The Experts below are selected from a list of 468 Experts worldwide ranked by ideXlab platform
Frank M Dautzenberg - One of the best experts on this subject based on the ideXlab platform.
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125i antiSauvagine 30 a novel and specific high affinity radioligand for the characterization of corticotropin releasing factor type 2 receptors
Neuropharmacology, 2001Co-Authors: Jacqueline Higelin, Gabrielle Pylang, Cristina Paternoster, Gareth J Ellis, Arvind Patel, Frank M DautzenbergAbstract:Corticotropin-releasing factor (CRF) receptors type 1 (CRF1) and type 2 (CRF2) differ from each other in their pharmacological properties. The human and ovine CRF versions bind to CRF1 receptors with significantly higher affinity than to CRF2 receptors. Recently antiSauvagine-30, an N-terminally truncated version of the CRF analog Sauvagine, was characterized as a specific antagonist to mouse CRF2B. We have synthesized the radiolabeled version 125I-antiSauvagine-30 and tested it for its affinity at human CRF1 (hCRF1), hCRF2A, Xenopus CRF1 (xCRF1) and xCRF2 receptors. In control binding studies 125I-labeled hCRF, Sauvagine and astressin were also bound to these receptors. 125I-antiSauvagine-30 exclusively bound to hCRF2A and xCRF2 but not to hCRF1 and xCRF1 receptors. 125I-antiSauvagine-30 binding to hCRF2A and xCRF2 receptors was saturable and of high affinity (hCRF2A: Kd=125 pM; xCRF2: Kd=1.1 nM). In displacement binding experiments using 125I-antiSauvagine-30 as radioligand several CRF analogs bound to hCRF2A and xCRF2 receptors with similar rank orders as reported with other CRF radioligands. Finally, preliminary studies using 125I-antiSauvagine-30 binding to membrane homogenates prepared from different rat brain structures showed that the peptide bound specifically to brain areas expressing CRF2 receptors. These data demonstrate that 125I-antiSauvagine-30 is the first high-affinity ligand to specifically label CRF2 receptors.
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isolation and pharmacological characterization of two functional splice variants of corticotropin releasing factor type 2 receptor from tupaia belangeri
Journal of Neuroendocrinology, 1999Co-Authors: Monika Palchaudhuri, Frank M Dautzenberg, Sandra Wille, Richard L Hauger, E FuchsAbstract:From brain, heart and muscle tissue of the tree shrew (Tupaia belangeri), a higher order mammal, cDNA clones were isolated that encoded two functional splice variants of the corticotropin-releasing factor (CRF) type 2 receptor (CRF-R2). The first, full-length splice variant, amplified from brain and heart tissue, encoded a CRF receptor protein that is 410 amino acids in length and approximately 96% homologous to human CRF-R2alpha. The second, full-length splice variant, derived from skeletal muscle tissue, encoded a 437-amino acid CRF receptor protein that is approximately 92% homologous to human CRF-R2beta. Semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) amplifications and RNase protection analyses, showed that tree shrew CRF-R2alpha (tCRF-R2alpha) and tree shrew CRF-R2beta (tCRF-R2beta) were coexpressed in brain tissue but not in heart and skeletal muscle tissue. Finally, human embryonic kidney 293 (HEK293) cells stably transfected with tCRF-R2alpha and tCRF-R2beta were used to demonstrate that the CRF analogs urocortin and Sauvagine bind with significantly greater affinity (21- to 140-fold) to these two CRF-R2 splice variants than do human/rat and ovine CRF analogs. In keeping with these results of our CRF binding studies, EC50 values were substantially lower for urocortin-and Sauvagine-stimulated than for h/rCRF-and oCRF-stimulated cyclic AMP accumulation in HEK293 cells stably transfected with tCRF-R2alpha or tCRF-R2beta cDNAs. The tree shrew therefore constitutes an important animal model in which to investigate the role of CRF receptor subtypes in the stress response.
Donald R. Gehlert - One of the best experts on this subject based on the ideXlab platform.
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A Novel Brain-Penetrant, Orally Available Corticotropin- Releasing Factor Receptor 1 Antagonist with Efficacy in Animal Models of Alcoholism
2013Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Markus HeiligAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo[1,2-b]pyridazine (MTIP) inhibited 125 I-Sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125 I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of �1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plusmaze was affected by MTIP (1–10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a geneti
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3 4 chloro 2 morpholin 4 yl thiazol 5 yl 8 1 ethylpropyl 2 6 dimethyl imidazo 1 2 b pyridazine a novel brain penetrant orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
The Journal of Neuroscience, 2007Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Andrea Cippitelli, A D Le, Jianliang Lu, Erik James Hembre, Jeffrey W Cramer, Min SongAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF 1 ) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2- b ]pyridazine (MTIP) inhibited 125 I-Sauvagine binding to rat pituitary membranes and cloned human CRF 1 with subnanomolar affinities, with no detectable activity at the CRF 2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125 I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED 50 of ∼1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5- a ]pyrimidine) and CP154526 ( N -butyl- N -ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1–10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
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3 4 chloro 2 morpholin 4 yl thiazol 5 yl 8 1 ethylpropyl 2 6 dimethyl imidazo 1 2 b pyridazine a novel brain penetrant orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
The Journal of Neuroscience, 2007Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Andrea Cippitelli, Erik James Hembre, Jeffrey W Cramer, Min Song, David L Mckinzie, Michelle MorinAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-Sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
Michael G Rosenfeld - One of the best experts on this subject based on the ideXlab platform.
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a Sauvagine corticotropin releasing factor receptor expressed in heart and skeletal muscle
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Toshimitsu Kishimoto, Richard V Pearse, Michael G RosenfeldAbstract:Abstract Corticotropin-releasing factor (CRF) mediates many critical aspects of the physiological response to stress. These effects are elicited by binding to specific high-affinity receptors, which are coupled to guanine nucleotide stimulatory factor (Gs)-response pathways. Recently, a gene encoding a receptor for CRF, expressed in pituitary and the central nervous system (PC-CRF receptor), was isolated and characterized. Here we report the identification and characterization of a second, distinct CRF receptor that is expressed primarily in heart and skeletal muscle and exhibits a specific ligand preference and antagonist sensitivity compared with the PC-CRF receptor. We refer to this second receptor as the heart/muscle (HM)-CRF receptor.
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identification of a seven transmembrane helix receptor for corticotropin releasing factor and Sauvagine in mammalian brain
Neuron, 1993Co-Authors: Chiaping Chang, Richard V Pearse, Shawn M Oconnell, Michael G RosenfeldAbstract:Abstract We have identified and characterized cDNAs encoding a novel receptor that is a member of a distinct class of seven transmembrane helix, G s coupled receptors. This receptor mediates ligand-dependent stimulation of intracellular cAMP levels in response to physiologic concentrations of corticotropin-releasing factor (CRF) and to the related frog skin peptide, Sauvagine. The pattern of CRF receptor mRNA expression in the brain, pituitary gland, and other organs corresponds precisely to that predicted for the classic CRF receptor, suggesting that this receptor serves to mediate the known biological effects of CRF on behavior, stress, and homeostasis. Alternative splicing events generate a second, relatively abundant gene product expressed in a distinct ontogenic pattern. These findings serve to identify the receptor for an important neuropeptide.
Min Song - One of the best experts on this subject based on the ideXlab platform.
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3 4 chloro 2 morpholin 4 yl thiazol 5 yl 8 1 ethylpropyl 2 6 dimethyl imidazo 1 2 b pyridazine a novel brain penetrant orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
The Journal of Neuroscience, 2007Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Andrea Cippitelli, A D Le, Jianliang Lu, Erik James Hembre, Jeffrey W Cramer, Min SongAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF 1 ) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2- b ]pyridazine (MTIP) inhibited 125 I-Sauvagine binding to rat pituitary membranes and cloned human CRF 1 with subnanomolar affinities, with no detectable activity at the CRF 2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125 I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED 50 of ∼1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5- a ]pyrimidine) and CP154526 ( N -butyl- N -ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1–10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
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3 4 chloro 2 morpholin 4 yl thiazol 5 yl 8 1 ethylpropyl 2 6 dimethyl imidazo 1 2 b pyridazine a novel brain penetrant orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
The Journal of Neuroscience, 2007Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Andrea Cippitelli, Erik James Hembre, Jeffrey W Cramer, Min Song, David L Mckinzie, Michelle MorinAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-Sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
Chafiq Hamdouchi - One of the best experts on this subject based on the ideXlab platform.
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A Novel Brain-Penetrant, Orally Available Corticotropin- Releasing Factor Receptor 1 Antagonist with Efficacy in Animal Models of Alcoholism
2013Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Markus HeiligAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethylimidazo[1,2-b]pyridazine (MTIP) inhibited 125 I-Sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125 I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of �1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plusmaze was affected by MTIP (1–10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a geneti
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3 4 chloro 2 morpholin 4 yl thiazol 5 yl 8 1 ethylpropyl 2 6 dimethyl imidazo 1 2 b pyridazine a novel brain penetrant orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
The Journal of Neuroscience, 2007Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Andrea Cippitelli, A D Le, Jianliang Lu, Erik James Hembre, Jeffrey W Cramer, Min SongAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF 1 ) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2- b ]pyridazine (MTIP) inhibited 125 I-Sauvagine binding to rat pituitary membranes and cloned human CRF 1 with subnanomolar affinities, with no detectable activity at the CRF 2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125 I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED 50 of ∼1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5- a ]pyrimidine) and CP154526 ( N -butyl- N -ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1–10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
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3 4 chloro 2 morpholin 4 yl thiazol 5 yl 8 1 ethylpropyl 2 6 dimethyl imidazo 1 2 b pyridazine a novel brain penetrant orally available corticotropin releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism
The Journal of Neuroscience, 2007Co-Authors: Donald R. Gehlert, Annika Thorsell, Philip A. Hipskind, Chafiq Hamdouchi, Andrea Cippitelli, Erik James Hembre, Jeffrey W Cramer, Min Song, David L Mckinzie, Michelle MorinAbstract:We describe a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-Sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I-Sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of approximately 1.3 mg/kg and an oral bioavailability of 91.1%. Compared with R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine) and CP154526 (N-butyl-N-ethyl-4,9-dimethyl-7-(2,4,6-trimethylphenyl)-3,5,7-triazabicyclo[4.3.0]nona-2,4,8,10-tetraen-2-amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (1-10 mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3 g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
