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Biomedical subjects

B E Leonard

Publications and source records attributed to B E Leonard.

At least 73 records · Page 4Linked to original sources
PubMed1997

Lisuride prevents learning and memory impairment and attenuates the increase in extracellular dopamine induced by transient global cerebral ischemia in rats.

In this experiment, we tested the efficacy of neuroprotection with lisuride, a dopamine agonist, using the 4-vessel occlusion rat model. Functional improvement was evaluated with two behavior tests exploring learning and memorization capacity in the rat, the Morris water maze and the 14-unit T-maze, 18 days after ischemia. Extracellular dopamine levels during ischemia were determined in search of a possible neuroprotection mechanism. Dopamine and its metabolites, DOPAC and HVA, as well as the serotonin metabolite, 5-HIAA, were assayed with HPLC-EC, in striatal extracellular fluid obtained by in vivo microdialysis in the awake rat. Lisuride was administered at a total dose of 10 ng by continuous intrastriatal infusion or at the dose of 0.5 mg/kg by i.p. infusion, 160 minutes before onset of ischemia for the neurochemical study and at the dose of 0.5 mg/kg via i.p. infusion, 1 hour before occlusion of the carotid arteries, for the behavior tests. Behavioral testing showed significantly better recovery in both sets of behavioral tests, with more pronounced positive results with the 14-unit T-maze, in comparison with the saline-treated animals. Microdialysis confirmed a significant attenuation of the ischemia-induced dopamine surge, whatever the mode of administration, compared with saline-treated animals. These results show that lisuride offers significant neuroprotection from the effect of experimental transient global forebrain cerebral ischemia in the rat; the mechanism would imply, at least in part, reduced levels of extracellular dopamine.

Animals↗
PubMed1997

BIMT 17: a putative antidepressant with a fast onset of action?

BIMT 17, the only compound reported to be a full 5-HT1A agonist and a 5-HT2A antagonist at the frontal cortex, was assessed in three animal paradigms sensitive to antidepressants in rats: olfactory bulbectomy (OB), differential-reinforcement-of-low rate 72-s (DRL 72-s) and learned helplessness (LH). In the OB rats, BIMT 17, given once daily for 14 consecutive days at an i.p. dose of 10 mg/kg, but not of 20 mg/kg, reduced the increase in ambulation of OB rats, 24 h after the last administration. In the DRL 72-s test, BIMT 17 had a different profile than imipramine. A single i.p. injection of 5, 10, 15 or 20 mg/kg BIMT 17, in contrast to the same doses of imipramine, did not affect response and reinforcement rate in DRL 72-s 1 h after the administration. On the other hand, BIMT 17 slightly shifted the peak of the interresponse time (IRT) distribution towards shorter IRT duration, while imipramine shifted the peak of the IRT distribution towards longer IRT duration. In the LH test, acute oral doses (36, 48 or 60 mg/kg) of BIMT 17, given 30 min before testing, reduced the number of escape failures in LH without altering the intertrial crossings. This effect was also induced by a repeated, but not single, administration with 8 or 16 mg/kg imipramine. The plasma levels following i.p. 10 or oral 48 mg/kg BIMT 17 were in the same range. These results indicate that BIMT 17 does not behave like imipramine in all the tests, and suggest that BIMT 17 acts through different mechanisms of action than imipramine. Only clinical trials will tell whether these mechanisms will be relevant, but if so, BIMT 17 might induce a faster onset of therapeutic activity.

Animals↗
PubMed1997

Protective effects of vanoxeamine (GBR 12909) against ischaemia-induced hyperactivity and neurodegeneration in the gerbil model of cerebral ischaemia.

In Mongolian gerbils, bilateral carotid occlusion (BCO) followed by reperfusion causes uniform destruction of the CA1 pyramidal neurons in the hippocampus, and this damage correlates with an increase in locomotor activity. Various drugs, such as NMDA antagonists, calcium channel blockers, and free radical scavengers, have provided neuroprotection against ischaemia-induced damage. More recently, the neuroprotective effects of dopamine have been investigated. A large release of dopamine has been shown to occur at the onset of ischaemia, and dopamine levels return to basal values following reperfusion. In the present study, we investigated the effects of vanoxeamine (GBR 12909) (5 or 10 mg/kg i.p., administered 1 h prior to occlusion) on behavioural and histological changes following global ischaemia in the Mongolian gerbil. Ischaemia was induced by bilateral carotid occlusion for 5 min. Both doses of GBR 12909 significantly potientiated the hyperactivity of the BCO animals measured in the home cage during the first 24 h following surgery and in the locomotor activity arena after 24 h and 48 h. Significant neuroprotection of cells in the CA1 region of the bippocampus was observed in drug-treated animals 96 h postsurgery. The neuroprotective effect of GBR 12909 may be ascribed to sensitisation of the dopamine D, autoreceptor, consequently reducing the release of dopamine that occurs following ischaemia. Alternatively, GBR 12909 may have a direct interaction with the Na+ ion channel-glutamate complex, resulting in reduced release of glutamate and thereby reducing NMDA receptor activation and neuronal damage.

Animals↗
PubMed1997

Effect of chronic treatment with piracetam and tacrine on some changes caused by thymectomy in the rat brain.

Thymectomized rats, 5 weeks after surgery, showed a significant impairment in learning and memory as shown by deficits in passive avoidance and in the Morris water maze test. The behaviour of the thymectomized rats in the "open field" apparatus was largely unchanged. Following treatment for 20 days with either piracetam (500 mg/kg) or tacrine (3.0 mg/kg), the deficit in passive avoidance learning was largely reversed. Chronic treatment with tacrine also reversed the deficit in the behaviour of the thymectomized rats in the Morris water maze. The effects of thymectomy on the biogenic amines and some of their metabolites in the amygdaloid cortex, hypothalamus, striatum and olfactory bulbs were also determined. Relative to the sham-operated controls, thymectomy resulted in a reduction in the noradrenaline concentration in the amygdala, hypothalamus, and olfactory bulbs. This effect was reversed by chronic piracetam and tacrine treatments. The concentration of dopamine was also reduced in the olfactory bulbs after thymectomy whereas in the striatum the concentration of 5-hydroxytryptamine (5-HT; serotonin) was increased. The concentration of gamma amino butyric acid (GABA) was determined in amygdaloid cortex and hippocampus only. The only significant change occurred following chronic treatment of thymectomized rats with tacrine, when a significant elevation of GABA was found. Neither piracetam nor tacrine produced any change in the amines of their metabolites in the sham-operated controls. Tacrine, however, elevated the dopamine and reduced the 5-HT content of the hypothalamus and increased the 3,4-dihydroxylphenylacetic acid concentration of the striatum of thymectomized rats. Examination of the differential white blood cell count of the thymectomized rats showed that the percentage of lymphocytes was decreased, and the percentage of neutrophils increased, relative to the sham-operated controls. Chronic lacrine, but not piracetam, treatment reversed the lesion-induced changes.

Animals↗
PubMed1997

Forced swim test-induced neurochemical endocrine, and immune changes in the rat.

The forced swim test (FST) is a behavioral paradigm that is widely used as a screening test for antidepressant activity in rodents. The objectives of the present study were to characterize the corticosterone and immune responses and in addition to examine neurotransmitter levels, in five brain regions at intervals (15, 30, 60, 90, and 120 min) following the second exposure to the FST. There was a significant but transient reduction in noradrenaline and 5-HT concentrations, in the hypothalamus 15 min post-FST exposure. 5-HT turnover in the frontal cortex and amygdala was significantly increased between 20-120 min post-FST exposure. The FST elicited a robust corticosterone response that peaked significantly at 30 min and had almost returned to baseline 120 min after exposure. There was a significant reduction in total white blood cell count 120 min after the FST, which was accompanied by a significantly reduced percentage of lymphocytes 90 and 120 min post-FST exposure. In addition, there was a significant but transient suppression of both PHA and Con A-induced lymphocyte proliferation 15 min following FST exposure. This study demonstrates that there are neurochemical changes that are coincident with the endocrine and immune changes associated with FST exposure in rats. Furthermore, this model could be used to examine the effects of manipulation of this stress response by antidepressant drugs. Such an investigation could add to our understanding of the interactions between antidepressants, stress and the neuroendocrine and immune systems.

Animals↗
PubMed1997

Behavioural and neurochemical effects of dizocilpine in the olfactory bulbectomized rat model of depression.

The activity of dizocilpine (MK-801; 0.1 and 0.3 mg/kg) administered once daily intraperitoneally (I.P.) was assessed in the olfactory bulbectomized rat model of depression. Olfactory bulbectomy (OB) is associated with a variety of behavioural abnormalities, such as hyperactivity in the "open field" test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioural deficit. In the present study, chronic treatment with 0.1 and 0.3 mg/kg of dizocilpine (I.P.) antagonized the lesion-induced hyperactivity in the "open field" test. Acute treatment with dizocilpine was associated with an increase in locomotor activity in both sham-operated and OB rats, with a greater response in the sham-operated group. Following chronic treatment, this hyperactivity was found to be greater in the OB-treated animals compared with the sham-treated animals. Olfactory bulbectomy reduced serotonin (5-HT), noradrenaline (NA), and dopamine (DA) concentrations in the frontal cortex. Chronic dizocilpine administration did not alter the 5-HT or NA response. In contrast, chronic administration of dizocilpine to OB animals did attenuate the OB-related deficit in DA. In the OB-operated control animals, there was an increase in DOPAC levels. In conclusion, chronic dizocilpine administration displays antidepressant-like activity in the OB rat model of depression. However, unlike conventional antidepressants, dizocilpine does not correct the 5-HT and NA neurotransmitter deficits that occur in this model.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

The olfactory bulbectomized rat as a model of depression: an update.

The olfactory bulbectomized (OB) rat has been proposed as an animal model of depression. The following behavioural changes have been observed following bilateral olfactory bulbectomy: hyperactivity in an enclosed arena, such as the open-field; enhanced nocturnal hyperactivity in a 24-hr home cage activity monitor; deficits in memory, as shown by passive avoidance behaviour and in the Morris maze and the 8-arm radial maze; increased open arm entries in the elevated plus-maze; and changes in food motivated and conditioned taste aversion behaviour. Alterations in the noradrenergic, serotonergic, cholinergic, gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmitter systems are also associated with olfactory bulbectomy. The variety of immune changes following olfactory bulbectomy includes reduced neutrophil phagocytosis, lymphocyte mitogenesis, lymphocyte number and negative acute phase proteins, increased leucocyte adhesiveness/aggregation, monocyte phagocytosis, neutrophil number and positive acute phase proteins. An enhanced nocturnal secretion of corticosterone is observed in OB rats, which is normally suppressed by dexamethasone. The most commonly employed behavioural indicator of antidepressant activity is attenuation of the OB-related hyperactivity in the open-field. However, many of the other behavioural, neurotransmitter and immune changes have been shown to be attenuated by chronic (but not acute) antidepressant treatment. Tricyclic antidepressants (amitriptyline, desipramine), atypical agents (mianserin), selective serotonin reuptake inhibitors (paroxetine, sertraline, fluvoxamine), reversible inhibitors of monoamine oxidase A (moclobemide), as well as putative antidepressants such as 5-hydroxytryptamine1A agonists (zalospirone, ipsapirone), noncompetitive N-methyl-D-aspartate antagonists (MK-801) and triazolobenzodiazepines (alprazolam, adinazolam), have demonstrated antidepressant-like activity in this model. As many of the changes exhibited by the OB rat are qualitatively similar to those observed in depressed patients, it may be concluded that the OB rat is a model of depression and not just a means whereby putative antidepressants may be tested.

Animals↗
PubMed1997

Altered expression of amyloid protein precursor mRNA in the rat hippocampus following trimethyltin intoxication: an in situ hybridization study.

Previous studies have reported increased levels of amyloid protein precursor (APP) and APP mRNA in the hippocampus and basal forebrain of patients with Alzheimer's disease. Similar changes have been found in the brains of aged rodents and transgenic mice. It now appears that alterations in the expression of individual isoforms of APP mRNA may have a role to play in amyloid-pathogenesis. Here we examined the effect of acute administration of the limbic system neurotoxin trimethyltin (TMT) (8 mg/kg i.p.) on APP-751 and APP-695 mRNA expression in the rat hippocampus (CA1, CA2, CA3 and CA4) using in situ hybridization techniques. We found that following TMT treatment the expression of APP-751 mRNA was increased in CA1 pyramidal cells while that of APP-695 mRNA remained unchanged. TMT also increased the numbers of APP-751 and APP-695 mRNA positively hybridized cells in the CA1 pyramidal layer. These findings suggest that an alteration in APP mRNA expression is involved in the response of the rodent brain to TMT intoxication.

Amyloid beta-Protein Precursor↗
PubMed1997

The effects of the 5-HT1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat.

5-HT1A receptor agonists have been shown to be effective clinically in the treatment of depression and anxiety. Flesinoxan is an example which is highly selective for the 5-HT1A receptor subtype. The objective of this study was to appraise the antidepressant potential of flesinoxan (1 and 3 mg/kg s.c.) in three tests which are indicative of antidepressant activity. These are (1) the forced swim test, following sub-acute administration, (2) 'open field' activity in the olfactory bulbectomised (OB) rat, following chronic administration, and (3) 8-OH-DPAT-induced hypothemia following chronic treatment. Both doses of flesinoxan significantly reduced the immobility time in the sham and OB groups when compared to their respective controls. In the 'open field', there was a significant increase in the ambulation of the OB control group. The higher dose of flesinoxan significantly reduced this deficit. In addition both doses of flesinoxan significantly attenuated the 8-OH-DPAT-induced hypothermic response. These effects of flesinoxan are quantitatively similar to those seen following the chronic administration of antidepressants. These studies illustrate the potential antidepressant properties of flesinoxan, and hence further emphasise the role of the 5-HT1A receptor in the pathogenesis of depression.

Animals↗
PubMed1997

Noradrenaline in basic models of depression.

This review reports anatomical studies evaluating central and peripheral alpha 2- and beta-adrenoceptors. The results suggest abnormalities exist in the noradrenergic system in depressed patients. Most animal models involve the use of stress to simulate depression in man. All models that have been developed lead to differential changes in noradrenergic function. We have assessed the effects of reboxetine, a novel, selective noradrenaline-reuptake inhibitor (NARI) in olfactory bulbectomised rats, a procedure that induces significant changes in amygdala function. Reboxetine is an effective antidepressant in the forced swim test and open field test in bulbectomised rats. Unlike the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAT hypothermia test, indicating that reboxetine is selective for the noradrenergic system. Owing to the abnormalities that occur in depression, it would seem sensible to target the noradrenergic system for treatment of this condition.

Adrenergic Uptake Inhibitors↗
PubMed1997

An appraisal of the pharmacological and toxicological effects of a single oral administration of 3,4-methylenedioxymethamphetamine (MDMA) in the rat.

This study examined some acute pharmacological and toxicological effects of 3,4 methylenedioxymethamphetamine (MDMA, "Ecstasy") over a range of doses (20, 40, 80, 160 and 320 mg/kg orally) in adult female rats. Deaths were observed from the 40 mg/kg MDMA group onwards. Reductions in body weight change, food and water intake were found in the 80 mg/kg group, whilst food intake alone was reduced in the 20 and 40 mg/kg groups. Significant hyperthermic responses were found over the first 8 hr following MDMA administration which were dose-related. A significant hyperactivity of approximately 9 hr duration was observed in the 20 mg/kg and 40 mg/kg groups, whereas there was evidence of a serotonin syndrome in the higher dosage groups. Thus, acute oral administration of MDMA results in a variety of measurable responses. The cause of death in this study is probably a combination of serotonin syndrome and hyperthermia.

Administration, Oral↗
PubMed1997

Effect of chronic pretreatment with the sigma ligand JO 1784 on CRF-induced changes in behaviour, neurotransmitter and immunological function in the rat.

The effects of the chronic administration of the sigma ligand JO 1784 (igmesine) CRF-induced changes in some behavioural, immune, endocrine and neurotransmitter parameters were studied. In the elevated plus maze, CRF (1.0 microgram i.c.v. daily x 5 days) induced a reduction in the number of entries and time spent on the open arms was significantly attenuated by the sigma ligand JO 1784 (3 mg/kg x 21 days) treatment. In the open field apparatus, the CRF-induced increase in the locomotor activity was also reduced by JO 1784 administration. JO 1784 treatment did not alter the concentration of the biogenic amine transmitters in the hypothalamus, nor reverse the increase in the turnover of serotonin and dopamine caused by CRF. JO 1784 treatment also failed to reverse a CRF-induced increase in the serum corticosterone, but it did reverse the reduction in phytohaemagglutinin and concanavalin A-induced lymphocyte proliferation caused by CRF but not the changes in the lymphocyte and neutrophil numbers caused by the peptide. These results demonstrate that JO 1784 has some antistress properties in CRF-treated rats.

Animals↗
PubMed1997

Behavioural effects of selective serotonin reuptake inhibitors following direct micro injection into the left red nucleus of the rat.

The behavioural effects of selective serotonin reuptake inhibitors (paroxetine, sertraline, citalopram, fluvoxamine, fluoxetine) and reference compounds (N,N'-di(o-tolyl)guanidine, haloperidol, 3-(3-hydroxyphenyl)-N-(l-propyl)piperidine and chlorpromazine) were studied for their ability to produce dystonia and torticollis following direct micro injection into the left red nucleus of the rat, an area of the brain containing a high density of sigma2 receptors but relatively devoid of biogenic amine receptors. Each animal was monitored for abnormalities in posture and movement for a period of 30 min and then sacrificed 40 min following drug administation. Only fluvoxamine (100 nmol) and fluoxetine (100 nmol) elicited acute dystonic behaviour (1-5 min). The onset of dystonia was accompanied by facial spasticity, vacuous chewing movements and grooming behaviour which reflected the extent of dystonia. The dystonic behaviour following the direct intrarubal injection of fluvoxamine and fluoxetine suggest the possible activation of sigma2 receptors while citalopram, sertraline and paroxetine were without effect. The results of this study support the role of sigma2 receptors in the regulation and control of movement and coordination and provides preliminary evidence to suggest the in vivo activity of sigma receptors by fluoxetine and fluvoxamine.

1-Naphthylamine↗
PubMed1997

The role of noradrenaline in depression: a review.

This review summarizes some of the evidence implicating a dysfunction in the noradrenergic system in depression. Whereas the results of studies reporting changes in the concentration of the main noradrenaline metabolite, 3-methoxy-4-hydroxyphenylglycol, are equivocal, changes in adrenoceptor density and function and changes in adrenoceptors associated with the pituitary-adrenal axis function strongly implicate a disorder in central noradrenergic transmission in depression. This dysfunction may be caused by changes in the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines. The effect of corticotrophin releasing factor in modulating the activity of noradrenergic neurons in the locus coeruleus may provide the link between environmental trigger factors and central noradrenergic dysfunction. At the cellular level, evidence is presented of a link between noradrenaline and glutamate (via the N-methyl-aspartate receptor) and receptors. Such a link may provide a basis for the future development of novel antidepressants.

Depressive Disorder↗
PubMed1996

The effects of central administration of neuropeptide Y on behavior, neurotransmitter, and immune functions in the olfactory bulbectomized rat model of depression.

The effects of subchronicly administered neuropeptide Y (NPY) intracerebroventricularly on behavioral, neurochemical, and immunological parameters were examined in sham operated and olfactory bulbectomized (OB) rats. In the untreated OB rats, an increase in ambulation, rearing, grooming, and defecation scores was found in the novel stressful environment of an "open field." Following 7 days of NPY administration, these behaviors were largely attenuated. In the elevated plus-maze apparatus, OB rats showed an increase in the number of entries into the open arms and time spent on the open arms compared with sham operated animals; NPY had no significant effect on the behavior of either sham operated or OB animals in this test. A decrease in the NA concentration was found in the amygdloid cortex of OB rats. NPY infusion significantly increased the NA concentration in amygdala, reduced 5-HIAA but increased 5-HT concentrations in the hypothalamus, and increased the dopamine level in the hippocampus. NPY administration also reversed the suppression of lymphocyte proliferation in the OB rat. However, the changes in the differential white blood cell count and the elevated phytohemagglutinin-induced chemiluminescence of mononuclear cells in the OB were not altered by NPY. These results suggest that NPY may have a modulatory effect on some behavioral, neurotransmitter, and immune aspects of the OB rat model of depression.

Animals↗