Sharon Cheetham - Academia.edu (original) (raw)
Papers by Sharon Cheetham
Piperazine Derivatives as Therapeutic Agents
Substituted 4-ARYLMETHYLENE-2-IMINO-2,3-DIHYDROTHIAZOLES and Derivatives and Their Pharmaceutical Use
Simultaneous determination of the effects of methamphetamine on GABA, glutamate and monoamines by microdialysis in the prefrontal cortex and hippocampus of rats
Drug and Alcohol Dependence, 2015
[3H]Nisoxetine—A radioligand for noradrenaline reuptake sites: Correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments
Neuropharmacology, 1996
Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurone... more Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurones. [3H]Nisoxetine binding to rat frontal cortical membranes was of high affinity. The binding data of both competition and saturation studies fitted a single site binding model. [3H]Nisoxetine binding was potently inhibited by the selective noradrenaline uptake inhibitors desipramine and protriptyline. In addition, a very good correlation was obtained between the ability of 25 monoamine reuptake inhibitors and related compounds both to inhibit [3H]nisoxetine binding and to inhibit [3H]noradrenaline uptake in rat frontal cortex. DSP-4 (10-100 mg/kg, i.p.) dose-dependently depleted cortical noradrenaline concentrations (51-100%), with no significant effects on 5-HT and dopamine. These depletions, which were used as a marker of loss of noradrenergic nerve terminals, were associated with a dose-dependent decrease in the number of [3H]nisoxetine binding sites (20-97%) with no change in binding affinity. Furthermore, a good correlation was obtained between cortical noradrenaline concentrations and the number of [3H]nisoxetine binding sites. These data support the view that [3H]nisoxetine binds to a single population of homogeneous sites associated with the noradrenaline transporter complex. Using this ligand, the effects of repeated administration of both antidepressant drugs with a range of pharmacological actions and of electroconvulsive shock on noradrenaline reuptake sites were examined. The number and affinity of [3H]nisoxetine binding sites were unaltered by all treatments. It is unlikely, therefore, that antidepressant therapy would produce adaptive changes in noradrenaline uptake sites.
FEBS Letters, 2005
We have investigated the effect of the sulfhydryl-reactive reagent, methyl thiosulfonate ethylamm... more We have investigated the effect of the sulfhydryl-reactive reagent, methyl thiosulfonate ethylammonium (MTSEA), on ligand binding to the human melanocortin-4 (MC4) receptor stably expressed in HEK-293 cells. MTSEA inhibited binding of the agonist, 125 I-NDPa-MSH, and the antagonist, 125 I-SHU9119, in a concentration-dependent manner. Pre-incubation of cells with either the agonist or antagonist protected from subsequent MTSEA inhibition of radioligand binding. Mutation of Cys130 in transmembrane helix 3 to alanine, whilst not affecting ligand binding, led to a complete loss of the inhibitory effect of MTSEA. Since other types of sulfhydryl-reactive reagents had no effect on ligand binding, we conclude that covalent modification of Cys130 by MTSEA disrupts ligand binding by neutralising a close-by negative charge, most likely on Asp126.
Receptor binding and functional evidence suggest that postsynaptic α2-adrenoceptors in rat brain are of the α2D subtype
European Journal of Pharmacology, 1995
This study has determined the subtype(s) of postsynaptic alpha 2-adrenoceptors in rat brain. This... more This study has determined the subtype(s) of postsynaptic alpha 2-adrenoceptors in rat brain. This question has been addressed by using two separate approaches, i.e. ligand displacement of [3H]2-(2-methoxy)-1,4-benzodioxan-2-yl)-2-imidazoline ([3H]RX 821002) from membranes prepared from rat cortex after noradrenergic denervation and, secondly, by antagonism of clonidine-induced mydriasis. After rats had been lesioned using N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 100 mg/kg i.p., 30 min after zimeldine 10 mg/kg i.p.), noradrenaline was undetectable in the cortex 3 days later. Displacement of [3H]RX 821002 with a range of agonists and antagonists which distinguish between the known alpha 2-adrenoceptor subtypes (alpha 2A-2D) yielded pKi values which correlated very well with reported values for the alpha 2D-adrenoceptor (r = 0.929; P < 0.001), but not the alpha 2A (r = 0.450; P = 0.192), alpha 2B (r = 0.280, P = 0.434) or alpha 2C (r = 0.283; P = 0.460) subtypes. Similarly, the potencies of various alpha 2-adrenoceptor antagonists to inhibit clonidine (0.03 mg/kg i.p.)-induced mydriasis in conscious rats correlated strongly with their pKi values for alpha 2D-adrenoceptors (r = 0.899; P = 0.015) but not alpha 2A-(r = 0.369; P = 0.472), alpha 2B-(r = -0.224; P = 0.670) or alpha 2C-adrenoceptors (r = 0.253; P = 0.584). These data are, therefore, consistent and argue strongly that postsynaptic alpha 2-adrenoceptors in the rat cortex and Edinger-Westphal nucleus are of the alpha 2D subtype.
Receptor Occupancy and Brain Free Fraction
Drug Metabolism and Disposition, 2009
This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a bett... more This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.
Diabetes, 2010
OBJECTIVE-Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system... more OBJECTIVE-Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.
Method of treating anxiety disorders
Endocrinology, Jul 1, 2013
GPR39 is an orphan member of the ghrelin receptor family that recently was suggested to be the re... more GPR39 is an orphan member of the ghrelin receptor family that recently was suggested to be the receptor for obestatin, a peptide derived from the ghrelin precursor. Here, we compare the effect of obestatin to the effect of Zn 2؉ on signal transduction and study the effect of obestatin on food intake. Although Zn 2؉ stimulated inositol phosphate turnover, cAMP production, arrestin mobilization, as well as cAMP response element-dependent and serum response element-dependent transcriptional activity in GPR39-expressing cells as opposed to mock-transfected cells, no reproducible effect was obtained with obestatin in the GPR39-expressing cells. Moreover, no specific binding of obestatin could be detected in two different types of GPR39-expressing cells using three different radioiodinated forms of obestatin. By quantitative PCR analysis, GPR39 expression was readily detected in peripheral organs such as duodenum and kidney but not in the pituitary and hypothalamus, i.e. presumed central target organs for obestatin. Obestatin had no significant and reproducible effect on acute food intake in either freely fed or fasted lean mice. It is concluded that GPR39 is probably not the obestatin receptor. In contrast, the potency and efficacy of Zn 2؉ in respect of activating signaling indicates that this metal ion could be a physiologically relevant agonist or modulator of GPR39. (Endocrinology
The neuropharmacology of ADHD drugs in vivo: Insights on efficacy and safety
Neuropharmacology, Sep 1, 2009
Schizophr Res, 1996
MDL 100907 is a selective and potent 5-HT2A antagonist with an atypical antipsychotic profile. MD... more MDL 100907 is a selective and potent 5-HT2A antagonist with an atypical antipsychotic profile. MDL 100 907 is active in dopaminergicaUy-based behavioral tests such as amphetamine-disrupted latent inhibition in rats and amphetaminestimulated locomotion in mice, as well as in behavioral tests that are not based on direct activation of the dopamine system, such as phencyclidine (PCP)-stimulated locomotion in rats and fenfluramine-or DOI-disrupted prepulse inhibition in rats.
Journal of diabetes research, 2015
Chronic pain is a common complication of diabetes. The aim of the present study was to characteri... more Chronic pain is a common complication of diabetes. The aim of the present study was to characterise pain behaviour in a high fat diet/streptozotocin (HFD/STZ) model of diabetes in the rat, investigate spinal mechanisms, and determine the effects of antidiabetic interventions. Three-week consumption of a high fat diet followed by single injection of STZ (45 mgkg(-1)) produced sustained changes in plasma insulin and glucose until day 120. Hindpaw mechanical withdrawal thresholds were significantly lowered in the model, but mechanically evoked responses of spinal neurones were unaltered, compared to HFD/vehicle rats. HFD/STZ rats had significantly lower numbers of spinal Iba-1 positive cells (morphologically identified as activated microglia) and spinal GFAP immunofluorescence (a marker of astrogliosis) in the spinal cord at day 50, compared to time-matched controls. The PPARγ ligand pioglitazone (10 mgkg(-1)) did not alter HFD/STZ induced metabolic changes or hindpaw withdrawal thresh...
Diabetes, metabolic syndrome and obesity : targets and therapy, 2014
The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibi... more The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone...
Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity
Handbook of experimental pharmacology, 2012
Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burde... more Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic s...
Brain 5-HT1 binding sites in depressed suicides
Psychopharmacology, 1990
5-HT1 and 5-HT1A binding sites were measured in brain tissue obtained at postmortem from 19 suici... more 5-HT1 and 5-HT1A binding sites were measured in brain tissue obtained at postmortem from 19 suicides, with definite evidence of depression, and 19 sex and age-matched controls. Thirteen of the depressed suicides had not been prescribed psychoactive drugs recently (drug-free suicides); six had been receiving antidepressant drugs, alone or in combination with other drugs (antidepressant-treated suicides). No significant differences were found in the number or affinity of 5-HT1 and 5-HT1A binding sites in frontal or temporal cortex between drug-free suicides and controls. The number of 5-HT1 sites was significantly lower (by 20%), affinity unaltered, in hippocampus and the affinity significantly lower (by 33%), number unaltered, in amygdala of drug-free suicides than controls. The number of 5-HT1 binding sites tended to be higher and the affinity lower in the antidepressant-treated compared to drug-free suicides, and significantly so in hippocampus. The present results, together with our previous studies, provide no evidence of altered cortical 5-HT markers in depressed suicides, but further emphasise abnormalities in the hippocampus.
Psychopharmacology, 1991
fi-Adrenoceptor binding sites were measured by saturation binding of [3H]CGP 12177 in nine brain ... more fi-Adrenoceptor binding sites were measured by saturation binding of [3H]CGP 12177 in nine brain regions from 13 suicides, with a firm retrospective diagnosis of depression, who had been receiving antidepressant drugs, and 11 matched controls. Significantly lower numbers of fl-adrenoceptor binding sites were found in thalamus and temporal cortex (Brodmann area 38), but not in other brain regions, of antidepressant-treated suicides compared to controls. The lower number of fl-adrenoceptor binding sites in thalamus appeared to be related to drug treatment, whereas lower numbers of fl-adrenoceptors in temporal cortex were also found in antidepressant-free suicides.
The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats
Psychopharmacology, 2007
Treatment with some antipsychotic drugs may result in excessive body weight gain which can have d... more Treatment with some antipsychotic drugs may result in excessive body weight gain which can have detrimental effects on patient compliance, morbidity and mortality. The aim of the present study was to investigate the effect of atypical antipsychotic drugs on dietary macronutrient selection, body weight, body composition and biochemical parameters related to obesity in female rats. Forty pair-housed, adult female hooded-Lister rats (250 +/- 5 g) were habituated to three diets containing principally protein, fat, or carbohydrate in a home cage self-selection paradigm. Olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), or vehicle was injected intraperitoneally once daily for 22 days; food selection, water intake, and body weight were recorded daily, while body composition and plasma hormones (insulin, glucose, nonesterified free fatty acid, total cholesterol, glycerol, triacylglycerol, leptin, and prolactin) were analyzed at the end of the study. Only olanzapine significantly increased body weight and food intake. Macronutrient selection was significantly altered after olanzapine and risperidone treatment (increased protein and decreased fat preference). Only olanzapine increased carcass fat content. Locomotor activity was significantly reduced in all treatment groups. Both olanzapine and risperidone significantly increased plasma prolactin. Olanzapine was without effect on any other biochemical parameter measured. Ziprasidone significantly reduced plasma leptin and nonsignificantly reduced NEFA, while risperidone significantly reduced fasting plasma glucose. This study supports our previous work demonstrating weight gain and increased feeding behavior induced by olanzapine and could have important implications for enhancing our understanding of the mechanisms by which olanzapine and other atypical antipsychotics induce weight gain in the clinic.
Brain GABAB binding sites in depressed suicide victims
Psychiatry Research, 1988
Binding sites for gamma-aminobutyric acid, type B (GABAB), were measured in post-mortem brain sam... more Binding sites for gamma-aminobutyric acid, type B (GABAB), were measured in post-mortem brain samples (frontal cortex, temporal cortex, and hippocampus) from a group of suicide victims and a group of sex- and age-matched controls. Retrospective psychiatric diagnosis was performed, and only suicide victims with clear evidence of depression in the absence of symptoms of other psychiatric or neurological disorders were studied. There were no significant differences between depressed suicides and controls in the number or affinity of GABAB binding sites in the frontal or temporal cortex and no difference in GABAB binding (measured at two concentrations) in the hippocampus. Thirteen of the depressed suicides had not been prescribed antidepressant drugs recently, and none were found in their blood at postmortem. The number of GABAB binding sites in the frontal and temporal cortex and GABAB binding in the hippocampus did not differ significantly between these drug-free suicides and matched controls. The Kd was higher, however, in the temporal cortex of the drug-free suicides than in the controls. A significant negative correlation was found between age and the number of GABAB binding sites in the temporal cortex (on the basis of pooled data from suicides and controls). These results indicate that GABAB binding sites are unaltered in the brains of depressed suicide victims.
[3H]5-hydroxytryptamine binding sites in postmortem human brain
Neuropharmacology, 1989
Binding sites for [3H]5-hydroxytryptamine (5-HT) in postmortem human frontal cortex, hippocampus ... more Binding sites for [3H]5-hydroxytryptamine (5-HT) in postmortem human frontal cortex, hippocampus and amygdala were studied by displacement with 5-HT selective drugs. The results demonstrated the selective labelling of 5-HT1-like sites by [3H]5-HT in the cortex, with little or no labelling of 5-HT2 or 5-HT3 sites. Self-displacement of the binding of [3H]5-HT is consistent with the presence of a single population of sites, indicating that 5-HT is non-selective for the 5-HT1 subtypes. Around 40% of the 5-HT1 sites in the frontal cortex and amygdala were of the 5-HT1A subtype, in contrast to 60% in the hippocampus. The drug RU 24969 consistently displaced with, a high affinity, a greater proportion of [3H]5-HT sites than did 8-OH-DPAT in all three regions of the brain. The nature of these additional sites was not established. A small proportion (less than 10%) of [3H]5-HT sites in the frontal cortex appeared to be of the 5-HT1C subtype, as these sites were displaced with high affinity by mianserin.
Piperazine Derivatives as Therapeutic Agents
Substituted 4-ARYLMETHYLENE-2-IMINO-2,3-DIHYDROTHIAZOLES and Derivatives and Their Pharmaceutical Use
Simultaneous determination of the effects of methamphetamine on GABA, glutamate and monoamines by microdialysis in the prefrontal cortex and hippocampus of rats
Drug and Alcohol Dependence, 2015
[3H]Nisoxetine—A radioligand for noradrenaline reuptake sites: Correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments
Neuropharmacology, 1996
Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurone... more Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurones. [3H]Nisoxetine binding to rat frontal cortical membranes was of high affinity. The binding data of both competition and saturation studies fitted a single site binding model. [3H]Nisoxetine binding was potently inhibited by the selective noradrenaline uptake inhibitors desipramine and protriptyline. In addition, a very good correlation was obtained between the ability of 25 monoamine reuptake inhibitors and related compounds both to inhibit [3H]nisoxetine binding and to inhibit [3H]noradrenaline uptake in rat frontal cortex. DSP-4 (10-100 mg/kg, i.p.) dose-dependently depleted cortical noradrenaline concentrations (51-100%), with no significant effects on 5-HT and dopamine. These depletions, which were used as a marker of loss of noradrenergic nerve terminals, were associated with a dose-dependent decrease in the number of [3H]nisoxetine binding sites (20-97%) with no change in binding affinity. Furthermore, a good correlation was obtained between cortical noradrenaline concentrations and the number of [3H]nisoxetine binding sites. These data support the view that [3H]nisoxetine binds to a single population of homogeneous sites associated with the noradrenaline transporter complex. Using this ligand, the effects of repeated administration of both antidepressant drugs with a range of pharmacological actions and of electroconvulsive shock on noradrenaline reuptake sites were examined. The number and affinity of [3H]nisoxetine binding sites were unaltered by all treatments. It is unlikely, therefore, that antidepressant therapy would produce adaptive changes in noradrenaline uptake sites.
FEBS Letters, 2005
We have investigated the effect of the sulfhydryl-reactive reagent, methyl thiosulfonate ethylamm... more We have investigated the effect of the sulfhydryl-reactive reagent, methyl thiosulfonate ethylammonium (MTSEA), on ligand binding to the human melanocortin-4 (MC4) receptor stably expressed in HEK-293 cells. MTSEA inhibited binding of the agonist, 125 I-NDPa-MSH, and the antagonist, 125 I-SHU9119, in a concentration-dependent manner. Pre-incubation of cells with either the agonist or antagonist protected from subsequent MTSEA inhibition of radioligand binding. Mutation of Cys130 in transmembrane helix 3 to alanine, whilst not affecting ligand binding, led to a complete loss of the inhibitory effect of MTSEA. Since other types of sulfhydryl-reactive reagents had no effect on ligand binding, we conclude that covalent modification of Cys130 by MTSEA disrupts ligand binding by neutralising a close-by negative charge, most likely on Asp126.
Receptor binding and functional evidence suggest that postsynaptic α2-adrenoceptors in rat brain are of the α2D subtype
European Journal of Pharmacology, 1995
This study has determined the subtype(s) of postsynaptic alpha 2-adrenoceptors in rat brain. This... more This study has determined the subtype(s) of postsynaptic alpha 2-adrenoceptors in rat brain. This question has been addressed by using two separate approaches, i.e. ligand displacement of [3H]2-(2-methoxy)-1,4-benzodioxan-2-yl)-2-imidazoline ([3H]RX 821002) from membranes prepared from rat cortex after noradrenergic denervation and, secondly, by antagonism of clonidine-induced mydriasis. After rats had been lesioned using N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 100 mg/kg i.p., 30 min after zimeldine 10 mg/kg i.p.), noradrenaline was undetectable in the cortex 3 days later. Displacement of [3H]RX 821002 with a range of agonists and antagonists which distinguish between the known alpha 2-adrenoceptor subtypes (alpha 2A-2D) yielded pKi values which correlated very well with reported values for the alpha 2D-adrenoceptor (r = 0.929; P < 0.001), but not the alpha 2A (r = 0.450; P = 0.192), alpha 2B (r = 0.280, P = 0.434) or alpha 2C (r = 0.283; P = 0.460) subtypes. Similarly, the potencies of various alpha 2-adrenoceptor antagonists to inhibit clonidine (0.03 mg/kg i.p.)-induced mydriasis in conscious rats correlated strongly with their pKi values for alpha 2D-adrenoceptors (r = 0.899; P = 0.015) but not alpha 2A-(r = 0.369; P = 0.472), alpha 2B-(r = -0.224; P = 0.670) or alpha 2C-adrenoceptors (r = 0.253; P = 0.584). These data are, therefore, consistent and argue strongly that postsynaptic alpha 2-adrenoceptors in the rat cortex and Edinger-Westphal nucleus are of the alpha 2D subtype.
Receptor Occupancy and Brain Free Fraction
Drug Metabolism and Disposition, 2009
This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a bett... more This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.
Diabetes, 2010
OBJECTIVE-Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system... more OBJECTIVE-Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.
Method of treating anxiety disorders
Endocrinology, Jul 1, 2013
GPR39 is an orphan member of the ghrelin receptor family that recently was suggested to be the re... more GPR39 is an orphan member of the ghrelin receptor family that recently was suggested to be the receptor for obestatin, a peptide derived from the ghrelin precursor. Here, we compare the effect of obestatin to the effect of Zn 2؉ on signal transduction and study the effect of obestatin on food intake. Although Zn 2؉ stimulated inositol phosphate turnover, cAMP production, arrestin mobilization, as well as cAMP response element-dependent and serum response element-dependent transcriptional activity in GPR39-expressing cells as opposed to mock-transfected cells, no reproducible effect was obtained with obestatin in the GPR39-expressing cells. Moreover, no specific binding of obestatin could be detected in two different types of GPR39-expressing cells using three different radioiodinated forms of obestatin. By quantitative PCR analysis, GPR39 expression was readily detected in peripheral organs such as duodenum and kidney but not in the pituitary and hypothalamus, i.e. presumed central target organs for obestatin. Obestatin had no significant and reproducible effect on acute food intake in either freely fed or fasted lean mice. It is concluded that GPR39 is probably not the obestatin receptor. In contrast, the potency and efficacy of Zn 2؉ in respect of activating signaling indicates that this metal ion could be a physiologically relevant agonist or modulator of GPR39. (Endocrinology
The neuropharmacology of ADHD drugs in vivo: Insights on efficacy and safety
Neuropharmacology, Sep 1, 2009
Schizophr Res, 1996
MDL 100907 is a selective and potent 5-HT2A antagonist with an atypical antipsychotic profile. MD... more MDL 100907 is a selective and potent 5-HT2A antagonist with an atypical antipsychotic profile. MDL 100 907 is active in dopaminergicaUy-based behavioral tests such as amphetamine-disrupted latent inhibition in rats and amphetaminestimulated locomotion in mice, as well as in behavioral tests that are not based on direct activation of the dopamine system, such as phencyclidine (PCP)-stimulated locomotion in rats and fenfluramine-or DOI-disrupted prepulse inhibition in rats.
Journal of diabetes research, 2015
Chronic pain is a common complication of diabetes. The aim of the present study was to characteri... more Chronic pain is a common complication of diabetes. The aim of the present study was to characterise pain behaviour in a high fat diet/streptozotocin (HFD/STZ) model of diabetes in the rat, investigate spinal mechanisms, and determine the effects of antidiabetic interventions. Three-week consumption of a high fat diet followed by single injection of STZ (45 mgkg(-1)) produced sustained changes in plasma insulin and glucose until day 120. Hindpaw mechanical withdrawal thresholds were significantly lowered in the model, but mechanically evoked responses of spinal neurones were unaltered, compared to HFD/vehicle rats. HFD/STZ rats had significantly lower numbers of spinal Iba-1 positive cells (morphologically identified as activated microglia) and spinal GFAP immunofluorescence (a marker of astrogliosis) in the spinal cord at day 50, compared to time-matched controls. The PPARγ ligand pioglitazone (10 mgkg(-1)) did not alter HFD/STZ induced metabolic changes or hindpaw withdrawal thresh...
Diabetes, metabolic syndrome and obesity : targets and therapy, 2014
The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibi... more The present study assessed the potential of the sodium glucose-linked transporter (SGLT)-2 inhibitor empagliflozin to decrease body weight when administered alone or in combination with the clinically effective weight-loss agents orlistat and sibutramine in obese rats fed a cafeteria diet. Female Wistar rats were exposed to a cafeteria diet to induce obesity. Empagliflozin was dosed once daily (10, 30, and 60 mg/kg) for 28 days. Combination studies were subsequently performed using a submaximal empagliflozin dose (10 mg/kg) with either sibutramine or orlistat. Body weight, food, and water intake were recorded daily. The effect of drug treatment on glucose tolerance, relevant plasma parameters, and carcass composition was determined. Empagliflozin dose-dependently reduced body weight, plasma leptin, and body fat though increased urinary glucose excretion. The combination of empagliflozin and orlistat significantly reduced body weight compared to animals treated with either drug alone...
Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity
Handbook of experimental pharmacology, 2012
Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burde... more Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic s...
Brain 5-HT1 binding sites in depressed suicides
Psychopharmacology, 1990
5-HT1 and 5-HT1A binding sites were measured in brain tissue obtained at postmortem from 19 suici... more 5-HT1 and 5-HT1A binding sites were measured in brain tissue obtained at postmortem from 19 suicides, with definite evidence of depression, and 19 sex and age-matched controls. Thirteen of the depressed suicides had not been prescribed psychoactive drugs recently (drug-free suicides); six had been receiving antidepressant drugs, alone or in combination with other drugs (antidepressant-treated suicides). No significant differences were found in the number or affinity of 5-HT1 and 5-HT1A binding sites in frontal or temporal cortex between drug-free suicides and controls. The number of 5-HT1 sites was significantly lower (by 20%), affinity unaltered, in hippocampus and the affinity significantly lower (by 33%), number unaltered, in amygdala of drug-free suicides than controls. The number of 5-HT1 binding sites tended to be higher and the affinity lower in the antidepressant-treated compared to drug-free suicides, and significantly so in hippocampus. The present results, together with our previous studies, provide no evidence of altered cortical 5-HT markers in depressed suicides, but further emphasise abnormalities in the hippocampus.
Psychopharmacology, 1991
fi-Adrenoceptor binding sites were measured by saturation binding of [3H]CGP 12177 in nine brain ... more fi-Adrenoceptor binding sites were measured by saturation binding of [3H]CGP 12177 in nine brain regions from 13 suicides, with a firm retrospective diagnosis of depression, who had been receiving antidepressant drugs, and 11 matched controls. Significantly lower numbers of fl-adrenoceptor binding sites were found in thalamus and temporal cortex (Brodmann area 38), but not in other brain regions, of antidepressant-treated suicides compared to controls. The lower number of fl-adrenoceptor binding sites in thalamus appeared to be related to drug treatment, whereas lower numbers of fl-adrenoceptors in temporal cortex were also found in antidepressant-free suicides.
The distinct effects of subchronic antipsychotic drug treatment on macronutrient selection, body weight, adiposity, and metabolism in female rats
Psychopharmacology, 2007
Treatment with some antipsychotic drugs may result in excessive body weight gain which can have d... more Treatment with some antipsychotic drugs may result in excessive body weight gain which can have detrimental effects on patient compliance, morbidity and mortality. The aim of the present study was to investigate the effect of atypical antipsychotic drugs on dietary macronutrient selection, body weight, body composition and biochemical parameters related to obesity in female rats. Forty pair-housed, adult female hooded-Lister rats (250 +/- 5 g) were habituated to three diets containing principally protein, fat, or carbohydrate in a home cage self-selection paradigm. Olanzapine (2 mg/kg), risperidone (0.5 mg/kg), ziprasidone (2.5 mg/kg), or vehicle was injected intraperitoneally once daily for 22 days; food selection, water intake, and body weight were recorded daily, while body composition and plasma hormones (insulin, glucose, nonesterified free fatty acid, total cholesterol, glycerol, triacylglycerol, leptin, and prolactin) were analyzed at the end of the study. Only olanzapine significantly increased body weight and food intake. Macronutrient selection was significantly altered after olanzapine and risperidone treatment (increased protein and decreased fat preference). Only olanzapine increased carcass fat content. Locomotor activity was significantly reduced in all treatment groups. Both olanzapine and risperidone significantly increased plasma prolactin. Olanzapine was without effect on any other biochemical parameter measured. Ziprasidone significantly reduced plasma leptin and nonsignificantly reduced NEFA, while risperidone significantly reduced fasting plasma glucose. This study supports our previous work demonstrating weight gain and increased feeding behavior induced by olanzapine and could have important implications for enhancing our understanding of the mechanisms by which olanzapine and other atypical antipsychotics induce weight gain in the clinic.
Brain GABAB binding sites in depressed suicide victims
Psychiatry Research, 1988
Binding sites for gamma-aminobutyric acid, type B (GABAB), were measured in post-mortem brain sam... more Binding sites for gamma-aminobutyric acid, type B (GABAB), were measured in post-mortem brain samples (frontal cortex, temporal cortex, and hippocampus) from a group of suicide victims and a group of sex- and age-matched controls. Retrospective psychiatric diagnosis was performed, and only suicide victims with clear evidence of depression in the absence of symptoms of other psychiatric or neurological disorders were studied. There were no significant differences between depressed suicides and controls in the number or affinity of GABAB binding sites in the frontal or temporal cortex and no difference in GABAB binding (measured at two concentrations) in the hippocampus. Thirteen of the depressed suicides had not been prescribed antidepressant drugs recently, and none were found in their blood at postmortem. The number of GABAB binding sites in the frontal and temporal cortex and GABAB binding in the hippocampus did not differ significantly between these drug-free suicides and matched controls. The Kd was higher, however, in the temporal cortex of the drug-free suicides than in the controls. A significant negative correlation was found between age and the number of GABAB binding sites in the temporal cortex (on the basis of pooled data from suicides and controls). These results indicate that GABAB binding sites are unaltered in the brains of depressed suicide victims.
[3H]5-hydroxytryptamine binding sites in postmortem human brain
Neuropharmacology, 1989
Binding sites for [3H]5-hydroxytryptamine (5-HT) in postmortem human frontal cortex, hippocampus ... more Binding sites for [3H]5-hydroxytryptamine (5-HT) in postmortem human frontal cortex, hippocampus and amygdala were studied by displacement with 5-HT selective drugs. The results demonstrated the selective labelling of 5-HT1-like sites by [3H]5-HT in the cortex, with little or no labelling of 5-HT2 or 5-HT3 sites. Self-displacement of the binding of [3H]5-HT is consistent with the presence of a single population of sites, indicating that 5-HT is non-selective for the 5-HT1 subtypes. Around 40% of the 5-HT1 sites in the frontal cortex and amygdala were of the 5-HT1A subtype, in contrast to 60% in the hippocampus. The drug RU 24969 consistently displaced with, a high affinity, a greater proportion of [3H]5-HT sites than did 8-OH-DPAT in all three regions of the brain. The nature of these additional sites was not established. A small proportion (less than 10%) of [3H]5-HT sites in the frontal cortex appeared to be of the 5-HT1C subtype, as these sites were displaced with high affinity by mianserin.