Cliona MacSweeney - Academia.edu (original) (raw)
Papers by Cliona MacSweeney
European Journal of Pharmacology, 1996
The forced swimming test is a behavioural model developed to predict the efficacy of antidepressa... more The forced swimming test is a behavioural model developed to predict the efficacy of antidepressant drugs. Few studies have been aimed at evaluating the mechanism of action of antidepressants in the forced swimming test. The present study was designed in order to further evaluate the mode of action of antidepressants in the forced swimming test, by using selective agonists and antagonists at 5-HT1A and 5-HT1B receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) induced anti-immobility effects with the tricyclic antidepressant imipramine (8 mg/kg, i.p.) and noradrenaline uptake inhibitors maprotiline (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.), but not with fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). These effects were antagonised by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (NAN 190) (0.5 mg/kg, i.p.). On the other hand, pretreatment with (+/-)-pindolol (32 mg/kg, i.p.) potentiated the effects of the selective serotonin reuptake inhibitors and was devoid of any activity with imipramine (8 mg/kg, i.p.), maprotiline (8 mg/kg, i.p.) or desipramine (16 mg/kg, i.p.). Prior administration of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) enhanced the antidepressant-like effects of the selective serotonin reuptake inhibitors and imipramine (8 mg/kg, i.p.) in the forced swimming test. The anti-immobility effects of the selective serotonin reuptake inhibitors in the forced swimming test seem to be mediated by presynaptic 5-HT1A receptors as well as postsynaptic 5-HT1B receptors. Antidepressant-like effects of the noradrenaline uptake inhibitors seem, on the other hand, to be mediated by postsynaptic 5-HT1A receptors. Considering the variety of 5-HT receptors, it is possible that other subtypes may participate in the anti-immobility effects of antidepressants in the forced swimming test.
European Neuropsychopharmacology, 2008
Journal of Endocrinology, 2008
Journal of Endocrinology, 2008
Journal of Psychopharmacology, 2011
![Research paper thumbnail of The discovery of novel 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamides as vasopressin V 1A receptor antagonists](https://attachments.academia-assets.com/48709492/thumbnails/1.jpg)
](International Journal of Food Microbiology, 2011
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide ... more The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V 1A receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V 1A antagonists.
Bioorganic & Medicinal Chemistry Letters, 2011
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V 1b antago... more Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V 1b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V 1b receptor and good selectivity with respect to related receptors V 1a , V 2 and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
European Neuropsychopharmacology, 1998
Psychopharmacology, 2009
Rationale Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially ... more Rationale Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist. Objectives The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior. Materials and methods The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was determined. Central administration of AVP induces a scratching response mediated through the V1a receptor. Inhibition of scratching was used as a behavioral measure of in vivo potency. JNJ-17308616 was tested in five models of anxiety: rat elevated plus-maze (EPM), rat-elevated zero-maze (EZM), rat-conditioned lick suppression (CLS), rat pup separation-induced ultrasonic vocalizations (USV), and mouse marble burying (MMB). Results High affinity for the human V1a receptor (K i 5.0 nM) was confirmed. However, the rat V1a receptor affinity was more modest (K i 216 nM), and the compound was not selective over the rat V2 receptor (K i 276 nM). At 100 mg/kg, JNJ-17308616 significantly reduced anxiety-like behavior in EPM, USV, and MMB; at 30 mg/kg, it was effective in EZM and CLS. JNJ-17308616 neither impaired social recognition nor reduced locomotor activity. Conclusions These results demonstrate the potential for V1a receptor antagonists as novel anxiolytics. Tool compounds that have greater V1a receptor selectivity than JNJ-17308616 are necessary to make precise conclusions about the role of the V1a receptor in affective disorders.
European Journal of Pharmacology, 1996
The forced swimming test is a behavioural model developed to predict the efficacy of antidepressa... more The forced swimming test is a behavioural model developed to predict the efficacy of antidepressant drugs. Few studies have been aimed at evaluating the mechanism of action of antidepressants in the forced swimming test. The present study was designed in order to further evaluate the mode of action of antidepressants in the forced swimming test, by using selective agonists and antagonists at 5-HT~A and 5-HT~R receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) induced anti-immobility effects with the tricyclic antidepressant imipramine (8 mg/kg, i.p.) and noradrenaline uptake inhibitors maprotiline (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.), but not with fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). These effects were antagonised by prior administration of l-(2-methoxypbenyl)-4-[-(2-phthalimido)butyl]piperazine) (NAN 190) (0.5 mg/kg, i.p.). On the other hand, pretreatment with (_+)-pindolol (32 mg/kg, i.p.) potentiated the effects of the selective serotonin reuptake inhibitors and was devoid of any activity with imipramine (8 mg/kg, i.p.), maprotiline (8 mg/kg, i.p.) or desipramine (16 mg/kg, i.p.). Prior administration of 5-methoxy-3-(l,2,3,6-tetrahydro-4-pyridyl)-I H-indole (RU 24969) enhanced the antidepressant-like effects of the selective serotonin reuptake inhibitors and imipramine (8 mg/kg, i.p.) in the forced swimming test. The anti-immobility effects of the selective serotonin reuptake inhibitors in the forced swimming test seem to be mediated by presynaptic 5-HTIA receptors as well as postsynaptic 5-HTIB receptors. Antidepressant-like effects of the noradrenaline uptake inhibitors seem, on the other hand, to be mediated by postsynaptic 5-HT~A receptors. Considering the variety of 5-HT receptors, it is possible that other subtypes may participate in the anti-immobility effects of antidepressants in the forced swimming test.
Behavioural Pharmacology, 2004
European Neuropsychopharmacology, 2008
[1] Finn et al., 2004, Imidazoline 2 (I2) receptor-and a2adrenoceptor-mediated modulation of hypo... more [1] Finn et al., 2004, Imidazoline 2 (I2) receptor-and a2adrenoceptor-mediated modulation of hypothalamicpituitary-adrenal axis activity in control and restraint stressed rats. J Psychopharmacol 18(1), 47−53.
Journal of Endocrinology, 2008
Exposure to chronic restraint (CR) modifies the hypothalamicpituitary-adrenal (HPA) axis response... more Exposure to chronic restraint (CR) modifies the hypothalamicpituitary-adrenal (HPA) axis response to subsequent acute stressors with adaptation of the response to a homotypic and sensitization of the response to a heterotypic stressor. Since vasopressin (AVP) activity has been reported to change during chronic stress, we investigated whether this was an important factor in HPA facilitation. We therefore tested whether vasopressin 1b receptor (AVPR1B) blockade altered the ACTH and corticosterone response to heterotypic stressors following CR stress. Adult male rats were exposed to CR, single restraint, or were left undisturbed in the home cage. Twentyfour hours after the last restraint, rats were injected with either a AVPR1B antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in saline, 0 . 2/kg, s.c.) and then exposed to either restraint, lipopolysaccharide (LPS) or white noise. CR resulted in the adaptation of the ACTH and corticosterone response to restraint and this effect was not prevented by pretreatment with Org. Although we found no effect of CR on LPS-induced ACTH and corticosterone secretion, both repeated and single episodes of restraint induced the sensitization of the ACTH, but not corticosterone response to acute noise. Pretreatment with Org reduced the exaggerated ACTH response to noise after both single and repeated exposure to restraint.
Behavioural Pharmacology, 2005
Progress in Brain Research, 2008
It has been argued that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a major... more It has been argued that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a major biological abnormality in patients suffering from psychiatric conditions such as major depression. Both arginine vasopressin (AVP) and corticotrophin releasing factor (CRF) are responsible for stimulating the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. CRF is thought to be the predominant secretagogue under normal conditions but AVP may play a more important role in situations of aberrant/chronic stress. Studies in patients suffering from melancholic depression indicate a hyper-responsiveness to agonism at the vasopressin receptor type 1B (V(1B)); patients display a heightened ACTH release after challenge with the mixed V(1B)/V(2) (vasopressin receptor type 2) agonist desmopressin in comparison to control subjects. A V(1B) antagonist has been developed which has significant selectivity for the human V(1B) receptor over the other members of the vasopressin receptor sub-family. The compound acts as an effective antagonist at both the human recombinant receptor (stably expressed in Chinese hamster ovary (CHO) cells) and the native rat V(1B) receptor (using isolated anterior pituitary cells), blocking the induction of luciferase and the release of ACTH, respectively. In vivo the compound can block the release of ACTH after challenge with a variety of V(1B) agonists. It can also attenuate the ACTH response to acute stressors in rats. Interestingly, this compound does not modulate the activity of the HPA axis under normal basal conditions.
Journal of Endocrinology, 2008
Vasopressin (AVP), produced in parvocellular neurons of the hypothalamic paraventricular nucleus,... more Vasopressin (AVP), produced in parvocellular neurons of the hypothalamic paraventricular nucleus, regulates, together with CRH, pituitary ACTH secretion. The pituitary actions of AVP are mediated through the G protein receptor V(1b) (V(1b)|R). In man, hyperactivity of the hypothalamic-pituitary-adrenal axis has been associated with depression and other stress-related conditions. There are also clinical data suggesting a role for AVP in the dysfunctional HPA axis described in some depressed patients. In this study, we have investigated the effect of a recently synthesised selective antagonist of the V(1b)R both on exogenous AVP-induced ACTH and corticosterone secretion, and on basal and stress-induced pituitary-adrenal activity. Adult male Sprague-Dawley rats treated with the V(1b)R antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in 0.9% saline, 2 ml/kg, s.c.). We found that blockade of the V(1b)R reduced the increase in both ACTH and corticosterone secretion induced by AVP (100 ng, i.v.). The same treatment had no effect either on basal ACTH and corticosterone levels or on the ultradian or diurnal rhythms of corticosterone secretion. Acute administration of the V(1b)R antagonist reduced ACTH secretion following both restraint and lipopolysaccharide, but did not antagonise the ACTH response to noise. The same treatment did not reduce corticosterone secretion in response to any of the three stressors used in this study. Our results confirm that this compound is an antagonist of the V(1b)R in the rat, and that its ability to reduce stress-induced ACTH responses is stressor dependent with differential modulation of pituitary and adrenal responses.
Journal of Neuroendocrinology, 2007
The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradi... more The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.
Journal of Psychopharmacology, 2011
The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-P... more The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-Plough, were investigated on glucocorticoid receptor nuclear translocation and DNA binding. In the in vitro study, AtT20 cells were treated with vehicle or with RU486, S-P or corticosterone (3-300 nM) or co-treated with vehicle or glucocorticoid receptor antagonists (3-300 nM) and 30 nM corticosterone. Both glucocorticoid receptor antagonists induced glucocorticoid receptor nuclear translocation but only RU486 induced DNA binding. RU486 potentiated the effect of corticosterone on glucocorticoid receptor nuclear translocation and DNA binding, S-P inhibited corticosterone-induced glucocorticoid receptor nuclear translocation, but not glucocorticoid receptor-DNA binding. In the in vivo study, adrenalectomized rats were treated with vehicle, RU486 (20 mg/kg) and S-P (50 mg/kg) alone or in combination with corticosterone (3 mg/kg). RU486 induced glucocorticoid receptor nuclear translocation in the pituitary, hippocampus and prefrontal cortex and glucocorticoid receptor-DNA binding in the hippocampus, whereas no effect of S-P on glucocorticoid receptor nuclear translocation or DNA binding was observed in any of the areas analysed. These findings reveal differential effects of RU486 and S-P on areas involved in regulation of hypothalamic-pituitary-adrenal axis activity in vivo and they are important in light of the potential use of this class of compounds in the treatment of disorders associated with hyperactivity of the hypothalamic-pituitary-adrenal axis.
Journal of Endocrinology, 2008
We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and d... more We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and delayed inhibition of corticosterone secretion in response to the synthetic glucocorticoid methylprednisolone (MPL). Male rats were implanted with a catheter in the right jugular vein, for blood sampling and MPL administration, and with an s.c. cannula for Org 34850 administration. All experiments were conducted at the diurnal hormonal peak in the late afternoon. Rats were connected to an automated sampling system and blood samples were collected every 5 or 10 min. Org 34850 (10 mg/kg, s.c.) or vehicle (5% mulgofen in saline) was injected at 1630 h; 30 min later, rats received an injection of MPL (500 mg/rat, i.v.) or saline (0 . 1 ml/rat). We found that an acute administration of MPL rapidly decreased the basal corticosterone secretion and this effect was not prevented by acute pretreatment with Org 34850. However, blockade of GR with Org 34850 prevented delayed inhibition of MPL on corticosterone secretion measured between 4 and 12 h after MPL administration. Our data suggest an involvement of GR in modulating delayed, but not fast, inhibition induced by MPL on basal corticosterone secretion.
European Journal of Pharmacology, 1996
The forced swimming test is a behavioural model developed to predict the efficacy of antidepressa... more The forced swimming test is a behavioural model developed to predict the efficacy of antidepressant drugs. Few studies have been aimed at evaluating the mechanism of action of antidepressants in the forced swimming test. The present study was designed in order to further evaluate the mode of action of antidepressants in the forced swimming test, by using selective agonists and antagonists at 5-HT1A and 5-HT1B receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) induced anti-immobility effects with the tricyclic antidepressant imipramine (8 mg/kg, i.p.) and noradrenaline uptake inhibitors maprotiline (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.), but not with fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). These effects were antagonised by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (NAN 190) (0.5 mg/kg, i.p.). On the other hand, pretreatment with (+/-)-pindolol (32 mg/kg, i.p.) potentiated the effects of the selective serotonin reuptake inhibitors and was devoid of any activity with imipramine (8 mg/kg, i.p.), maprotiline (8 mg/kg, i.p.) or desipramine (16 mg/kg, i.p.). Prior administration of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) enhanced the antidepressant-like effects of the selective serotonin reuptake inhibitors and imipramine (8 mg/kg, i.p.) in the forced swimming test. The anti-immobility effects of the selective serotonin reuptake inhibitors in the forced swimming test seem to be mediated by presynaptic 5-HT1A receptors as well as postsynaptic 5-HT1B receptors. Antidepressant-like effects of the noradrenaline uptake inhibitors seem, on the other hand, to be mediated by postsynaptic 5-HT1A receptors. Considering the variety of 5-HT receptors, it is possible that other subtypes may participate in the anti-immobility effects of antidepressants in the forced swimming test.
European Neuropsychopharmacology, 2008
Journal of Endocrinology, 2008
Journal of Endocrinology, 2008
Journal of Psychopharmacology, 2011
International Journal of Food Microbiology, 2011
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide ... more The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V 1A receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V 1A antagonists.
Bioorganic & Medicinal Chemistry Letters, 2011
Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V 1b antago... more Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V 1b antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V 1b receptor and good selectivity with respect to related receptors V 1a , V 2 and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.
European Neuropsychopharmacology, 1998
Psychopharmacology, 2009
Rationale Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially ... more Rationale Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist. Objectives The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior. Materials and methods The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was determined. Central administration of AVP induces a scratching response mediated through the V1a receptor. Inhibition of scratching was used as a behavioral measure of in vivo potency. JNJ-17308616 was tested in five models of anxiety: rat elevated plus-maze (EPM), rat-elevated zero-maze (EZM), rat-conditioned lick suppression (CLS), rat pup separation-induced ultrasonic vocalizations (USV), and mouse marble burying (MMB). Results High affinity for the human V1a receptor (K i 5.0 nM) was confirmed. However, the rat V1a receptor affinity was more modest (K i 216 nM), and the compound was not selective over the rat V2 receptor (K i 276 nM). At 100 mg/kg, JNJ-17308616 significantly reduced anxiety-like behavior in EPM, USV, and MMB; at 30 mg/kg, it was effective in EZM and CLS. JNJ-17308616 neither impaired social recognition nor reduced locomotor activity. Conclusions These results demonstrate the potential for V1a receptor antagonists as novel anxiolytics. Tool compounds that have greater V1a receptor selectivity than JNJ-17308616 are necessary to make precise conclusions about the role of the V1a receptor in affective disorders.
European Journal of Pharmacology, 1996
The forced swimming test is a behavioural model developed to predict the efficacy of antidepressa... more The forced swimming test is a behavioural model developed to predict the efficacy of antidepressant drugs. Few studies have been aimed at evaluating the mechanism of action of antidepressants in the forced swimming test. The present study was designed in order to further evaluate the mode of action of antidepressants in the forced swimming test, by using selective agonists and antagonists at 5-HT~A and 5-HT~R receptor sites. Agonists/antagonists and antidepressants were administered 45 min and 30 min, respectively, prior to testing. Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) induced anti-immobility effects with the tricyclic antidepressant imipramine (8 mg/kg, i.p.) and noradrenaline uptake inhibitors maprotiline (8 mg/kg, i.p.) and desipramine (16 mg/kg, i.p.), but not with fluoxetine (16 mg/kg, i.p.), citalopram (16 mg/kg, i.p.) or fluvoxamine (8 mg/kg, i.p.). These effects were antagonised by prior administration of l-(2-methoxypbenyl)-4-[-(2-phthalimido)butyl]piperazine) (NAN 190) (0.5 mg/kg, i.p.). On the other hand, pretreatment with (_+)-pindolol (32 mg/kg, i.p.) potentiated the effects of the selective serotonin reuptake inhibitors and was devoid of any activity with imipramine (8 mg/kg, i.p.), maprotiline (8 mg/kg, i.p.) or desipramine (16 mg/kg, i.p.). Prior administration of 5-methoxy-3-(l,2,3,6-tetrahydro-4-pyridyl)-I H-indole (RU 24969) enhanced the antidepressant-like effects of the selective serotonin reuptake inhibitors and imipramine (8 mg/kg, i.p.) in the forced swimming test. The anti-immobility effects of the selective serotonin reuptake inhibitors in the forced swimming test seem to be mediated by presynaptic 5-HTIA receptors as well as postsynaptic 5-HTIB receptors. Antidepressant-like effects of the noradrenaline uptake inhibitors seem, on the other hand, to be mediated by postsynaptic 5-HT~A receptors. Considering the variety of 5-HT receptors, it is possible that other subtypes may participate in the anti-immobility effects of antidepressants in the forced swimming test.
Behavioural Pharmacology, 2004
European Neuropsychopharmacology, 2008
[1] Finn et al., 2004, Imidazoline 2 (I2) receptor-and a2adrenoceptor-mediated modulation of hypo... more [1] Finn et al., 2004, Imidazoline 2 (I2) receptor-and a2adrenoceptor-mediated modulation of hypothalamicpituitary-adrenal axis activity in control and restraint stressed rats. J Psychopharmacol 18(1), 47−53.
Journal of Endocrinology, 2008
Exposure to chronic restraint (CR) modifies the hypothalamicpituitary-adrenal (HPA) axis response... more Exposure to chronic restraint (CR) modifies the hypothalamicpituitary-adrenal (HPA) axis response to subsequent acute stressors with adaptation of the response to a homotypic and sensitization of the response to a heterotypic stressor. Since vasopressin (AVP) activity has been reported to change during chronic stress, we investigated whether this was an important factor in HPA facilitation. We therefore tested whether vasopressin 1b receptor (AVPR1B) blockade altered the ACTH and corticosterone response to heterotypic stressors following CR stress. Adult male rats were exposed to CR, single restraint, or were left undisturbed in the home cage. Twentyfour hours after the last restraint, rats were injected with either a AVPR1B antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in saline, 0 . 2/kg, s.c.) and then exposed to either restraint, lipopolysaccharide (LPS) or white noise. CR resulted in the adaptation of the ACTH and corticosterone response to restraint and this effect was not prevented by pretreatment with Org. Although we found no effect of CR on LPS-induced ACTH and corticosterone secretion, both repeated and single episodes of restraint induced the sensitization of the ACTH, but not corticosterone response to acute noise. Pretreatment with Org reduced the exaggerated ACTH response to noise after both single and repeated exposure to restraint.
Behavioural Pharmacology, 2005
Progress in Brain Research, 2008
It has been argued that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a major... more It has been argued that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a major biological abnormality in patients suffering from psychiatric conditions such as major depression. Both arginine vasopressin (AVP) and corticotrophin releasing factor (CRF) are responsible for stimulating the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. CRF is thought to be the predominant secretagogue under normal conditions but AVP may play a more important role in situations of aberrant/chronic stress. Studies in patients suffering from melancholic depression indicate a hyper-responsiveness to agonism at the vasopressin receptor type 1B (V(1B)); patients display a heightened ACTH release after challenge with the mixed V(1B)/V(2) (vasopressin receptor type 2) agonist desmopressin in comparison to control subjects. A V(1B) antagonist has been developed which has significant selectivity for the human V(1B) receptor over the other members of the vasopressin receptor sub-family. The compound acts as an effective antagonist at both the human recombinant receptor (stably expressed in Chinese hamster ovary (CHO) cells) and the native rat V(1B) receptor (using isolated anterior pituitary cells), blocking the induction of luciferase and the release of ACTH, respectively. In vivo the compound can block the release of ACTH after challenge with a variety of V(1B) agonists. It can also attenuate the ACTH response to acute stressors in rats. Interestingly, this compound does not modulate the activity of the HPA axis under normal basal conditions.
Journal of Endocrinology, 2008
Vasopressin (AVP), produced in parvocellular neurons of the hypothalamic paraventricular nucleus,... more Vasopressin (AVP), produced in parvocellular neurons of the hypothalamic paraventricular nucleus, regulates, together with CRH, pituitary ACTH secretion. The pituitary actions of AVP are mediated through the G protein receptor V(1b) (V(1b)|R). In man, hyperactivity of the hypothalamic-pituitary-adrenal axis has been associated with depression and other stress-related conditions. There are also clinical data suggesting a role for AVP in the dysfunctional HPA axis described in some depressed patients. In this study, we have investigated the effect of a recently synthesised selective antagonist of the V(1b)R both on exogenous AVP-induced ACTH and corticosterone secretion, and on basal and stress-induced pituitary-adrenal activity. Adult male Sprague-Dawley rats treated with the V(1b)R antagonist (Org, 30 mg/kg, s.c.) or vehicle (5% mulgofen in 0.9% saline, 2 ml/kg, s.c.). We found that blockade of the V(1b)R reduced the increase in both ACTH and corticosterone secretion induced by AVP (100 ng, i.v.). The same treatment had no effect either on basal ACTH and corticosterone levels or on the ultradian or diurnal rhythms of corticosterone secretion. Acute administration of the V(1b)R antagonist reduced ACTH secretion following both restraint and lipopolysaccharide, but did not antagonise the ACTH response to noise. The same treatment did not reduce corticosterone secretion in response to any of the three stressors used in this study. Our results confirm that this compound is an antagonist of the V(1b)R in the rat, and that its ability to reduce stress-induced ACTH responses is stressor dependent with differential modulation of pituitary and adrenal responses.
Journal of Neuroendocrinology, 2007
The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradi... more The activity of the hypothalamic-pituitary-adrenal (HPA) axis is characterised both by an ultradian pulsatile pattern of glucocorticoid secretion and an endogenous diurnal rhythm. Glucocorticoid feedback plays a major role in regulating HPA axis activity and this mechanism occurs via two different receptors: mineralocorticoid (MR) and glucocorticoid receptors (GR). In the present study, the effects of both acute and subchronic treatment with the GR antagonist Org 34850 on basal and stress-induced HPA axis activity in male rats were evaluated. To investigate the effect of Org 34850 on basal diurnal corticosterone rhythm over the 24-h cycle, an automated blood sampling system collected samples every 10 min. Acute injection of Org 34850 (10 mg/kg, s.c.) did not affect basal or stress-induced corticosterone secretion, but was able to antagonise the inhibitory effect of the glucocorticoid agonist methylprednisolone on stress-induced corticosterone secretion. However, 5 days of treatment with Org 34850 (10 mg/kg, s.c., two times a day), compared to rats treated with vehicle (5% mulgofen in 0.9% saline, 1 ml/kg, s.c.), increased corticosterone secretion over the 24-h cycle and resulted in changes in the pulsatile pattern of hormone release, but had no significant effect on adrenocorticotrophic hormone secretion or on stress-induced corticosterone secretion. Subchronic treatment with Org 34850 did not alter GR mRNA expression in the hippocampus, paraventricular nucleus of the hypothalamus or anterior-pituitary, or MR mRNA expression in the hippocampus. Our data suggest that a prolonged blockade of GRs is required to increase basal HPA axis activity. The changes observed here with ORG 34850 are consistent with inhibition of GR-mediated negative feedback of the HPA axis. In light of the evidence showing an involvement of dysfunctional HPA axis in the pathophysiology of depression, Org 34850 could be a potential treatment for mood disorders.
Journal of Psychopharmacology, 2011
The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-P... more The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-Plough, were investigated on glucocorticoid receptor nuclear translocation and DNA binding. In the in vitro study, AtT20 cells were treated with vehicle or with RU486, S-P or corticosterone (3-300 nM) or co-treated with vehicle or glucocorticoid receptor antagonists (3-300 nM) and 30 nM corticosterone. Both glucocorticoid receptor antagonists induced glucocorticoid receptor nuclear translocation but only RU486 induced DNA binding. RU486 potentiated the effect of corticosterone on glucocorticoid receptor nuclear translocation and DNA binding, S-P inhibited corticosterone-induced glucocorticoid receptor nuclear translocation, but not glucocorticoid receptor-DNA binding. In the in vivo study, adrenalectomized rats were treated with vehicle, RU486 (20 mg/kg) and S-P (50 mg/kg) alone or in combination with corticosterone (3 mg/kg). RU486 induced glucocorticoid receptor nuclear translocation in the pituitary, hippocampus and prefrontal cortex and glucocorticoid receptor-DNA binding in the hippocampus, whereas no effect of S-P on glucocorticoid receptor nuclear translocation or DNA binding was observed in any of the areas analysed. These findings reveal differential effects of RU486 and S-P on areas involved in regulation of hypothalamic-pituitary-adrenal axis activity in vivo and they are important in light of the potential use of this class of compounds in the treatment of disorders associated with hyperactivity of the hypothalamic-pituitary-adrenal axis.
Journal of Endocrinology, 2008
We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and d... more We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and delayed inhibition of corticosterone secretion in response to the synthetic glucocorticoid methylprednisolone (MPL). Male rats were implanted with a catheter in the right jugular vein, for blood sampling and MPL administration, and with an s.c. cannula for Org 34850 administration. All experiments were conducted at the diurnal hormonal peak in the late afternoon. Rats were connected to an automated sampling system and blood samples were collected every 5 or 10 min. Org 34850 (10 mg/kg, s.c.) or vehicle (5% mulgofen in saline) was injected at 1630 h; 30 min later, rats received an injection of MPL (500 mg/rat, i.v.) or saline (0 . 1 ml/rat). We found that an acute administration of MPL rapidly decreased the basal corticosterone secretion and this effect was not prevented by acute pretreatment with Org 34850. However, blockade of GR with Org 34850 prevented delayed inhibition of MPL on corticosterone secretion measured between 4 and 12 h after MPL administration. Our data suggest an involvement of GR in modulating delayed, but not fast, inhibition induced by MPL on basal corticosterone secretion.