Shaun Jordan | Aston University (original) (raw)

Papers by Shaun Jordan

Research paper thumbnail of ARIPIPRAZOLE INCREASES SERINE 9 PHOSPHORYLATION OF GLYCOGENSYNTHASE KINASE3BETA IN CHINESE HAMSTER OVARY CELLS EXPRESSING HUMAN DOPAMINE D2LONG RECEPTORS

Schizophrenia Research, 2008

Research paper thumbnail of Interaction of the novel antipsychotic aripiprazole with 5HT 1A and 5HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies

Psychopharmacology, 2007

Background Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-qui... more Background Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors. Materials and methods This study examined aripiprazole’s interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties. Results Aripiprazole produced increases in [35S]GTPγS binding to rat hippocampal membranes. Its potency (pEC50 = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT1A-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT1A-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT1A receptors (K i = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT2A receptors (K i = 3.4 nM), moderate affinity to 5-HT2C (K i = 15 nM) and 5-HT7 (K i = 39 nM) receptors, and low affinity to 5-HT6 receptors (K i = 214 nM) and 5-HT transporter (K i = 98 nM). In addition, aripiprazole potently blocked 5-HT2A-receptor-mediated increases in intracellular Ca2+ levels in a rat pituitary cell line (IC50 = 11 nM). Discussion These results support a partial agonist activity for aripiprazole at 5-HT1A receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.

Research paper thumbnail of The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT 1A receptor

European Journal of Pharmacology, 2002

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone,... more Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer.

Research paper thumbnail of Dopamine D 2 receptor partial agonists display differential or contrasting characteristics in membrane and cell-based assays of dopamine D 2 receptor signaling

Progress in Neuro-psychopharmacology & Biological Psychiatry, 2007

Research paper thumbnail of In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D 2 receptors

European Journal of Pharmacology, 2006

Research paper thumbnail of In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function

European Journal of Pharmacology, 2004

In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basa... more In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basal extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex and striatum of conscious, freely moving rats. Acute aripiprazole administration did not affect dopamine output, but produced moderate increases in DOPAC and HVA concentrations, in medial prefrontal cortex or striatum of drug-naïve rats. Similarly, aripiprazole did not affect dopamine output but produced moderate elevations in DOPAC and HVA concentrations in the striatum of chronic aripiprazole-pretreated rats. Olanzapine produced comparatively larger elevations in dopamine, DOPAC, and HVA in both regions, which, in the striatum, were diminished after chronic olanzapine exposure. Aripiprazole reduced extracellular 5-HIAA concentrations in the medial prefrontal cortex and striatum of drug-nai;ve rats, but not in chronic aripiprazole-pretreated rats. Together, these data provide in vivo evidence of aripiprazole-induced changes in forebrain dopaminergic and serotonergic function that may reflect its partial agonist activity at presynaptic dopamine D(2) and 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors.

Research paper thumbnail of Altered emotional behaviors in the diabetes mellitus OLETF type 1 congenic rat

Research paper thumbnail of In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signalling

Journal of Psychopharmacology, 2007

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor ... more Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Research paper thumbnail of In vitro profile of the antidepressant candidate OPC14523 at rat and human 5HT 1A receptors

European Journal of Pharmacology, 2005

Research paper thumbnail of Aripiprazole protects cortical neurons from glutamate toxicity

European Journal of Pharmacology, 2011

Research paper thumbnail of Discriminative stimulus properties of ethoxy idazoxan

Journal of Psychopharmacology, 1995

The technique of drug discrimination was used to examine the ability of the highly selective α(2)... more The technique of drug discrimination was used to examine the ability of the highly selective α(2)-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α( 1)-adrenoceptors or I(2) imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α(2)-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α(2)-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α(2)-adrenoceptor antagonist L659,066. However, the α(2)-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I(2) imidazoline receptors over α(2)-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I(2) receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α(1)-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.

Research paper thumbnail of Antidepressant-like effects of the I2 ligands idazoxan and 2BFI in the rat porsolt test

European Neuropsychopharmacology, 1996

Research paper thumbnail of Discriminative stimulus produced by the imidazoline I2 site ligand, 2 BFI

Journal of Psychopharmacology, 1996

2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) b... more 2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) binding sites and very low aflinity for α(2)-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I(2) sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α(2)-adrenoceptor/I( 2) site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α( 2)-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α( 2)-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.

Research paper thumbnail of Central α -2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm

Psychopharmacology, 1993

Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination s... more Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination studies. This cue may be mediated by itsα-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg−1, IP) or a saline vehicle. Theα-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg−1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selectiveα-2 adrenoceptor antagonists RX811059 (2.5 mg kg−1) and fluparoxan (3 mg kg−1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated byα-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally actingα-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.

Research paper thumbnail of Functional Studies of Specific Imidazoline2 Receptor Ligands

Annals of The New York Academy of Sciences, 1995

Research paper thumbnail of Discriminative stimulus properties of ethoxy idazoxan

Journal of Psychopharmacology, 1995

The technique of drug discrimination was used to examine the ability of the highly selective α(2)... more The technique of drug discrimination was used to examine the ability of the highly selective α(2)-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α( 1)-adrenoceptors or I(2) imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α(2)-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α(2)-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α(2)-adrenoceptor antagonist L659,066. However, the α(2)-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I(2) imidazoline receptors over α(2)-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I(2) receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α(1)-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.

Research paper thumbnail of Antidepressant-like effects of the I2 ligands idazoxan and 2BFI in the rat porsolt test

European Neuropsychopharmacology, 1996

Research paper thumbnail of Discriminative stimulus produced by the imidazoline I2 site ligand, 2 BFI

Journal of Psychopharmacology, 1996

2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) b... more 2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) binding sites and very low aflinity for α(2)-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I(2) sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α(2)-adrenoceptor/I( 2) site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α( 2)-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α( 2)-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.

Research paper thumbnail of Central α -2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm

Psychopharmacology, 1993

Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination s... more Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination studies. This cue may be mediated by itsα-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg−1, IP) or a saline vehicle. Theα-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg−1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selectiveα-2 adrenoceptor antagonists RX811059 (2.5 mg kg−1) and fluparoxan (3 mg kg−1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated byα-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally actingα-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.

Research paper thumbnail of Functional Studies of Specific Imidazoline2 Receptor Ligands

Annals of The New York Academy of Sciences, 1995

Research paper thumbnail of ARIPIPRAZOLE INCREASES SERINE 9 PHOSPHORYLATION OF GLYCOGENSYNTHASE KINASE3BETA IN CHINESE HAMSTER OVARY CELLS EXPRESSING HUMAN DOPAMINE D2LONG RECEPTORS

Schizophrenia Research, 2008

Research paper thumbnail of Interaction of the novel antipsychotic aripiprazole with 5HT 1A and 5HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies

Psychopharmacology, 2007

Background Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-qui... more Background Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone) is a novel antipsychotic with a mechanism of action that differs from current typical and atypical antipsychotics. Aripiprazole interacts with a range of receptors, including serotonin [5-hydroxytryptamine (5-HT)] and dopamine receptors. Materials and methods This study examined aripiprazole’s interactions with 5-HT systems in vitro and in vivo to further clarify its pharmacologic properties. Results Aripiprazole produced increases in [35S]GTPγS binding to rat hippocampal membranes. Its potency (pEC50 = 7.2) was similar to that of ziprasidone (7.1) and greater than that of 5-HT (6.7) and buspirone (6.4), a 5-HT1A-receptor partial agonist, whereas its intrinsic activity was similar to that of ziprasidone and buspirone. The stimulatory effect of aripiprazole was blocked by WAY-100635, a 5-HT1A-receptor antagonist. In in vivo electrophysiology studies, aripiprazole produced a dose-related reduction in the firing rate of 5-HT-containing dorsal raphe neurons in rats, which was both prevented and reversed by WAY-100635 administration. Aripiprazole showed a high affinity for human 5-HT1A receptors (K i = 4.2 nM) using parietal cortex membrane preparations. In membranes from cells expressing human recombinant receptors, aripiprazole bound with high affinity to 5-HT2A receptors (K i = 3.4 nM), moderate affinity to 5-HT2C (K i = 15 nM) and 5-HT7 (K i = 39 nM) receptors, and low affinity to 5-HT6 receptors (K i = 214 nM) and 5-HT transporter (K i = 98 nM). In addition, aripiprazole potently blocked 5-HT2A-receptor-mediated increases in intracellular Ca2+ levels in a rat pituitary cell line (IC50 = 11 nM). Discussion These results support a partial agonist activity for aripiprazole at 5-HT1A receptors in vitro and in vivo, and suggest important interactions with other 5-HT-receptor subtypes. This receptor activity profile may contribute to the antipsychotic activity of aripiprazole in humans.

Research paper thumbnail of The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT 1A receptor

European Journal of Pharmacology, 2002

Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone,... more Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy]-3,4-dihydro-2(1H)-quinolinone, a novel antipsychotic with partial agonist activity at dopamine D2 receptors, bound with high affinity to recombinant human 5-HT(1A) receptors (h5-HT(1A)) in Chinese hamster ovary cell membranes and displayed potent, partial agonism at 5-HT(1A) receptors in a guanosine-5'-O-(3-[(35)S]thio)-triphosphate ([(35)S]GTP gamma S)-binding assay that was blocked completely by a selective 5-HT(1A) receptor antagonist. An interaction with 5-HT(1A) receptors may contribute to the overall efficacy of aripiprazole against symptoms of schizophrenia, including anxiety, depression, cognitive and negative symptoms, and to its favorable side-effect profile. Combined with previous studies demonstrating the potent partial agonism of aripiprazole at dopamine D2 receptors, this study suggests aripiprazole is the first dopamine-serotonin system stabilizer.

Research paper thumbnail of Dopamine D 2 receptor partial agonists display differential or contrasting characteristics in membrane and cell-based assays of dopamine D 2 receptor signaling

Progress in Neuro-psychopharmacology & Biological Psychiatry, 2007

Research paper thumbnail of In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D 2 receptors

European Journal of Pharmacology, 2006

Research paper thumbnail of In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function

European Journal of Pharmacology, 2004

In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basa... more In vivo microdialysis was used to monitor the effects of oral aripiprazole and olanzapine on basal extracellular concentrations of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex and striatum of conscious, freely moving rats. Acute aripiprazole administration did not affect dopamine output, but produced moderate increases in DOPAC and HVA concentrations, in medial prefrontal cortex or striatum of drug-naïve rats. Similarly, aripiprazole did not affect dopamine output but produced moderate elevations in DOPAC and HVA concentrations in the striatum of chronic aripiprazole-pretreated rats. Olanzapine produced comparatively larger elevations in dopamine, DOPAC, and HVA in both regions, which, in the striatum, were diminished after chronic olanzapine exposure. Aripiprazole reduced extracellular 5-HIAA concentrations in the medial prefrontal cortex and striatum of drug-nai;ve rats, but not in chronic aripiprazole-pretreated rats. Together, these data provide in vivo evidence of aripiprazole-induced changes in forebrain dopaminergic and serotonergic function that may reflect its partial agonist activity at presynaptic dopamine D(2) and 5-HT(1A) receptors and antagonist activity at 5-HT(2A) receptors.

Research paper thumbnail of Altered emotional behaviors in the diabetes mellitus OLETF type 1 congenic rat

Research paper thumbnail of In vitro functional characteristics of dopamine D2 receptor partial agonists in second and third messenger-based assays of cloned human dopamine D2Long receptor signalling

Journal of Psychopharmacology, 2007

Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor ... more Aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP have been classified as dopamine D(2) receptor partial agonists based largely on their activity in second messenger-based assays of dopamine D(2) receptor signalling. Nevertheless, signal transduction amplification might result in these compounds behaving as dopamine D(2) receptor full agonists at a more downstream level of signalling. We compared the intrinsic activity (E(max), expressed as a percentage of the maximal effect of dopamine) of aripiprazole, (+)terguride, OPC-4392 and (-)3-PPP using second (calcium (Ca(2+)) mobilization) and third (extracellular signal-regulated kinase 2 (ERK2) phosphoprotein expression) messenger readouts of cloned human dopamine D(2long) (hD(2L)) receptor signalling in CHO cells. These compounds were all less potent and displayed lower intrinsic activity in the Ca(2+) assay (aripiprazole = 24.3%, (+)terguride = 56.9%, OPC-4392 = 58.6% and (-)3-PPP = 75.1%), and aripiprazole (E(max) = 54.5%) displayed a substantially lower intrinsic activity than (+)terguride (E(max) = 92.3%), OPC-4392 (E(max) = 93.1%) and (-)3-PPP (E(max) = 101.1%) in the more downstream-based ERK2 phosphoprotein expression assay. These drug effects on Ca(2+) mobilization and ERK2 phosphoprotein expression were mediated through dopamine hD(2L) receptors, as they all were blocked by (-)raclopride, whereas (-)raclopride and other dopamine D(2) receptor antagonists (haloperidol, risperidone, ziprasidone, olanzapine, clozapine and quetiapine) were inactive on their own in both assays. These data are consistent with clinical evidence that only dopamine D(2) receptor partial agonists with a sufficiently low enough intrinsic activity will prove effective against the positive symptoms of schizophrenia, and also highlight the importance of using downstream-based assays in the discovery of novel D(2) receptor partial agonist therapeutics.

Research paper thumbnail of In vitro profile of the antidepressant candidate OPC14523 at rat and human 5HT 1A receptors

European Journal of Pharmacology, 2005

Research paper thumbnail of Aripiprazole protects cortical neurons from glutamate toxicity

European Journal of Pharmacology, 2011

Research paper thumbnail of Discriminative stimulus properties of ethoxy idazoxan

Journal of Psychopharmacology, 1995

The technique of drug discrimination was used to examine the ability of the highly selective α(2)... more The technique of drug discrimination was used to examine the ability of the highly selective α(2)-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α( 1)-adrenoceptors or I(2) imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α(2)-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α(2)-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α(2)-adrenoceptor antagonist L659,066. However, the α(2)-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I(2) imidazoline receptors over α(2)-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I(2) receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α(1)-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.

Research paper thumbnail of Antidepressant-like effects of the I2 ligands idazoxan and 2BFI in the rat porsolt test

European Neuropsychopharmacology, 1996

Research paper thumbnail of Discriminative stimulus produced by the imidazoline I2 site ligand, 2 BFI

Journal of Psychopharmacology, 1996

2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) b... more 2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) binding sites and very low aflinity for α(2)-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I(2) sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α(2)-adrenoceptor/I( 2) site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α( 2)-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α( 2)-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.

Research paper thumbnail of Central α -2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm

Psychopharmacology, 1993

Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination s... more Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination studies. This cue may be mediated by itsα-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg−1, IP) or a saline vehicle. Theα-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg−1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selectiveα-2 adrenoceptor antagonists RX811059 (2.5 mg kg−1) and fluparoxan (3 mg kg−1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated byα-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally actingα-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.

Research paper thumbnail of Functional Studies of Specific Imidazoline2 Receptor Ligands

Annals of The New York Academy of Sciences, 1995

Research paper thumbnail of Discriminative stimulus properties of ethoxy idazoxan

Journal of Psychopharmacology, 1995

The technique of drug discrimination was used to examine the ability of the highly selective α(2)... more The technique of drug discrimination was used to examine the ability of the highly selective α(2)-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α( 1)-adrenoceptors or I(2) imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α(2)-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α(2)-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α(2)-adrenoceptor antagonist L659,066. However, the α(2)-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I(2) imidazoline receptors over α(2)-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I(2) receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α(1)-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.

Research paper thumbnail of Antidepressant-like effects of the I2 ligands idazoxan and 2BFI in the rat porsolt test

European Neuropsychopharmacology, 1996

Research paper thumbnail of Discriminative stimulus produced by the imidazoline I2 site ligand, 2 BFI

Journal of Psychopharmacology, 1996

2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) b... more 2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) binding sites and very low aflinity for α(2)-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I(2) sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α(2)-adrenoceptor/I( 2) site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α( 2)-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α( 2)-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.

Research paper thumbnail of Central α -2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm

Psychopharmacology, 1993

Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination s... more Clonidine produces an interoceptive discriminative stimulus or “cue” in rat drug discrimination studies. This cue may be mediated by itsα-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg−1, IP) or a saline vehicle. Theα-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg−1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selectiveα-2 adrenoceptor antagonists RX811059 (2.5 mg kg−1) and fluparoxan (3 mg kg−1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated byα-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally actingα-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.

Research paper thumbnail of Functional Studies of Specific Imidazoline2 Receptor Ligands

Annals of The New York Academy of Sciences, 1995