- Email: [email protected]
250 – Occupancy of NMDA receptors by ketamine in living humans correlates with psychotic symptom induction – a [123I]CNS-1261 SPET Study
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ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
249 – ASENAPINE: SELECTIVE CHRONIC AND DOSE-DEPENDENT EFFECTS ON ADRENERGIC AND MUSCARINIC CHOLINERGIC RECEPTORS
Presenting Author details: [email protected] De Crespigny Park, SE5 8AF London, United Kingdom, Tel.: +44 20 78480357.
Y.K. Choi 1, M. Gardner 1, E.H.F. Wong 2, B. Henry 3, M. Shahid 3, F. Tarazi 1.
Background: Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the NMDA receptor. We used [123I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction. Methods: Ten healthy controls underwent two SPET scans with [123I] CNS-1261. On each occasion, they received either a bolus-infusion of either ketamine or saline. The Brief Psychiatric Rating Scale was administered at the end of each scan, and blood was taken to estimate ketamine blood levels. Predefined regions of interest were used to estimate regional VT of [123I]CNS-1261 for pre- and post-ketamine or saline scans. Regional change in VT from baseline was calculated for ketamine and saline. Two normalized-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and non-specific effects. Results: Ketamine-induced reduction in [123I]CNS-1261 VT in all regions showed the strongest correlation with BPRS negative subscale (p b 0.01). With the normalised-to-cortex measures, there was a significant difference between ketamine- and saline-induced change in BI in thalamus (reduction) and middle inferior frontal cortex (increase). BI in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p b 0.001). Conclusions: [123I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. The fact that ketamine-induced reduction in NMDA receptor binding by [123I]CNS-1261 appeared to be related primarily to negative symptoms suggests that ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and that positive symptoms may arise through a different neurochemical pathway.
1
Harvard Medical School, Belmont, MA, USA Employed at Pfizer Global R&D Ann Arbor, MI, USA at the time of the research 3 Organon Laboratories, Ltd, Lanarkshire, UK 2
Presenting Author details: [email protected] Mailman Research Center, Department of Psychiatry and Neuroscience, 02478 Belmont, United States, Tel.: +1 617 855 3176. Background: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. We examined the chronic effects of multiple doses of asenapine on alphaadrenergic receptors and muscarinic cholinergic receptors. Methods: Four groups of male Sprague–Dawley rats (7 per group) received twice-daily subcutaneous injections of asenapine 0.03, 0.1, or 0.3 mg/kg or vehicle for 4 weeks. Animals were sacrificed and coronal sections (10 μm) were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), entorhinal cortex, nucleus accumbens, caudate putamen and hippocampus. Specific binding was quantified using near-saturation concentrations of radioligands. Results: Asenapine 0.03, 0.1 and 0.3 mg /kg produced dose-dependent increases in alpha1-adrenergic receptors in the mPFC (30%, 39%, and 57%, respectively) and DFC (27%, 37%, 53%). Similarly, alpha2adrenergic receptors were increased in the mPFC (36%, 43%, 50%) and DFC (41%, 44%, 52%). Asenapine did not affect alpha-adrenergic receptors in the other brain regions examined. Increases in muscarinic cholinergic receptors in the mPFC (26%, 31%, 43%) and DFC (27%, 34%, 41%), as well as in hippocampal CA1 (40%, 44%, 42%) and CA3 (25%, 52%, 48%) regions were also documented. Conclusions: Extended treatment with asenapine caused selective and dose-dependent effects on alpha-adrenergic receptors and muscarinic cholinergic receptors in rat forebrain, probably related to induce elevations in norepinephrine and acetylcholine levels. Modulation of central adrenergic and cholinergic function, together with effects on serotonin receptors, may be relevant to a drug's efficacy in improving the negative and cognitive symptoms of schizophrenia. doi:10.1016/j.schres.2007.12.316
doi:10.1016/j.schres.2007.12.317
251 – ASENAPINE ACTIVATES CORTICAL AND SUBCORTICAL CATECHOLAMINE SYSTEMS BY DIFFERENT MECHANISMS T.H. Svensson 1, O. Frånberg 1, V. Ivanov 1, M. Shahid 2, M.M. Marcus 1. 1
250 – OCCUPANCY OF NMDA RECEPTORS BY KETAMINE IN LIVING HUMANS CORRELATES WITH PSYCHOTIC SYMPTOM INDUCTION – A [123I]CNS-1261 SPET STUDY
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 2 Organon Laboratories Ltd, Newhouse, Lanarkshire, UK
J.M. Stone 1, K. Erlandsson 2, E. Arstad 2, L. Squassante 3, V. Teneggi 3, R. Bressan 1, P.J. Ell 3, L.S. Pilowsky 1.
Presenting Author details: [email protected] Nanna Svartz v 2, SE-171 77 Stockholm, Sweden, Tel.: +46 8 52487921.
1 Institute of Psychiatry, King's College London, London, United Kingdom 2 Institute of Nuclear Medicine, University College London, London, UK 3 GlaxoSmithKline (GSK), Via A. Fleming N 4, Verona 37135, Italy
Background: Asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, possesses higher affinity for several 5-HT receptors and the á2 adrenoceptor than for D2 receptors. Preclinically, asenapine exhibits an antipsychotic-like effect in doses that do not induce catalepsy. Moreover, like several atypical
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
249 – ASENAPINE: SELECTIVE CHRONIC AND DOSE-DEPENDENT EFFECTS ON ADRENERGIC AND MUSCARINIC CHOLINERGIC RECEPTORS
Presenting Author details: [email protected] De Crespigny Park, SE5 8AF London, United Kingdom, Tel.: +44 20 78480357.
Y.K. Choi 1, M. Gardner 1, E.H.F. Wong 2, B. Henry 3, M. Shahid 3, F. Tarazi 1.
Background: Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the NMDA receptor. We used [123I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction. Methods: Ten healthy controls underwent two SPET scans with [123I] CNS-1261. On each occasion, they received either a bolus-infusion of either ketamine or saline. The Brief Psychiatric Rating Scale was administered at the end of each scan, and blood was taken to estimate ketamine blood levels. Predefined regions of interest were used to estimate regional VT of [123I]CNS-1261 for pre- and post-ketamine or saline scans. Regional change in VT from baseline was calculated for ketamine and saline. Two normalized-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and non-specific effects. Results: Ketamine-induced reduction in [123I]CNS-1261 VT in all regions showed the strongest correlation with BPRS negative subscale (p b 0.01). With the normalised-to-cortex measures, there was a significant difference between ketamine- and saline-induced change in BI in thalamus (reduction) and middle inferior frontal cortex (increase). BI in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p b 0.001). Conclusions: [123I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. The fact that ketamine-induced reduction in NMDA receptor binding by [123I]CNS-1261 appeared to be related primarily to negative symptoms suggests that ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and that positive symptoms may arise through a different neurochemical pathway.
1
Harvard Medical School, Belmont, MA, USA Employed at Pfizer Global R&D Ann Arbor, MI, USA at the time of the research 3 Organon Laboratories, Ltd, Lanarkshire, UK 2
Presenting Author details: [email protected] Mailman Research Center, Department of Psychiatry and Neuroscience, 02478 Belmont, United States, Tel.: +1 617 855 3176. Background: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder. We examined the chronic effects of multiple doses of asenapine on alphaadrenergic receptors and muscarinic cholinergic receptors. Methods: Four groups of male Sprague–Dawley rats (7 per group) received twice-daily subcutaneous injections of asenapine 0.03, 0.1, or 0.3 mg/kg or vehicle for 4 weeks. Animals were sacrificed and coronal sections (10 μm) were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), entorhinal cortex, nucleus accumbens, caudate putamen and hippocampus. Specific binding was quantified using near-saturation concentrations of radioligands. Results: Asenapine 0.03, 0.1 and 0.3 mg /kg produced dose-dependent increases in alpha1-adrenergic receptors in the mPFC (30%, 39%, and 57%, respectively) and DFC (27%, 37%, 53%). Similarly, alpha2adrenergic receptors were increased in the mPFC (36%, 43%, 50%) and DFC (41%, 44%, 52%). Asenapine did not affect alpha-adrenergic receptors in the other brain regions examined. Increases in muscarinic cholinergic receptors in the mPFC (26%, 31%, 43%) and DFC (27%, 34%, 41%), as well as in hippocampal CA1 (40%, 44%, 42%) and CA3 (25%, 52%, 48%) regions were also documented. Conclusions: Extended treatment with asenapine caused selective and dose-dependent effects on alpha-adrenergic receptors and muscarinic cholinergic receptors in rat forebrain, probably related to induce elevations in norepinephrine and acetylcholine levels. Modulation of central adrenergic and cholinergic function, together with effects on serotonin receptors, may be relevant to a drug's efficacy in improving the negative and cognitive symptoms of schizophrenia. doi:10.1016/j.schres.2007.12.316
doi:10.1016/j.schres.2007.12.317
251 – ASENAPINE ACTIVATES CORTICAL AND SUBCORTICAL CATECHOLAMINE SYSTEMS BY DIFFERENT MECHANISMS T.H. Svensson 1, O. Frånberg 1, V. Ivanov 1, M. Shahid 2, M.M. Marcus 1. 1
250 – OCCUPANCY OF NMDA RECEPTORS BY KETAMINE IN LIVING HUMANS CORRELATES WITH PSYCHOTIC SYMPTOM INDUCTION – A [123I]CNS-1261 SPET STUDY
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 2 Organon Laboratories Ltd, Newhouse, Lanarkshire, UK
J.M. Stone 1, K. Erlandsson 2, E. Arstad 2, L. Squassante 3, V. Teneggi 3, R. Bressan 1, P.J. Ell 3, L.S. Pilowsky 1.
Presenting Author details: [email protected] Nanna Svartz v 2, SE-171 77 Stockholm, Sweden, Tel.: +46 8 52487921.
1 Institute of Psychiatry, King's College London, London, United Kingdom 2 Institute of Nuclear Medicine, University College London, London, UK 3 GlaxoSmithKline (GSK), Via A. Fleming N 4, Verona 37135, Italy
Background: Asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, possesses higher affinity for several 5-HT receptors and the á2 adrenoceptor than for D2 receptors. Preclinically, asenapine exhibits an antipsychotic-like effect in doses that do not induce catalepsy. Moreover, like several atypical