Search PubMed⌕ Search

Biomedical subjects

B E Leonard

Publications and source records attributed to B E Leonard.

At least 19 recordsLinked to original sources
PubMed2005

Ketter's hypothesis of the mood effects of antiepileptic drugs coupled to the mechanism of action of topiramate and levetiracetam.

Mood-modulating profiles of antiepileptic drugs (AEDs) have been classified by Ketter, Post, and Theodore [Neurology 1999; 53 (5, Suppl. 2) S53-76] into two classes: the first class is assumed to have deactivating effects related to GABA potentiation, and the second class is assumed to have activating effects that are associated with glutamate attenuation. We tested this hypothesis by reviewing the multiple mechanisms of action of topiramate (TPM) and levetiracetam (LEV) together with clinical behavioral side effects of patients who had been treated with TPM and LEV in a tertiary referral center for epilepsy. We found LEV to manifest activating and deactivating side effects equally and TPM to act as a deactivating AED, with tiredness/sleepiness side effects being predominant. TPM, in comparison to LEV, was found to be associated with a high incidence of side effects. Testing the hypothesis of Ketter et al. (1999) the deactivating effects of TPM may be coupled to a predominance of potentiation of GABA, but the oversimplified basis of the model needs to be acknowledged.

Adult↗
PubMed2004

Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats.

Central or peripheral administration of the proinflammatory cytokine interleukin (IL)-1beta can impair performance on spatial memory tasks and also elevate circulating concentration of corticosterone. The present experiment provides independent confirmation that intracerebroventricular administration of 10 ng IL-1beta in the rat can have a selective effect on the retrieval of trial unique information about the location of food on an eight-arm radial maze. The probable involvement of corticosterone in IL-1beta-induced memory impairment was indicated by elevated corticosterone levels after IL-1beta administration. Further evidence comes from the blockade of the associated impairment in working memory by coadministration of the glucocorticoid receptor antagonist RU486. Ingestion of diet containing omega-3 fatty acid eicosapentaenoic acid (EPA) is known to antagonize the synthesis of prostaglandin (PG) E2 from aracadonic acid, and the present study confirmed that ethyl EPA (1%) reduced IL-1beta-elevated concentrations of PGE2 and corticosterone. Furthermore, rats given the ethyl-EPA diet for 8 weeks were unaffected by the disruptive effects of IL-1beta on working memory. IL-1beta-induced suppression of mitogen-stimulated release of the anti-inflammatory cytokine IL-10 was also blocked by treatment with ethyl-EPA. Collectively, these data demonstrate that IL-1beta can impair memory function by elevating the concentration of corticosterone and that prior consumption of 1% ethyl-EPA can block both the neuroendocrine and cognitive effects of IL-1beta. These findings in turn may indicate beneficial effects of ethyl-EPA in the treatment of cognitive and affective disorders in which inflammation and stress play a critical role.

Administration, Oral↗
PubMed2004

Editorial.

Explore the source record for details and available documents.

Binding Sites↗
PubMed2004

Sigma receptors and sigma ligands: background to a pharmacological enigma.

Although it is now well established that the sigma receptors are distinct from neurotransmitter, neuropeptide and steroid receptors, their precise physiological role, and possible involvement in the pathology of neurological and psychiatric disorders, remains an enigma. The purpose of this short review is to provide a basis upon which to explain the pharmacological properties of such a diverse group of drugs as the antidepressants, antipsychotics and neuroprotective agents. However, a greater understanding of the importance of the sigma receptors will depend on the development of more potent and selective sigma agonists and antagonists if the therapeutic potential of the sigma receptors is to be fully realised.

Animals↗
PubMed2003

Effects of acute and chronic administration of selective monoamine re-uptake inhibitors in the rat forced swim test.

The rat forced swim test (FST) is a model that is used extensively as a screening test for antidepressant activity. It has previously been reported that thorough analysis of behaviour in this model reveals two distinct types of active response - climbing and swimming - and that these are separately evoked by re-uptake inhibitors selective for noradrenaline (NA) and serotonin (5-HT), respectively. In the present study, utilising re-uptake inhibitors selective for NA, talsupram, and 5-HT, 5-chloro-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)- phthalan (Lu 10-134-C), we examined if this scoring technique could detect the antidepressant potential of a selective serotonin re-uptake inhibitor (SSRI), and whether re-uptake inhibitors selective for distinct monoamine systems induce exclusive behavioural responses. We also analysed if chronic antidepressant administration for three weeks was more effective than acute treatment. We found Lu 10-134-C (40 mg/kg; PO) to be behaviourally active in this paradigm. Although treatment with talsupram (40 mg/kg; PO) resulted solely in climbing behaviour, Lu 10-134-C induced both climbing and swimming behaviour. However, chronic pre-treatment with either re-uptake inhibitor (20 mg/kg; twice daily; PO) failed to augment the response observed with acute treatment. Similarly, chronic administration of either compound was without effect on the basal, or stress-induced, serum corticosterone concentrations or anterior pituitary (AP) preproopiomelanocorticotropin (POMC) mRNA expression. These results suggest that selective monoamine re-uptake inhibition produces distinct, but not necessarily exclusive, behavioural responses in the forced swim test.

Adrenergic Uptake Inhibitors↗
PubMed2002

The effect of lofepramine and other related agents on the motility of Tetrahymena pyriformis.

Tricyclic antidepressants (TCAs) were introduced almost 50 years ago. Whilst there is no doubt that TCAs are effective in treating depression, they are also more cardiotoxic when taken in overdose than other antidepressant groups. Lofepramine is a more recently introduced modified TCA, which in animals and man has low toxicity when compared to older TCAs. Paradoxically, lofepramine is extensively metabolised to desipramine, which has considerable toxicity, both experimentally and in overdose. The toxicity of such compounds is attributed, in part, to a membrane stabilising effect (MSA) on cell membranes. This MSA causes gross effects to the cell structure and in turn, normal cell activity. The aim of this study was to compare the MSA of lofepramine with that of desipramine and amitriptyline in order to see if this might help to explain the low toxicity of lofepramine. The local anaesthetic agent lignocaine was also studied for comparison. Each compound was enclosed in a beta-cyclodextrin to increase its solubility in aqueous medium. The extent of MSA was determined as a measure of the effect on the swimming speed of the protozoan Tetrahymena pyriformis using a video image analysis system. The IC50s for the various drugs were then correlated with their respective octanol-water partition coefficient values (Pow). Amitriptyline had an IC50 of 1.26+/-0.29 mM, desipramine 75.99+/-14.40 mM, while lofepramine had an IC50 of 357.40+/-25.00 mM. Lignocaine had an IC50 of 85.73+/-18.30 mM. There was also a significant correlation between the IC50 values and the Pow values.

Amitriptyline↗
PubMed2001

Modulation of MK-801-induced behaviour by noradrenergic agents in mice.

RATIONALE: Inhibition of glutamatergic N-methyl-D-aspartate (NMDA) receptors following the administration of NMDA receptor antagonists results in psychotic-like behaviour. Whereas it is known that pharmacological manipulation of dopaminergic and serotonergic pathways affect this drug-induced psychosis, a role for noradrenaline has not yet been clearly defined. OBJECTIVES: Thus, in the present study, we assessed a possible role for noradrenaline in the behavioural response to the non-competitive NMDA receptor anatgonist, MK-801, in male CD-I mice. RESULTS: MK-801 (0.02-1.28 mg/kg; ED50 0.2 mg/kg; s.c.) induced a dose-dependent increase in locomotor, stereotypic and ataxic behaviours. Pre-treatment with the noradrenaline re-uptake inhibitors, desipramine (10 mg/kg; i.p.) and reboxetine (20 mg/kg; i.p.), attenuated the locomotor, stereotypic and ataxic response to MK-801 (0.2 mg/kg; s.c.). The noradrenergic system was lesioned with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, 50 mg/kg; i.p., 7 and 4 days prior to challenge) to reduce noradrenaline concentrations in the cortex by 70%-80%. Whereas DSP-4 lesioning had little effect on the response to MK-801, it completely reversed the attenuating effects of reboxetine. Pre-treatment with the alpha2 adrenoceptor agonist, clonidine (0.2 mg/kg; i.p.), and the antagonist, yohimbine (2 mg/kg; i.p.), attenuated and potentiated the response to MK-801, respectively. Pre-treatment with the alpha1 adrenoceptor antagonist, prazosin (2 mg/kg; i.p.), reduced the MK-801-induced response. CONCLUSIONS: It therefore appears that presynaptic noradrenergic alpha2 and postsynaptic alpha1 adrenoceptor stimulation exert opposing effects on the behavioural expression of MK-801 in mice.

Adrenergic Agents↗
PubMed2001

Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats.

The substituted amphetamine 3,4 methylenedioxyamphetamine (MDA) is a popular recreational drug of abuse. Administration of MDA to experimental animals has been shown to induce damage to serotonergic axons and nerve terminals. However, there is a lack of information on whether these treatments can produce any long-term changes in behavioural performance particularly under stressful conditions. In the present study, MDA (7.5 mg/kg; i.p.) was administered twice daily to adult male Sprague Dawley rats for four days. Four weeks following the last dose, spontaneous behaviors of these animals were tracked and scored in a novel "open field" environment using an automated video registration and computer interpretation system. Changes in behavior were observed in MDA treated animals including reductions in exploratory oriented behaviors (locomotion and rearing) and increases in grooming behavior when compared to vehicle treated controls. MDA-treated animals also displayed an enhanced locomotor and stereotyped response to d-amphetamine (12 mg/kg; i.p.). Significant reductions in 5-HT concentrations (20-30%) were observed in the frontal cortex, amygdala, striatum, and hypothalamus as a result of MDA treatment. In addition, [3H] paroxetine binding was reduced by (40%) in the cortex of MDA treated rats indicating that the decrease in 5-HT concentrations were accompanied by a reduction in intact presynaptic 5-HT nerve terminals. Changes in behavioural performance in a novel "open field" environment and following d-amphetamine challenge might be considered as a behavioural model of serotonergic deficit induced by MDA. The findings of this study also suggest that MDA use may increase both the abuse potential, and the propensity to develop psychosis as a result of abusing other psychostimulants such as d-amphetamine.

Animals↗
PubMed2001

Beta-amyloid(1-42)-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex.

Ample experimental evidence suggests that beta-amyloid (A beta), when injected into the rat magnocellular nucleus basalis (MBN), impels excitotoxic injury of cholinergic projection neurons. Whereas learning and memory dysfunction is a hallmark of A beta-induced cholinergic deficits, anxiety, or hypoactivity under novel conditions cannot be attributed to the loss of cholinergic MBN neurons. As mood-related behavioral parameters are primarily influenced by the central serotonergic system, in the present study we investigated whether A beta(1-42) toxicity in the rat MBN leads to an altered serotonergic innervation pattern in the rat basal forebrain and cerebral cortex 7 days postsurgery. A beta infusion into the MBN elicited significant anxiety in the elevated plus maze. A beta toxicity on cholinergic MBN neurons, expressed as the loss of acetylcholinesterase-positive cortical projections, was accompanied by sprouting of serotonergic projection fibers in the MBN. In contrast, the loss of serotonin-positive fiber projections, decreased concentrations of both serotonin and 5-hydroxyindoleacetic acid, and decline of cortical 5-HT(1A) receptor binding sites indicated reduced serotonergic activity in the somatosensory cortex. In conclusion, the A beta-induced primary cholinergic deficit in the MBN and subsequent cortical cholinergic denervation bidirectionally modulate serotonergic parameters in the rat basal forebrain and cerebral cortex. We assume that enhanced serotonin immunoreactivity in the damaged MBN indicates intrinsic processes facilitating neuronal recovery and cellular repair mechanisms, while diminished cortical serotonergic activity correlates with the loss of the subcortical cholinergic input, thereby maintaining the balance of neurotransmitter concentrations in the cerebral cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

The immune system, depression and the action of antidepressants.

It is well established that the hypothalamic-pituitary-adrenal axis (HPA) is activated by both external and internal stressors which result in the hypersecretion of adrenal glucocorticoids. In major depression the prolonged elevation of the glucocorticoid concentration leads to a desensitisation of the central glucocorticoid receptors and probably those receptors located on macrophages. These changes may account for the observation that many aspects of cellular immunity are activated in depression (for example, the increased release of pro-inflammatory cytokines from activated macrophages in the periphery and brain, and the increased release of acute phase proteins from the liver) even though other aspects of immunity (for example, natural killer cell activity and T-cell replication) are depressed. It is also known that some of the pro-inflammatory cytokines are potent activators of the HPA axis. Evidence is provided that the consequences of the hypersecretion of glucocorticoids and pro-inflammatory cytokines result in the malfunctioning of noradrenergic and serotonergic neurotransmission in the brain, changes which are reflected in the major symptoms of depression. Support for this view is provided by observations of the effects of some of these cytokines in non-depressed individuals being treated with pro-inflammatory and related cytokines for cancer. This has led to the hypothesis that depression is a form of sickness behaviour which forms the basis of the macrophage theory of depression. The review concludes with a discussion of the role of antidepressants in attenuating the adverse effects of glucocorticoids and pro-inflammatory cytokines on central neurotransmission. Although the precise mechanisms whereby antidepressants these changes is uncertain, there is evidence that they reduce the release of pro-inflammatory cytokines from activated macrophages and thereby facilitate the feedback inhibition of the HPA axis; this results in a reduction in the release of glucocorticoids from the adrenal glands. In addition, many antidepressants have been shown to increase the release of endogenous cytokine antagonists such as interleukin-1 receptor antagonist and interleukin-10. Evidence is also presented to show that different classes of antidepressants act as cyclooxygenase inhibitors which, by lowering the concentration of inflammatory prostaglandins in the brain, reduce the detrimental impact of the inflammatory changes on neurotransmitter function. An advantage of the macrophage hypothesis is that it extends the biogenic amine hypothesis of depression to take account of changes in the endocrine and immune systems which also play a crucial role in the aetiology of depression. In addition, the macrophage hypothesis may broaden the basis of understanding the mechanism of action of antidepressants.

Adjuvants, Immunologic↗
PubMed2001

Changes in the immune system in depression and dementia: causal or co-incidental effects?

It is now widely accepted that psychological stress and psychiatric illness can compromise immune function. Furthermore the mechanisms whereby such changes occur are probably associated with the activities of the cytokines and other inflammatory mediators of the immune system which are known to initiate changes in behaviour. This review aims to summarise the experimental and clinical evidence that implicates the pro-inflammatory cytokines in the pathological changes seen in major depression and in Alzheimer's disease (AD). In major depression, evidence is provided to show that both activation (e.g., macrophage activity, acute phase proteins) and inhibition (e.g., natural killer cell activity) of the immune system occur. Many of the behavioural changes seen in depression are simulated by three pro-inflammatory cytokines (IL-1, IL-6 and TNF-alpha), which may produce their impact on the brain by activating cyclooxygenase, nitric acid synthase and corticotrophin releasing factor. Effective antidepressant treatments largely attenuate the immune changes thereby raising the possibility that the normalisation of central biogenic amine function that are conventionally implicated in the cause of depression may be secondary to those of the pro-inflammatory cytokines. With respect to AD, while the cause(s) are unknown, there is both experimental and clinical evidence to suggest that inflammatory processes in the brain caused in particular by TNF-alpha together with the subsequent rise in free radicals, are instrumental in causing the pathological changes which underlie the disease. Evidence in favour of the inflammatory hypothesis is supported by the finding that nonsteroidal anti-inflammatory drugs slow down the progression of the disease.Although, more research is needed into the inter-relationships between the various pro-inflammatory cytokines and the behavioural changes invoked in major depression and AD, the immunological hypothesis has been important in stimulating new concepts regarding the causes of the pathological changes in these diseases and how effective drug treatments may attenuate them.

Adjuvants, Immunologic↗
PubMed2001

The toxicity profile of a single dose of paroxetine: an alternative approach to acute toxicity testing in the rat.

In this study we have examined the effect of a single administration of the selective serotonin reuptake inhibitor, paroxetine (120-300 mg kg(-1), orally) in a recently developed rodent model of acute toxicity testing. Reduced body-weight, food consumption, water consumption and body temperature were observed in all paroxetine-treated groups, which were reversible within 7 days. Five days after administration, a dose-dependent increase in red blood cells, haemoglobin and haematocrit was observed with the 3 higher dose levels of paroxetine, which was significant in the 240 and 300 mg kg(-1) treatment groups (P < 0.05). Hyperactivity was apparent in the first 24 hr following treatment, as was evidence of the serotonin syndrome. When the animals were sacrificed (11 days after drug administration), an increase in liver weight was observed in the highest dose. These results are in agreement with those previously observed with paroxetine at the preclinical and clinical levels. They demonstrate that this rodent model, because of its multi-parameter nature, is a useful method for examining the consequences of a single high dose of an antidepressant drug.

Animal Testing Alternatives↗
PubMed2001

Stress, norepinephrine and depression.

Stress is an important precipitant factor in depression, and the changes in various body systems that occur in depression are similar to those observed in response to stress. This paper discusses the interactions among the immune, endocrine and norepinephrine systems that are evident in patients with depression, as well as those affected by stress. Many of the stress-induced changes can be reversed by antidepressants, particularly norepinephrine reuptake inhibitors.

Corticotropin-Releasing Hormone↗
PubMed2000

An in-vivo magnetic resonance imaging study of the olfactory bulbectomized rat model of depression.

The olfactory bulbectomized (OB) rat is a well-accepted animal model of depression. The present magnetic resonance imaging (MRI) investigation demonstrates alterations in signal intensities in cortical, hippocampal, caudate and amygdaloid regions in OB animals, but not in sham operated controls. Ventricular enlargement was also evident in OB animals. These alterations have implications with regard to the face and construct validity of this model.

Amygdala↗
PubMed2000

Methylenedioxymethamphetamine (MDMA; Ecstasy) suppresses IL-1beta and TNF-alpha secretion following an in vivo lipopolysaccharide challenge.

In this study we examined the effects of methylenedioxymethamphetamine (MDMA) administration on responsiveness to an in vivo immune challenge with lipopolysaccharide (LPS; 100 microg/kg; i.p.). LPS produced an increase in circulating IL-1beta and TNF-alpha in control animals. MDMA (20 mg/kg; i.p.) significantly impaired LPS-induced IL-1beta and TNF-alpha secretion. The suppressive effect of MDMA on IL-1beta secretion was transient and returned to control levels within 3 hours of administration. In contrast, the MDMA-induced suppression of TNF-alpha secretion was evident for up to 12 hours following administration. In a second study we examined the effect of co-administration of MDMA (5, 10 and 20 mg/kg; i.p.) on LPS-induced IL-1beta and TNF-alpha secretion, and demonstrated that all three doses potently suppressed LPS-induced TNF-alpha secretion, but only MDMA 10 and 20 mg/kg suppressed LPS-induced IL-1beta secretion. In addition, serum MDMA concentrations displayed a dose-dependent increase, with the concentrations achieved following administration of 5 and 10 mg/kg being in the range reported in human MDMA abusers. In order to examine the possibility that the suppressive effect of MDMA on IL-1beta and TNF-alpha could be due to a direct effect of the drug on immune cells, the effect of in vitro exposure to MDMA on IL-1beta and TNF-alpha production in LPS-stimulated diluted whole blood was evaluated. However IL-1beta or TNF-alpha production were not altered by in vitro exposure to MDMA. In conclusion, these data demonstrate that acute MDMA administration impairs IL-1beta and TNF-alpha secretion following an in vivo LPS challenge, and that TNF-alpha is more sensitive to the suppressive effects of MDMA than is IL-1beta. However the suppressive effect of MDMA on IL-1beta and TNF-alpha could not be attributed to a direct effect on immune cells. The relevance of these findings to MDMA-induced immunomodulation is discussed.

Animals↗
PubMed2000

Prolonged c-Jun expression in the basolateral amygdala following bulbectomy: possible implications for antidepressant activity and time of onset.

Olfactory bulbectomy is a well established animal model of depression. Neurochemical and behavioral alterations observed following olfactory bulbectomy, are due, in part, to the neurodegeneration of specific brain structures. Amygdaloid dysfunction in particular, is known to play a substantial role in the syndrome of the olfactory bulbectomized rat. The present study examined both short- and long-term alterations in immediate early gene expression, tyrosine hydroxylase and serotonin immunoreactivity, and classical silver staining, following olfactory bulbectomy in the basolateral amygdala. The results indicated no consistent change in Fos expression observed over the experimental period. Following bulbectomy, long term (up to 64 days post-lesion) Jun expression, not coincident with silver staining, was observed in the basolateral nucleus. The basolateral nucleus was also intensely immunoreactive for serotonin at this timepoint post-bulbectomy. Thus, following bulbectomy long term alterations in Jun expression occurs in the serotonin rich basolateral amygdala. As a site of action for antidepressant compounds, alterations at the immediate early gene level in this region may have implications both for the model, and antidepressant drug action therein.

Amygdala↗
PubMed2000

Characterization of D-fenfluramine-induced hypothermia: evidence for multiple sites of action.

The effects of D-fenfluramine on core body temperature has been largely investigated under conditions of either high or low ambient temperature, whereas little research has focused on this response under normal environmental conditions. Moreover, there has been neglect in research on the mechanisms underlying changes in body temperature. In this study, we demonstrate that D-fenfluramine (5 and 10 mg/kg) induces a sustained decrease in body temperature in the rat under normal ambient temperatures. Pre-treatment with the selective serotonin reuptake inhibitor sertraline (5 mg/kg), the full 5-HT(1A) receptor antagonist 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinyl benzamide], WAY 100635 (0.15 mg/kg) and the 5-HT(2C) receptor antagonist benzofuran-2-carboxamidine, RO 43-0440 (2.5 mg/kg) blocked D-fenfluramine-induced hypothermia. Depletion of 5-hydroxytryptamine (5-HT) stores following treatment with the serotonergic neurotoxin parachlorophenylalanine reversed the initial hypothermic effects of D-fenfluramine but not the later effects, as D120 min post-challenge) in animals pre-treated with parachlorophenylalanine. Such findings are consistent with a requirement for D-fenfluramine uptake into 5-HT neurons followed by release of 5-HT from intracellular stores and stimulation of post-synaptic 5-HT receptors to reduce body temperature. The hypothermic response to D-fenfluramine was potentiated by ketanserin pre-treatment 30 min post-challenge but then antagonized at later time intervals. Pre-treatment with the dopamine, D(2) antagonist, haloperidol (1 mg/kg) and sulpiride (30 mg/kg) had a similar effect in blocking the hypothermia as WAY 100635, suggesting a role for dopamine D(2) receptors in the response. Pre-treatment with the alpha(2)-adrenoceptor antagonist yohimbine failed to block the hypothermic response. These results suggest multiple sites of action mediating D-fenfluramine-induced hypothermia and may be the result of a combined effect of D-fenfluramine and its active metabolite norfenfluramine affecting not only the release of 5-HT but also stimulation of post-synaptic receptors.

Adrenergic alpha-Antagonists↗