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S. K. Kulkarni - One of the best experts on this subject based on the ideXlab platform.

  • Possible involvement of sigma-1 receptors in the anti-immobility action of bupropion, a Dopamine Reuptake Inhibitor.
    Fundamental & clinical pharmacology, 2008
    Co-Authors: Ashish Dhir, S. K. Kulkarni
    Abstract:

    Sigma receptors particularly, sigma-1 subtype is known to modulate the release of catecholamines in the brain and may participate in the mechanism of action of various antidepressants. The present study investigated the possible involvement of sigma receptors in modulating the anti-immobility-like effect of bupropion (a Dopamine Reuptake Inhibitor) using the forced swim test (FST) in mice. Bupropion produced dose-dependent (10-40 mg/kg, i.p.) reduction in immobility period and the ED 50 value was found to be 18.5 (7.34-46.6) mg/kg, i.p. (+)-Pentazocine (2.5 mg/ kg, i.p.), a high-affinity sigma-1 receptor agonist, produced synergistic response when it was co-administered with a subeffective dose of bupropion (10 mg/kg, i.p.). On the contrary, pretreatment with progesterone (10 mg/kg, s.c.), a sigma-1 receptor antagonist neurosteroid, rimcazole (5 mg/kg, i.p.), another sigma-1 receptor antagonist, or BD 1047 (1 mg/kg, i.p.), a novel sigma-1 receptor antagonist, reversed the anti-immobility effects of bupropion (20 mg/kg, i.p.). The various modulators used in the study did not show any effect per se on locomotor activity except bupropion which at a higher dose (15-40 mg/kg, i.p.) significantly increased the locomotor activity. The results for the first time demonstrated the involvement of sigma-1 receptors in the anti-immobility effects of bupropion.

  • involvement of nitric oxide no signaling pathway in the antidepressant action of bupropion a Dopamine Reuptake Inhibitor
    European Journal of Pharmacology, 2007
    Co-Authors: Ashish Dhir, S. K. Kulkarni
    Abstract:

    The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a Dopamine Reuptake Inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, Dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED(50) values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of Dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) Inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct Inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 Inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its Dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.

Carol A Venanzi - One of the best experts on this subject based on the ideXlab platform.

  • Singular value decomposition analysis of the torsional angles of Dopamine Reuptake Inhibitor GBR 12909 analogs: effect of force field and charges
    Journal of Molecular Modeling, 2011
    Co-Authors: Deepangi Pandit, Anna Fiorentino, Supreet Bindra, Carol A Venanzi
    Abstract:

    Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of large, flexible molecules, such as the Dopamine Reuptake Inhibitor GBR 12909 ( 1 ), is complicated by the fact that they can take on a wide range of closely-related conformations. The first step in the analysis is to classify the conformers into groups. Over 600 conformers each of a piperazine ( 2 ) and piperidine ( 3 ) analog of 1 were generated by random search conformational analysis using the Merck Molecular Force Field (MMFF94). Singular value decomposition (SVD) was used to group the conformers of 2 and 3 by the similarity of their non-ring torsional angles. SVD uncovered subtle differences in their conformer populations due to that fact that the conformers separate along different principal components, and ultimately to the fact that different torsional angles are the chief contributors to these components. The results were compared to our previous SVD analysis (Fiorentino, et al., Journal of Computational Chemistry, 2006, 27, 609-620) of conformer populations of 2 and 3 generated by the Tripos force field and Gasteiger-Hückel charges. Except for the dominant contribution of angle B3 to principal component 8 seen with both force fields, the angles which are chiefly responsible for the grouping of the conformers of 2 and 3 are different with both force fields. This illustrates that SVD is useful in identifying unique groupings of conformers in large data sets of flexible molecules—a first step in selecting representative conformers for 3D-QSAR modeling studies.

  • conformational analysis of piperazine and piperidine analogs of gbr 12909 stochastic approach to evaluating the effects of force fields and solvent
    Journal of Molecular Modeling, 2011
    Co-Authors: Milind Misra, Deepangi Pandit, Kathleen M Gilbert, William Roosma, William J Skawinski, Carol A Venanzi
    Abstract:

    Analogs of the flexible Dopamine Reuptake Inhibitor, GBR 12909 (1), may have potential utility in the treatment of cocaine abuse. As a first step in the 3D-QSAR modeling of the Dopamine transporter (DAT)/serotonin transporter (SERT) selectivity of these compounds, we carried out conformational analyses of two analogs of 1: a piperazine (2) and a related piperidine (3). Ensembles of conformers consisting of local minima on the potential energy surface of the molecule were generated in the vacuum phase and in implicit solvent by random search conformational analysis using the Tripos and MMFF94 force fields. Some differences were noted in the conformer populations due to differences in the treatment of the tertiary amine nitrogen and ether oxygen atom types by the force fields. The force fields also differed in their descriptions of internal rotation around the C(sp3)–O(sp3) bond proximal to the bisphenyl moiety. Molecular orbital calculations at the HF/6-31G(d) and B3LYP/6-31G(d) levels of C–O internal rotation in model compound (5), designed to model the effect of the proximity of the bisphenyl group on C-O internal rotation, showed a broad region of low energy between −60° to 60° with minima at both −60° and 30° and a low rotational barrier at 0°, in closer agreement with the MMFF94 results than the Tripos results. Molecular mechanics calculations on model compound (6) showed that the MMFF94 force field was much more sensitive than the Tripos force field to the effects of the bisphenyl moiety on C–O internal rotation.

  • singular value decomposition of torsional angles of analogs of the Dopamine Reuptake Inhibitor gbr 12909
    Journal of Computational Chemistry, 2006
    Co-Authors: Anna Fiorentino, Milind Misra, Deepangi Pandit, Kathleen M Gilbert, R A Dios, Carol A Venanzi
    Abstract:

    Analysis of large, flexible molecules, such as the Dopamine Reuptake Inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely related conformations. The first step in the analysis is to classify the conformers into groups. Here, Singular Value Decomposition (SVD) was used to group conformations of GBR 12909 analogs by the similarity of their nonring torsional angles. The significance of the present work, the first application of SVD to the analysis of very flexible molecules, lies in the development of a novel scaling technique for circular data and in the grouping of molecular conformations using a technique that is independent of molecular alignment. Over 700 conformers each of a piperazine (2) and piperidine (3) analog of 1 were studied. Analysis of the score and loading plots showed that the conformers of 2 separate into three large groups due to torsional angles on the naphthalene side of the molecule, whereas those of 3 separate into nine groups due to torsional angles on the bisphenyl side of the molecule. These differences are due to nitrogen inversion at the unprotonated piperazinyl nitrogen of 2, which results in a different ensemble of conformers than those of 3, where no inversion is possible at the corresponding piperidinyl carbon.

  • novel feature extraction technique for fuzzy relational clustering of a flexible Dopamine Reuptake Inhibitor
    ChemInform, 2005
    Co-Authors: Milind Misra, Amit Banerjee, Rajesh N Dave, Carol A Venanzi
    Abstract:

    This paper describes a novel clustering methodology for classifying over 700 conformations of a flexible analogue of GBR 12909, a Dopamine Reuptake Inhibitor that has completed phase I clinical trials as a treatment for cocaine abuse. The major aspect of the clustering methodology includes an efficient data-conditioning scheme where a systematic feature extraction procedure based on the structural properties of the molecule was used to reduce the associated feature space. This allowed region-specific clustering that focused on individual pharmacophore elements of the molecule. For clustering of the reduced feature set, the fuzzy clustering partitional method was utilized. Due to the relational nature of the feature data, fuzzy relational clustering was employed, and it successfully detected natural groups defined by rotational minima around N(sp3)−C(sp3), O(sp3)−C(sp3), and C(sp3)−C(sp2) bonds. The proposed clustering methodology also employed several cluster validity measures, which corroborated the part...

Lauren V Riters - One of the best experts on this subject based on the ideXlab platform.

  • selective behavioral responses to male song are affected by the Dopamine agonist gbr 12909 in female european starlings sturnus vulgaris
    Brain Research, 2010
    Co-Authors: Benjamin A. Pawlisch, Lauren V Riters
    Abstract:

    Female songbirds use attributes of male song to select mates. Different types of male song differ in incentive value (or the ability to attract females). Dopamine plays a role in incentive value and reward; however, little is known about its role in selective female behavioral responses to male courtship signals. We examined the effects of the indirect Dopamine agonist (Dopamine Reuptake Inhibitor) GBR-12909 on female songbird responses to male song stimuli. Female European starlings were played recordings of long starling song (presumed high incentive value), short starling song (presumed lower incentive value), or purple martin song (lowest incentive value). Vehicle-treated females investigated nest boxes playing starling song more than purple martin song. However, GBR-12909 disrupted preferential responses to the starling song stimuli. GBR-12909 also increased cFOS immunolabeling in the ventromedial nucleus of the hypothalamus (VMH) at the same dose that disrupted female selective responses to male starling song. The results suggest that Dopamine receptors play an important role in female selective responses to biologically meaningful stimuli and that the VMH may be influenced by Dopamine to alter female responses to male song.

  • pharmacological manipulations of Dopamine and opioids have differential effects on sexually motivated song in male european starlings
    Physiology & Behavior, 2006
    Co-Authors: Molly B Schroeder, Lauren V Riters
    Abstract:

    Vocal communication is common among social vertebrates, though little is known about the neural mechanisms regulating the motivation to communicate. This study examined a possible role for Dopamine and opioids in sexually motivated song in male European starlings. The Dopamine Reuptake Inhibitor GBR-12909 increased singing behavior, whereas the D1 Dopamine receptor antagonist SCH-23390 decreased song, suggesting a role for Dopamine in the motivation to sing. In contrast, the opioid agonist fentanyl decreased song, and the antagonist naloxone has previously been shown to increase song, findings consistent with a role for opioids in reward associated with song production. These results suggest that Dopamine and opioids play opposing roles in the regulation of the motivation to communicate.

Maurizio Fava - One of the best experts on this subject based on the ideXlab platform.

  • exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion sertraline and placebo in the embarc clinical trial
    Psychological Medicine, 2020
    Co-Authors: Yuensiang Ang, Gerard E Bruder, John G Keilp, Ashleigh Rutherford, Daniel M Alschuler, Pia Pechtel, Christian A Webb, Thomas J Carmody, Maurizio Fava
    Abstract:

    Background Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. Methods In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin Reuptake Inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/Dopamine Reuptake Inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. Results Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. Conclusion These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

  • efficacy of bupropion and the selective serotonin Reuptake Inhibitors in the treatment of major depressive disorder with high levels of anxiety anxious depression a pooled analysis of 10 studies
    The Journal of Clinical Psychiatry, 2008
    Co-Authors: George I Papakostas, Stephen M Stahl, Vivian L Tucker, Alok Krishen, Cheryl A Seifert, Elizabeth P Goodale, Maurizio Fava
    Abstract:

    Objective The goal of this work was to compare the efficacy of the norepinephrine and Dopamine Reuptake Inhibitor bupropion with the selective serotonin Reuptake Inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). Method Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. Results Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. Conclusions There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

  • resolution of sleepiness and fatigue in major depressive disorder a comparison of bupropion and the selective serotonin Reuptake Inhibitors
    Biological Psychiatry, 2006
    Co-Authors: George I Papakostas, David J Nutt, Lindsay A Hallett, Vivian L Tucker, Alok Krishen, Maurizio Fava
    Abstract:

    Background The purpose of this study was to examine whether the treatment of major depressive disorder (MDD) with the norepinephrine-Dopamine Reuptake Inhibitor (NDRI) bupropion results in a greater resolution of sleepiness and fatigue than with the selective serotonin Reuptake Inhibitors (SSRIs). Methods Six double-blind, randomized clinical trials comparing bupropion ( n = 662) with an SSRI ( n = 655) for the treatment of MDD were pooled. Hypersomnia scores were defined as the sum of scores of the Hamilton Depression Rating Scale (HDRS) items #22, 23, and 24. Fatigue scores were defined as the score of HDRS item #13. Results There was a greater improvement in hypersomnia scores among bupropion-treated than SSRI-treated ( p p = .0008). There was also a greater improvement in fatigue scores among bupropion-treated ( p p = .0005) than placebo-treated patients as well as a greater improvement in fatigue scores among bupropion-treated than SSRI-treated patients ( p = .0078). Fewer bupropion-remitters than SSRI-remitters experienced residual hypersomnia (20.5% vs. 32.1%; p = .0014) or residual fatigue (19.5% vs. 30.2%; p = .0020). Conclusion Treatment of MDD with the NDRI bupropion resulted in a greater resolution of sleepiness and fatigue than SSRIs treatment. Although preliminary, these results warrant prospectively designed studies examining potential differences between bupropion and the SSRIs on these specific depressive symptoms.

George I Papakostas - One of the best experts on this subject based on the ideXlab platform.

  • resolution of sleepiness and fatigue a comparison of bupropion and selective serotonin Reuptake Inhibitors in subjects with major depressive disorder achieving remission at doses approved in the european union
    Journal of Psychopharmacology, 2014
    Co-Authors: James Cooper, Vivian L Tucker, George I Papakostas
    Abstract:

    Unlike selective serotonin Reuptake Inhibitors (SSRIs), bupropion may be classified as a dual noradrenaline and Dopamine Reuptake Inhibitor, a difference with potential implications for the treatment of residual sleepiness and fatigue in major depressive disorder (MDD). Post-hoc analysis of subjects with remitted MDD was performed on data pooled from six double-blind, randomized trials comparing the European Union (EU)-approved dose of ≤300 mg/day bupropion with SSRIs (sertraline, paroxetine or escitalopram) for the resolution of sleepiness and fatigue. Hypersomnia score was defined as the sum of scores of the Hamilton Depression Rating Scale (HDRS) items 22, 23, and 24; fatigue score as HDRS item 13 score; and remission as HDRS-17≤7. Similar proportions of bupropion- and SSRI-treated subjects achieved remission at study endpoint (169/343, 49.3% vs 324/656, 49.4%; last observation carried forward (LOCF), p=0.45). Fewer bupropion-treated remitters had residual symptoms of sleepiness (32/169, 18.9% vs 104/324, 32.1%; p<0.01) and fatigue (33/169, 19.5% vs 98/324, 30.2%; p<0.05). Bupropion-treated remitters also showed greater improvement (mean change from baseline) in sleepiness (p<0.05) and fatigue scores (p<0.01) at endpoint: benefits were evident from week 2 for sleepiness (p<0.01) and week 4 for fatigue (p<0.01). Bupropion treatment at the EU-approved dose of ≤300 mg/day may offer advantages over SSRIs in the resolution of sleepiness and fatigue in remitted MDD patients.

  • efficacy of bupropion and the selective serotonin Reuptake Inhibitors in the treatment of major depressive disorder with high levels of anxiety anxious depression a pooled analysis of 10 studies
    The Journal of Clinical Psychiatry, 2008
    Co-Authors: George I Papakostas, Stephen M Stahl, Vivian L Tucker, Alok Krishen, Cheryl A Seifert, Elizabeth P Goodale, Maurizio Fava
    Abstract:

    Objective The goal of this work was to compare the efficacy of the norepinephrine and Dopamine Reuptake Inhibitor bupropion with the selective serotonin Reuptake Inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). Method Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. Results Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. Conclusions There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

  • resolution of sleepiness and fatigue in major depressive disorder a comparison of bupropion and the selective serotonin Reuptake Inhibitors
    Biological Psychiatry, 2006
    Co-Authors: George I Papakostas, David J Nutt, Lindsay A Hallett, Vivian L Tucker, Alok Krishen, Maurizio Fava
    Abstract:

    Background The purpose of this study was to examine whether the treatment of major depressive disorder (MDD) with the norepinephrine-Dopamine Reuptake Inhibitor (NDRI) bupropion results in a greater resolution of sleepiness and fatigue than with the selective serotonin Reuptake Inhibitors (SSRIs). Methods Six double-blind, randomized clinical trials comparing bupropion ( n = 662) with an SSRI ( n = 655) for the treatment of MDD were pooled. Hypersomnia scores were defined as the sum of scores of the Hamilton Depression Rating Scale (HDRS) items #22, 23, and 24. Fatigue scores were defined as the score of HDRS item #13. Results There was a greater improvement in hypersomnia scores among bupropion-treated than SSRI-treated ( p p = .0008). There was also a greater improvement in fatigue scores among bupropion-treated ( p p = .0005) than placebo-treated patients as well as a greater improvement in fatigue scores among bupropion-treated than SSRI-treated patients ( p = .0078). Fewer bupropion-remitters than SSRI-remitters experienced residual hypersomnia (20.5% vs. 32.1%; p = .0014) or residual fatigue (19.5% vs. 30.2%; p = .0020). Conclusion Treatment of MDD with the NDRI bupropion resulted in a greater resolution of sleepiness and fatigue than SSRIs treatment. Although preliminary, these results warrant prospectively designed studies examining potential differences between bupropion and the SSRIs on these specific depressive symptoms.