (1 mM) in the medium. 7. Overall the data strengthen the evidence for the neuroprotective effect of chlormethiazole in this model of focal ischaemia.

Amino Acids↗

PubMed1993

The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat.

Focal ischaemia in the rat cerebral cortex was produced by means of a photochemically induced thrombosis of cerebral arteries. This was achieved by intravenous infusion of the photosensitive dye Rose Bengal and illumination of the skull with focused green light. Initial experiments justified the use of tetrazolium staining as an index of infarct damage. Using this technique it was demonstrated that chlormethiazole (200 mg/kg, i.p.) given 5 min post ischaemia markedly reduced the area of infarcted cortical tissue. A second experiment replicated this observation and showed that, in contrast, nimodipine (0.5 mg/kg, i.p.) given 5 min post infarct was without effect on infarct size. The pattern of Evans Blue extravasation indicated that the infarct developed over a 24-h period with the major damage occurring in the first 4.5 h. The spread of the infarct beyond the initial core of damage was decreased by an estimated value of almost 50% by injection of chlormethiazole (200 mg/kg, i.p.) 5 min after the light exposure. These data indicate that chlormethiazole is an effective drug in protecting against the effects of focal ischaemia in the rat and, taken with earlier observations that chlormethiazole protects against the effects of global ischaemia in the gerbil, suggest that the drug may be an effective treatment against the ischaemic cell death that can occur following a stroke or cardiac arrest.

Animals↗

PubMed1993

Rapid induction of conditioned opiate withdrawal in the rat.

Previous studies of conditioned opiate withdrawal in animals either have suffered from a lack of readily quantifiable data (e.g., measurement of diarrhea and vocalization in rodents) or were very long and costly (e.g., disruption of operant responding in monkeys). In this study, an attempt was made to produce a rapid and quantifiable measure of conditioned opiate withdrawal in the rat. Rats were trained to lever-press for food reinforcement on a fixed-ratio-15 schedule. All rats were then implanted with two subcutaneous 75-mg morphine pellets and allocated into three groups. The paired group received four naloxone injections (0.025 mg/kg SC) in the operant chambers paired with a distinctive tone and smell. The unpaired group was also exposed to the tone and smell in the chambers on four occasions, but received the naloxone injections in the home cage. The saline control animals were never exposed to naloxone or the tone and smell. On the test day, all rats were exposed to the tone and smell and injected with saline. The paired group showed a significant reduction in operant responding in response to the tone and smell when compared either with the other two groups, or to their own response rates on the previous day. In a second experiment, the paired and unpaired groups were again challenged with the tone and smell and a saline injection 1 month after removal of the morphine pellets. Again, the paired group showed a significant disruption of response. These results suggest that the conditioned stimulus acquired significant behavior-disruptive properties manifest even in the absence of opiate receptor occupancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1993

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro. 7. Several NMDA antagonists prevent methamphetamine-induced neurotoxicity; however chlormethiazole is not an NMDA antagonist. Inhibition of striatal dopamine function prevents methamphetamine-induced toxicity of both dopamine and 5-HT pathways. Therefore the attenuation of the enhanced dopamine release which occurs in animals given chlormethiazole may be associated with the protective action of this drug against methamphetamine-induced neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

CRF antagonist reverses the "anxiogenic" response to ethanol withdrawal in the rat.

The role of the neuropeptide corticotropin-releasing factor (CRF) in mediating the behavioral effects of ethanol withdrawal in the rat was examined using the elevated plus-maze test. In Experiment 1, CRF (0.5 microgram ICV) reduced the percentage of time spent on the open arms of the elevated plus-maze, consistent with an "anxiogenic-like" effect. CRF also reduced the total number of arm entries, indicating a reduction in general activity. Low doses (5 and 25 micrograms ICV) of the CRF antagonist, alpha-helical CRF produced no behavioral effects in the elevated plus-maze, while a higher dose (50 micrograms ICV) elicited CRF-like activity. In experiment 2, rats were maintained for 2-3 weeks on a liquid diet containing ethanol (8.5-11.5% v/v) or sucrose. Eight hours after withdrawal from the ethanol diet rats displayed "anxiogenic-like" responses as well as a reduction in general activity in the elevated plus-maze compared with rats withdrawn from control diet. Alpha-helical CRF significantly antagonized the "anxiogenic-like" effects of ethanol withdrawal in the plus-maze. General activity and physical signs of ethanol withdrawal such as tail stiffness, body tremor and ventromedial distal flexion were unaffected by alpha-helical CRF. Blood Alcohol Levels (BALs) determined immediately after removal of the ethanol diet showed no group differences in ethanol consumption. These results suggest that increased activity of central CRF systems may mediate the anxiogenic effects of ethanol withdrawal.

Animals↗

PubMed1991

Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses.

1. The concentration of tacrine (tetrahydroaminoacridine or THA) in plasma, regions of brain and cerebral extracellular fluid has been studied in the rat at various times following injection of a dose of 5 mg kg-1, i.p. 2. The peak plasma THA concentration was 2.46 nmol ml-1, and occurred 30 min post injection and clearance was first order (t1/2 = 90 min). The concentration in the brain peaked between 30-60 min, and was around 30 times plasma concentration (striatum peak concentration = 65 +/- 3 nmol g-1). Extracellular cerebral concentration measured by in vivo microdialysis was similar to plasma concentration with the peak occurring 100 min post-injection. 3. No evidence was obtained by in vivo dialysis for THA inducing dopamine release from striatum or 5-hydroxytryptamine (5-HT) release from the frontal cortex. Enhanced release of dopamine did occur after (+)-amphetamine (5 mg kg-1, i.p.) injection, while KCl (100 mM) in the probe released both dopamine and 5-HT. 4. Since the minimum plasma THA concentration achieved in this study was at least twice that found in the plasma of patients given THA for the treatment of dementia, these results suggest that monoamine release in the brain does not occur during therapy.

Animals↗

PubMed1991

Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil.

1. The effect of chlormethiazole, and other drugs which potentiate gamma-aminobutyric acid (GABA) function on delayed neuronal death in the hippocampus has been examined in the gerbil. 2. Chlormethiazole (100 mg kg-1, i.p.) and two other drugs previously reported to be neuroprotective (dizocilpine, 3 mg kg-1, i.p. and ifenprodil, 4 mg kg-1, i.p.) were all found to prevent neurodegeneration of CA1/CA2 neurones in the hippocampus when given 30 min before a 5 min episode of bilateral carotid artery occlusion. 3. Chlormethiazole (100 mg kg-1) was neuroprotective when given up to 3 h, after the ischaemic episode. 4. Given 1 h after the cartoid artery occlusion, chlormethiazole produced significant protection against hippocampal neurodegeneration at a dose of 50 mg kg-1, but not at 25 mg kg-1. 5. Phenobarbitone (100 mg kg-1, i.p.) and Saffan (alphaxalone, 45 mg kg-1 plus alphadalone, 15 mg kg-1, i.p.) were not protective when given 1 h after the ischaemic episode while pentobarbitone (30 mg kg-1, i.p.) had a modest protective effect. 6. Evidence is presented to show that neither the operating procedure nor the chlormethiazole administration lowered rectal or cerebral temperature. 7. The data suggest that chlormethiazole may be a useful treatment in the prevention of neurodegeneration following stroke or cardiac arrest.

Animals↗

PubMed1991

Differential effects of ethanol on punished responding in the P and NP rats.

The effects of ethanol administration (0, 0.25, 0.5, 0.75 and 1.0 g/kg intraperitoneal) were examined in a conflict test in 24 alcohol-preferring (P)-rats, 17 alcohol-nonpreferring (NP)-rats, and 24 heterogeneous Wistar rats. The conflict test was a modified Geller-Seifter procedure employing an unpunished random interval 30-sec component and an incremental shock conflict component. Heterogeneous Wistar rats displayed significant increases in punished responding with doses of 0.5, 0.75, and 1.0 g/kg of ethanol. P-rats did not show a significant increase in punished responding until 0.75 g/kg ethanol. NP rats displayed significant increases in punished responding with all doses tested (0.25, 0.5, and 0.75 g/kg). There were no group differences in the effects of ethanol on unpunished responding. Thus NP-rats were more sensitive and P-rats were less sensitive to the anticonflict effects of ethanol than heterogeneous Wistar rats. The results suggest that the P and NP rats may show a profile of sensitivity to the anticonflict effects of ethanol similar to the sensitivity to the intoxicating effects of ethanol observed in family history positive and family history negative human subjects.

Alcoholism↗

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↗

PubMed1989

Antagonistic effects of caffeine and yohimbine in animal tests of anxiety.

The effect of a combination of caffeine and yohimbine was investigated in the social interaction, elevated plus-maze and punished-drinking tests of anxiety. Caffeine (40 mg/kg i.p.) had anxiogenic-like effects in the social interaction and plus-maze tests. Yohimbine (2.5 mg/kg i.p.) was anxiogenic-like in the plus-maze and displayed anticonflict activity. Unexpectedly, caffeine and yohimbine antagonized each others' effects in the social interaction and elevated plus-maze tests.

Animals↗

PubMed1989

Flumazenil prevents the development of chlordiazepoxide withdrawal in rats tested in the social interaction test of anxiety.

Rats were chronically treated with chlordiazepoxide (CDP 10 mg/kg/day) or vehicle for 27 days. Twenty-four hours after their last dose, they received flumazenil (4 mg/kg) or vehicle and were tested in the social interaction test, in a low-light, familiar arena. CDP withdrawal significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. This was completely reversed by flumazenil. A second group received CDP for 27 days and, in addition, received a single dose of flumazenil (4 mg/kg) 6 days before testing. Flumazenil prevented the development of the anxiogenic withdrawal response in these rats.

Animals↗

PubMed1989

Flumazenil but not nitrendipine reverses the increased anxiety during ethanol withdrawal in the rat.

After 7 day's gradual introduction of ethanol, rats were maintained for a further 4 weeks on a liquid diet containing 10% ethanol (mean daily dose 11.8 +/- 0.2 g/kg/day). Control-treated rats received liquid diet alone. Pairs of rats were tested in the social interaction test of anxiety 8 h after withdrawal. Withdrawal from ethanol significantly reduced the time spent in social interaction compared with controls, indicating an anxiogenic withdrawal response. Nitrendipine (50 mg/kg) had no effect on, whereas flumazenil (4 mg/kg) significantly reversed, this withdrawal response. This reversal appeared to be long-lasting as there was still no evidence of increased anxiety when rats were again withdrawn after 3 more days of ethanol diet.

Animals↗

PubMed1989

Effects of a single or repeated administration of the benzodiazepine inverse agonist FG7142 on behaviour and cortical adrenoceptor binding in the rat.

We have reported previously an increase in the number of beta-adrenoceptors in mouse cerebral cortex 7 days after kindling of seizures by repeated once-daily administration of the benzodiazepine receptor inverse agonist, FG7142. In subsequent experiments, an even larger increase in beta-adrenoceptor number was found 7 days after a single injection of this compound. The present experiments investigated whether FG7142-induced changes in adrenoceptor binding are also found in the rat and whether the effects of a single and repeated injections of this drug differ quantitatively. In view of the anxiogenic effects of FG7142, we have also tested for parallel changes in behaviours associated with anxiety and exploration. Nine days after a single injection of FG7142, the number of beta-adrenoceptors in the cerebral cortex was greater than that found after repeated administration of this compound; this difference was statistically significant. There was no difference in beta-adrenoceptor binding to tissues from chronically FG7142-treated and vehicle-injected animals and there were no changes in alpha 2-adrenoceptor binding or noradrenaline levels after either a single or repeated FG7142 treatment. Neither single nor repeated FG7142 treatment modified spontaneous behaviour in either the elevated plus-maze test of anxiety or the holeboard test of exploration. The behavioural effects of yohimbine and clenbuterol in these tests were also unaffected by FG7142. We discuss the possibility that the difference in the effects of a single and repeated administration of FG7142 on beta-adrenoceptor binding is related to the expression of kindled seizures.

Animals↗

PubMed1989

Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors.

The purpose of this study was to determine the mechanism by which caffeine increases anxiety. Rats were tested in the social interaction test of anxiety after administration of caffeine (20 or 40 mg/kg) alone or in combination with various compounds. In order to investigate the role of adenosine receptors, caffeine was given in combination with 2-chloroadenosine (0.1 and 1 mg/kg). To investigate the role of benzodiazepine receptors, chlordiazepoxide (5 mg/kg), a benzodiazepine antagonist, flumazenil (RO 15-1788, 1 and 10 mg/kg) and a triazolobenzodiazepine U-43,465 (32 mg/kg) were used. Finally, an alpha 2-receptor agonist, clonidine (0.1 and 0.025 mg/kg) and a beta-adrenoceptor antagonist, DL-propranolol (5 mg/kg), were used to study the role of noradrenergic systems in the effects of caffeine. Caffeine (20 and 40 mg/kg) reduced the time spent in social interaction and this effect was antagonized by chlordiazepoxide, U-43,465 and DL-propranolol, but not by flumazenil, 2-chloroadenosine or clonidine. It was therefore concluded that the anxiogenic effect of caffeine was unlikely to be due to its effects at adenosine or benzodiazepine receptors. It is suggested that the reversal of caffeine's effects by chordiazepoxide may have been "functional," i.e., merely a cancellation of two opposite effects. It is discussed whether the reversal of caffeine's effects by propranolol and U-43,465 are functional, or reflect a noradrenergic site of action.

2-Chloroadenosine↗

PubMed1989

Evidence that the increased anxiety detected in the elevated plus-maze during chlordiazepoxide withdrawal is not due to enhanced noradrenergic activity.

Rats displayed a reduction in the percentage of time spent on the open arms of the elevated plus-maze 24-30 hours after withdrawal from chronic chlordiazepoxide treatment (10 mg/kg/day IP for 4 weeks). This indicated an anxiogenic response in this test. This anxiogenic response was not significantly reversed by DL-propranolol (5 and 10 mg/kg IP) or clonidine (0.02 and 0.04 mg/kg IP). These results provide no evidence to suggest that the anxiogenic effects of chlordiazepoxide withdrawal are mediated by an increase in noradrenergic activity. The possible involvement of multiple transmitter systems in benzodiazepine withdrawal symptomology is discussed.

Animals↗

PubMed1988

Behavioral effects of acute and chronic administration of caffeine in the rat.

This study investigated the effects of acute and chronic caffeine treatment on behavior in the social interaction, holeboard and home-cage aggression tests and on proconvulsant actions with pentylenetetrazol. Acutely-treated rats received an IP injection of caffeine (20 or 40 mg/kg). Chronically-treated rats received caffeine in their drinking water for 21 days (50 or 100 mg/kg/day) followed by an injection of caffeine on the test day (20 or 40 mg/kg respectively). Acutely, the higher dose of caffeine (40 mg/kg) decreased levels of social interaction. In the holeboard test, 20 mg/kg of acute caffeine increased motor activity whilst 40 mg/kg reduced head-dipping behavior. In the home-cage aggression test, acute caffeine (40 mg/kg) reduced offensive aggressive behaviors. After chronic treatment with caffeine none of these behaviors differed significantly from controls. After both acute and chronic treatment, caffeine (20 and 40 mg/kg) was proconvulsant with pentylenetetrazol.

Aggression↗