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An association study between panic disorder and serotonin 2C receptor DNA marker
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P Poster Presentations dose-dependent anxiolytic effect was found between O.Ol and 3 iLg/kg po. The first significantly effective dose was 0.3 iLglkg and an EDso of 0.05 iLglkg po (0.001-0.205, c.L. 95%) was estimated. At 0.3 iLg/kg po a significant effect was seen up to 6 h post administration. No tolerance or rebound anxiogenesis on withdrawal was seen after 7 days of treatment with fully anxiolytic doses. In the rat GV 150013 reversed the anxiogenesis induced by FG 7142. The first significantly effective dose obtained was 3 iLglkg po. GV 150013 was also found effective in the marmoset human threat test. The first significantly effective dose was 0.3 iLglkg sc. In all three tests GV 150013 was more potent than a benzodiazepine anxiolytic (diazepam in the mouse, chlordiazepoxide in the rat and marmoset) and showed similar efficacy. Thus, GV 150013 has potential as a novel anxiolytic agent.
1
P-1 0-251 An Association Study Between Panic Disorder and Serotonin 2C Receptor DNAMarker
y. Inada, H. Yoneda, Y. Inayama, Y. Nonomura, K. Kuroda, H. Asaba, T. Sakai. Department ofNeuropsychiatry, Osaka Medical College, Takatsuki, Japan
Serotonin (5HT) receptors play an important role in the central nervous system. They were subtyped pharmacologically and each subtype may be associated with psychiatric disorders or psychiatric symptoms. We investigated genetic association between panic disorder and polymorphic serotonin 2C (5HT2C) receptor gene. The subjects were 24 panic disorders and 50 normal controls. The 5HT2C receptor gene located on the chromosome X. Lappa1ainen et al. (I995) identified a cys-to-ser polymorphism at amino acid 23 in the first hydrophobic region of the 5HT2C receptor. Genomic DNA corresponding to the 5HT2C receptor gene was amplified by PCR. Digestion of the 104 bp PCR product with Hinfl yielded 2 alleles. There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no association between panic disorder and 5HT2C receptor gene. These results indicated that 5HT2C receptor does not directly relate to developing panic disorder.
1P-1 0-261 5-HT2C Receptor Antagonists and Anxiety Disorders
T.P.Blackburn, S. Lightowler, G.A. Kennett, M.D. Wood, D.N. Middlemiss. Department ofPsychiatry Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK Abnormalities in the serotonergic system in patients with anxiety disorders, in particular panic and obsessive compulsive disorders, have been reported by several groups (see review [1D. The metabolite of the antidepressant trazadone, m-chlorophenylpiperazine (m-CPP), has been reported to have some selectivity for the 5-HT2C receptor and increase panic attacks and exacerbate OCD in patients, possibly by an action at hypersensitive 5-HT2C receptors [I]. Furthermore, our own work has shown that chronic administration of the selective serotonin reuptake inhibitor paroxetine caused a functional desensitisation of 5-HT2C receptors [2]. These data and the recent evidence that paroxetine and other SSRIs are effective in panic disorder points to abnormalities in 5-HT2C receptor function or post translational processess in the pathophysiology of panic disorder. At SmithKline Beecham we have developed selective 5-HT2C/2B receptor antagonists of which SB 221284 (1(3-Pyridylcarbamoyl)-5-methylthio-6-trifluoromethylindoline) has been shown to possess high affinity for the human 5-HT2C receptor (pKi 8.6) and (pKi 8.3) for the human 5-HT2B receptors. The compound is orally active in a rat functional model of 5-HT2C activation, m-CPP-induced hypolocomotion (1050 1.5 mglkg) and shows good anxiolytic activity in animal models (rat social interaction test, minimum effective dose (MED) 1.0 mglkg and rat Geller Seifter test MED 1.0 mg/kg). Thus. our studies to date would suggest that a selective 5-HT2C receptor antagonist may have an anxiolytic-like profile in man. [II Kennett GA,Curro Opin. Invest. Drugs 2 (1993) 317-362. [2] Kennett GA,etal., Neurophannacol. 33 (1994) 1581-1588.
1
P-1 0-27 1 Anxiolytic Effects of Y-23684 in Normal Humans
with High- and LOW-Anxiety Y. Mizuki, M. Suetsugi, M. Yamada. Dept. ofNeuropsychiat., Yamaguchi Univ., Ube, Japan
The appearance ofFmEl, which is EEG theta rhythm in the frontal midline area during performance of mental tasks, reflects relief from anxiety in humans. Anxiolytic effects of Y-23684, a benzodiazepine receptor partial agonist, were investigated using 24 male university students with (Fme group, n = 12) and without (non-FmEl group, n = 12) FmEl. The subjects were given placebo, 5 mg diazepam, 2 mg and 4 mg Y-23684 in a double-blind, crossover design. STAI scores were determined, and EEGs during the performance of an arithmetic addition task were recorded for 5 min. The test was repeated twice: before and 2 hrs after the drug administration. Placebo decreased the state anxiety scores and increased the amount of FmEl and task performance in the non-Fme group. Diazepam and 4 mg Y-23684 produced a decrease in the state anxiety scores and an increase in the FmEl amount after the drug ingestion in both groups. Y-23684 and diazepam did not influence the task performance in the FmEl group, but decreased the performance in the non-FmEl group. However, there were no differences in the state anxiety, the FmEl amount and the task performance between 5 mg diazepam and 4 mg Y-23684. These results suggest that the anxiolytic effect of 4 mg Y-23684 may be comparable to that of 5 mg diazepam.
IP-1 0-281
Anticonvulsant and Anxiolytic Effects of LY300164, an Orally Effective AMPA Antagonist J.D. Leander. CNS Research, Eli Lilly & Co., Indianapolis, IN, USA LY300164 is an analog of GYKI 52466[1], and the active (-) isomer of GYKI 53405 (LY293606). These are non-competitive antagonists of the AMPA sub-type of glutamate receptors. The (+) isomer of LY293606 appears to be pharmacologically inactive. At 30 min post p.o. dosing, LY300164 was a potent antagonist (ED50 = 0.65 mgikg) of lethality induced by ATPA, an analog of AMPA that more readily crosses the blood-brain-barrier, and maximal electroshock-induced seizures (ED50 = 4.6 mglkg), and produced impairment on the horizontal screen test (ED50 = 8.5 mg/kg) in mice. Daily treatment (3 weeks) with the racemate LY293606 produced a dose-related (3.1-12.5 mglkg) blockade of the development of pentylenetetrazole-induced kindling in mice, and no development of tolerance to the anticonvulsant effects in the MES test, In rats lever pressing for food under a Mult VI-30 sec, VI-30 sec + FR-IO shock schedule of punishment, LY293606 increased punished responding, an "anxiolytic effect", at 10-40 mg/kg, p.o., whereas 80 mglkg produced complete response suppression for the 50 min test session. These data indicate that LY300164 has anticonvulsant and anxiolytic effects preclinically, and suggest that AMPA antagonists might have a variety of clinical uses. [1] Tarnawa, et al.,Bioorganic Med. Chern. Letters 3: 99,1993.
I
P-10-29 1 Benzodiazepine-Mediated Overactivation of 5-HT2 Behavioural Responses in Rodents
I. Leonsegui, L. Salvador-Carulla. Dpto. Neurosciencias, Unidad de Psiquitria y Psicologia Medica, Facultad de Medicina, Plaza Fragela SIN, lID03 Cadiz Objectives. The interaction between benzodiacepine (BZD) and serolonergic mechanisms has been explored by testing the effect of different BZD receptor ligands on the behavioural responses induced by serotonergic activation in rats and mice. Method. To study 5-HTIA and 5-HT2 mechanisms the following functional models were used: 5-hydroxytriptophan (5-HTP) and quipacine induced wet-dog-shake (WDS) response in rats, 5-HTP induced headtwitch response in mice, 5-HTP and 8-hydroxy-diproll-aminotetralin (DPAT)induced serotonin syndrome in rats and DPATinduced hypothermia in rats. Results. Acute BDZ agonists administration (ilunitrazepam-FNZ-, nitrazepam, triazolarn and diazepam) set off a dramatic increase in the frecuency and intensity of responses considered as a consecuence of 5-HT2 mechanisms activation. Continuous FNZ administration induced a
P Poster Presentations dose-dependent anxiolytic effect was found between O.Ol and 3 iLg/kg po. The first significantly effective dose was 0.3 iLglkg and an EDso of 0.05 iLglkg po (0.001-0.205, c.L. 95%) was estimated. At 0.3 iLg/kg po a significant effect was seen up to 6 h post administration. No tolerance or rebound anxiogenesis on withdrawal was seen after 7 days of treatment with fully anxiolytic doses. In the rat GV 150013 reversed the anxiogenesis induced by FG 7142. The first significantly effective dose obtained was 3 iLglkg po. GV 150013 was also found effective in the marmoset human threat test. The first significantly effective dose was 0.3 iLglkg sc. In all three tests GV 150013 was more potent than a benzodiazepine anxiolytic (diazepam in the mouse, chlordiazepoxide in the rat and marmoset) and showed similar efficacy. Thus, GV 150013 has potential as a novel anxiolytic agent.
1
P-1 0-251 An Association Study Between Panic Disorder and Serotonin 2C Receptor DNAMarker
y. Inada, H. Yoneda, Y. Inayama, Y. Nonomura, K. Kuroda, H. Asaba, T. Sakai. Department ofNeuropsychiatry, Osaka Medical College, Takatsuki, Japan
Serotonin (5HT) receptors play an important role in the central nervous system. They were subtyped pharmacologically and each subtype may be associated with psychiatric disorders or psychiatric symptoms. We investigated genetic association between panic disorder and polymorphic serotonin 2C (5HT2C) receptor gene. The subjects were 24 panic disorders and 50 normal controls. The 5HT2C receptor gene located on the chromosome X. Lappa1ainen et al. (I995) identified a cys-to-ser polymorphism at amino acid 23 in the first hydrophobic region of the 5HT2C receptor. Genomic DNA corresponding to the 5HT2C receptor gene was amplified by PCR. Digestion of the 104 bp PCR product with Hinfl yielded 2 alleles. There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no association between panic disorder and 5HT2C receptor gene. These results indicated that 5HT2C receptor does not directly relate to developing panic disorder.
1P-1 0-261 5-HT2C Receptor Antagonists and Anxiety Disorders
T.P.Blackburn, S. Lightowler, G.A. Kennett, M.D. Wood, D.N. Middlemiss. Department ofPsychiatry Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK Abnormalities in the serotonergic system in patients with anxiety disorders, in particular panic and obsessive compulsive disorders, have been reported by several groups (see review [1D. The metabolite of the antidepressant trazadone, m-chlorophenylpiperazine (m-CPP), has been reported to have some selectivity for the 5-HT2C receptor and increase panic attacks and exacerbate OCD in patients, possibly by an action at hypersensitive 5-HT2C receptors [I]. Furthermore, our own work has shown that chronic administration of the selective serotonin reuptake inhibitor paroxetine caused a functional desensitisation of 5-HT2C receptors [2]. These data and the recent evidence that paroxetine and other SSRIs are effective in panic disorder points to abnormalities in 5-HT2C receptor function or post translational processess in the pathophysiology of panic disorder. At SmithKline Beecham we have developed selective 5-HT2C/2B receptor antagonists of which SB 221284 (1(3-Pyridylcarbamoyl)-5-methylthio-6-trifluoromethylindoline) has been shown to possess high affinity for the human 5-HT2C receptor (pKi 8.6) and (pKi 8.3) for the human 5-HT2B receptors. The compound is orally active in a rat functional model of 5-HT2C activation, m-CPP-induced hypolocomotion (1050 1.5 mglkg) and shows good anxiolytic activity in animal models (rat social interaction test, minimum effective dose (MED) 1.0 mglkg and rat Geller Seifter test MED 1.0 mg/kg). Thus. our studies to date would suggest that a selective 5-HT2C receptor antagonist may have an anxiolytic-like profile in man. [II Kennett GA,Curro Opin. Invest. Drugs 2 (1993) 317-362. [2] Kennett GA,etal., Neurophannacol. 33 (1994) 1581-1588.
1
P-1 0-27 1 Anxiolytic Effects of Y-23684 in Normal Humans
with High- and LOW-Anxiety Y. Mizuki, M. Suetsugi, M. Yamada. Dept. ofNeuropsychiat., Yamaguchi Univ., Ube, Japan
The appearance ofFmEl, which is EEG theta rhythm in the frontal midline area during performance of mental tasks, reflects relief from anxiety in humans. Anxiolytic effects of Y-23684, a benzodiazepine receptor partial agonist, were investigated using 24 male university students with (Fme group, n = 12) and without (non-FmEl group, n = 12) FmEl. The subjects were given placebo, 5 mg diazepam, 2 mg and 4 mg Y-23684 in a double-blind, crossover design. STAI scores were determined, and EEGs during the performance of an arithmetic addition task were recorded for 5 min. The test was repeated twice: before and 2 hrs after the drug administration. Placebo decreased the state anxiety scores and increased the amount of FmEl and task performance in the non-Fme group. Diazepam and 4 mg Y-23684 produced a decrease in the state anxiety scores and an increase in the FmEl amount after the drug ingestion in both groups. Y-23684 and diazepam did not influence the task performance in the FmEl group, but decreased the performance in the non-FmEl group. However, there were no differences in the state anxiety, the FmEl amount and the task performance between 5 mg diazepam and 4 mg Y-23684. These results suggest that the anxiolytic effect of 4 mg Y-23684 may be comparable to that of 5 mg diazepam.
IP-1 0-281
Anticonvulsant and Anxiolytic Effects of LY300164, an Orally Effective AMPA Antagonist J.D. Leander. CNS Research, Eli Lilly & Co., Indianapolis, IN, USA LY300164 is an analog of GYKI 52466[1], and the active (-) isomer of GYKI 53405 (LY293606). These are non-competitive antagonists of the AMPA sub-type of glutamate receptors. The (+) isomer of LY293606 appears to be pharmacologically inactive. At 30 min post p.o. dosing, LY300164 was a potent antagonist (ED50 = 0.65 mgikg) of lethality induced by ATPA, an analog of AMPA that more readily crosses the blood-brain-barrier, and maximal electroshock-induced seizures (ED50 = 4.6 mglkg), and produced impairment on the horizontal screen test (ED50 = 8.5 mg/kg) in mice. Daily treatment (3 weeks) with the racemate LY293606 produced a dose-related (3.1-12.5 mglkg) blockade of the development of pentylenetetrazole-induced kindling in mice, and no development of tolerance to the anticonvulsant effects in the MES test, In rats lever pressing for food under a Mult VI-30 sec, VI-30 sec + FR-IO shock schedule of punishment, LY293606 increased punished responding, an "anxiolytic effect", at 10-40 mg/kg, p.o., whereas 80 mglkg produced complete response suppression for the 50 min test session. These data indicate that LY300164 has anticonvulsant and anxiolytic effects preclinically, and suggest that AMPA antagonists might have a variety of clinical uses. [1] Tarnawa, et al.,Bioorganic Med. Chern. Letters 3: 99,1993.
I
P-10-29 1 Benzodiazepine-Mediated Overactivation of 5-HT2 Behavioural Responses in Rodents
I. Leonsegui, L. Salvador-Carulla. Dpto. Neurosciencias, Unidad de Psiquitria y Psicologia Medica, Facultad de Medicina, Plaza Fragela SIN, lID03 Cadiz Objectives. The interaction between benzodiacepine (BZD) and serolonergic mechanisms has been explored by testing the effect of different BZD receptor ligands on the behavioural responses induced by serotonergic activation in rats and mice. Method. To study 5-HTIA and 5-HT2 mechanisms the following functional models were used: 5-hydroxytriptophan (5-HTP) and quipacine induced wet-dog-shake (WDS) response in rats, 5-HTP induced headtwitch response in mice, 5-HTP and 8-hydroxy-diproll-aminotetralin (DPAT)induced serotonin syndrome in rats and DPATinduced hypothermia in rats. Results. Acute BDZ agonists administration (ilunitrazepam-FNZ-, nitrazepam, triazolarn and diazepam) set off a dramatic increase in the frecuency and intensity of responses considered as a consecuence of 5-HT2 mechanisms activation. Continuous FNZ administration induced a