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Effect of YM-43611 and neuroleptics on c-fos expression in the rat forebrain
P Poster Presentations
104
I P-9-21 Fos-Iike Immunoreactivity in the Rat Brain Induced
I
P-9-4 1 Effect of YM-43611 and Neuroleptics on c-tos
by Clozapine, Risperidone, Haloperidol, and Haloperidol Combined with Antidepressant. Kwang-Soo Kim, Won-Myong Bahk, Yang-Whan leon. Department of Psychiatry, St. Mary's Hospital, Catholic University Medical College, Seoul, Korea
Expression in the Rat Forebrain M. Narita, K. Kurokawa, K. Koshiya, K. Hidaka , J. Ohmori, K. Satoh, Departments of Psychiatryand Anatomy, Shiga University ofMedical Science, Otsu, Japan; IDDR, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan
High FLI induction in the medial prefrontal cortex by clozapine may be related to the negative symptom reduction in the schizophrenic patients by clozapine, and low FL1 induction in the striatum by clozapine to the absence of extrapyramidal symptoms ( I). Clinically ritanserin, a selective 5-HT 2/ lc antagonist, reduced the negative symptoms of the schizophrenic patients (2). We compared the FLI induction (cell numbers of Fos-positive neuron ± S.D.) in the medial prefrontal cortex, nucleus accumben s. striatum (medial and lateral). and lateral septal nucleus of the rat brain by clozap ine (CZP)(20 rng/kg), risperidone (RPD)(I rug/kg), haloperidol (HPD)(l mglkg ), HPD (I mglkg) with imipramine (lMI )(l mglkg), HPD (I mglkg) with f1uoxetine (FOX)(0.25 mglkg), HPD (I mglkg) with mianserin (MSR){2 mglkg), HPD (I mglkg) with buspirone (BUS)(l rng/kg), HPD ( I mg/kg) with (DES )(2 rng/kg). The highest FLI in the medial prefrontal cortex was induced by RPD (74.9 ± 2.2), HPD with MSR (62.3 ± 3.2), HPD with BUS (59.9 ± 1.9), ard CZP (57. 1 ± 3.9). HPD with 1MI (53.8 ± 2.6). The highest FLI in the nucleus accumbens was induced by HPD (91.0 ± 1.9), HPD with BUS (69.9 ± 6.6), CZP (59.4 ± 1.3), RPD (51.9 ± 6.9). The lowest FLI in the lateral striatum was induced by CZP (30 ± 0.9), HPD with BUS (30.5 ± 5.4), and HPD with DES (38.3 ± 3.9), RPD (40.6 ± 3.4), These results suggest that the combination of buspirone, or mianserine, with haloperidol in the schizophrenic patients may be effective on the negative symptoms of schizophrenia and on the extrapyramidal symptoms by haloperidol.
The pharmacological characteristics of YM-43611, a novel, potent and selective dopamine D3 and D4 antagonist [I) , were compared with two reference neuroleptics, haloperidol and clozap ine, in terms of modification of immediate-early gene, c-fos. expression in the rat forebrain . After subcutaneous injection of YM-4361l (0.1, 1.0, 10,0 rug/kg), haloperidol (I mglkg) or clozapine (25 mglkg), Fos-immunocytochemi stry was conducted and the distribution of Fos positive neurons were compared. Similar to two reference neuroleptics, YM-436I I enhanced Fos-like immunoreactivity in the septum, nucleus accumben s (shell), limbic cortex and hypothalamic regions in a dose dependent manner. A significant increase in the number of immunoreactive cells was observed in the shell of the nucleus accumbens after injection of YM-436 I I (10.0 mglkg) or either of two other drugs. On the other hand. there were some differences noticed between the drugs. Specifically, haloperidol elevated the number of positive cells in the striatum and the core of the nucleus accumbens, while YM-436 I I ( 1.0. 10.0 mglkg) and clozap ine did not. YM-43611 (10.0 mg/kg) and clozapine produced marked increases of Fos-like immunoreactive cells located in the lateral septal nucleus and the limbic cortex. Although the distribution of the target cell bodies were not identical, these findings demonstrated that YM-4361 1 and clozapine have similar characteristics on the regional c-fos expression in the rat forebrain.
I P-9-3 ! Similar Effects of Chronic Clozapine and 'Seroquel'
IP-9-5'
(ICI 204,636) Administration on l.FosB Expression in the Forebrain
a.s. Robertson I . 1 Dept. of Pharmacology; University of Ottawa. Ottawa, Ontario. Canada; 2 Dept. of Biochemistry. Medical Institute ofBioregulation, Kyushu University, Fukuoka, Japan
F. Ansari I, Y. Nakabeppu ~.
We have recently demonstrated that the immediate-early gene product ~FosB is a marker of chronic neuronal activation. This observation suggests that repeated administration of typical and atypical neuroleptics may produce distinct patterns of tiFosB expression that can be used to identify such compounds and their neuronal targets. To test this hypothesis, we compared the effects of chronic haloperidol, clozapine and 'Ser oquel' rrcr 204,636) administration on ~ Fos B - l ike immunoreactivity (L'> FosBLI) in the rodent forebrain. Administration of haloperidol (2 mglkg/day) for 19 days induced a homogeneou s elevation of neurons which displayed tiFosB-LI in the ventral. medial and dorsolateral aspects of the striatum. Chronic haloperidol administration did not enhance L'>FosB-LI in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapine (20 mglkg/day) and leI 204.636 (20 rug/kg/day) for 19 days elevated L'> FosB-LI not only in the ventral striatum but also in the prefrontal cortex and lateral septal nucleus. However, these compounds had weak effects on L'>FosB-LI in the dorsolateral striatum. These findings suggest that a preferential action on limbic structures such as the prefrontal cortex, ventral striatum and lateral septal nucleus may account for the unique ability of chronic clozapine and ICI 204,636 administration to reduce both the negative and positive symptoms of schizophrenia without generating extrapyramidal side effects. Results from studies on the phenotypical and connecti onal identity of neurons which display haloperidol-, cJozapine and ICI 204.636-induced ti FosB-LI will also be presented. "Seroquel" is a trademark, the propert y of Zeneca Limited.
[I] Hidaka et al., J. Neurochem. 65: (1995) S165.
Receptor Mechanisms Mediating Clozapine-Induced c-tos Expression H.C. Fibiger. Division ofNeurological Sciences, Department of Psychiatry, University ofBritish Columbia, Vancouver, Canada
The atypical antipsychotic clozapine has activity at many neurotransmitter receptors (including dopaminergic, noradrenergic, serotonergic , muscarinic and histaminergic) and at present. the key mechanisms by which this compound produces its unique pattern of clinical effects are not established. Clozapine also increases regional c-fos expression in a unique manner, being highly active in medial prefrontal cortex. nucleus accumbens and lateral septal nucleus. In contrast to typical neuroleptics which consistently increase c-fos expression in the dorsolateral striatum. recent studies suggest that the antimuscarinic actions of clozapine may contribute to its failure to be active in this brain region, Other studies suggest that its actions a a I noradrenergic and 5HT~ serotonergic receptors do not explain the effects of clozapine on regional c-fos expression. In contrast, a combination of in situ hybridization and immunohistochemical techniques have shown that clozapine increases Fos immunoreactivity in dopamine D3 expressing neurons in the nucleus accumbens and lateral septal nucleus. This contrasts with haloperidol which increases c-fos expression in these regions in neurons that do not express D3 receptors, These results indicate that clozapine and haloperidol target different populations of neurons in the nucleus accumbens and lateral septal nucleus. They also implicate muscarinic and D3 receptors in the unique actions of clozapine.
Ip-9-s l Differential Roles of D2, D3 and 04 Receptors in Dopamine-Related Behaviors as Assessed With a Novel 03/04 Antagonist YM-43611 K. Koshiya, K. Nakatoh, H. Hattori, S. Usuda. Institutefor Drug
Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan Dopamine D2, D3 and D4 receptors which belong to the D2 receptor subfamily are differentially distributed in the brain and therefore supposed to have distinct physiological functions as well. In this study, we assessed the involvement of these receptors in various behaviors related to dopaminergic system by using haloperidol (HAL ). a typical D2 antag-
104
I P-9-21 Fos-Iike Immunoreactivity in the Rat Brain Induced
I
P-9-4 1 Effect of YM-43611 and Neuroleptics on c-tos
by Clozapine, Risperidone, Haloperidol, and Haloperidol Combined with Antidepressant. Kwang-Soo Kim, Won-Myong Bahk, Yang-Whan leon. Department of Psychiatry, St. Mary's Hospital, Catholic University Medical College, Seoul, Korea
Expression in the Rat Forebrain M. Narita, K. Kurokawa, K. Koshiya, K. Hidaka , J. Ohmori, K. Satoh, Departments of Psychiatryand Anatomy, Shiga University ofMedical Science, Otsu, Japan; IDDR, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan
High FLI induction in the medial prefrontal cortex by clozapine may be related to the negative symptom reduction in the schizophrenic patients by clozapine, and low FL1 induction in the striatum by clozapine to the absence of extrapyramidal symptoms ( I). Clinically ritanserin, a selective 5-HT 2/ lc antagonist, reduced the negative symptoms of the schizophrenic patients (2). We compared the FLI induction (cell numbers of Fos-positive neuron ± S.D.) in the medial prefrontal cortex, nucleus accumben s. striatum (medial and lateral). and lateral septal nucleus of the rat brain by clozap ine (CZP)(20 rng/kg), risperidone (RPD)(I rug/kg), haloperidol (HPD)(l mglkg ), HPD (I mglkg) with imipramine (lMI )(l mglkg), HPD (I mglkg) with f1uoxetine (FOX)(0.25 mglkg), HPD (I mglkg) with mianserin (MSR){2 mglkg), HPD (I mglkg) with buspirone (BUS)(l rng/kg), HPD ( I mg/kg) with (DES )(2 rng/kg). The highest FLI in the medial prefrontal cortex was induced by RPD (74.9 ± 2.2), HPD with MSR (62.3 ± 3.2), HPD with BUS (59.9 ± 1.9), ard CZP (57. 1 ± 3.9). HPD with 1MI (53.8 ± 2.6). The highest FLI in the nucleus accumbens was induced by HPD (91.0 ± 1.9), HPD with BUS (69.9 ± 6.6), CZP (59.4 ± 1.3), RPD (51.9 ± 6.9). The lowest FLI in the lateral striatum was induced by CZP (30 ± 0.9), HPD with BUS (30.5 ± 5.4), and HPD with DES (38.3 ± 3.9), RPD (40.6 ± 3.4), These results suggest that the combination of buspirone, or mianserine, with haloperidol in the schizophrenic patients may be effective on the negative symptoms of schizophrenia and on the extrapyramidal symptoms by haloperidol.
The pharmacological characteristics of YM-43611, a novel, potent and selective dopamine D3 and D4 antagonist [I) , were compared with two reference neuroleptics, haloperidol and clozap ine, in terms of modification of immediate-early gene, c-fos. expression in the rat forebrain . After subcutaneous injection of YM-4361l (0.1, 1.0, 10,0 rug/kg), haloperidol (I mglkg) or clozapine (25 mglkg), Fos-immunocytochemi stry was conducted and the distribution of Fos positive neurons were compared. Similar to two reference neuroleptics, YM-436I I enhanced Fos-like immunoreactivity in the septum, nucleus accumben s (shell), limbic cortex and hypothalamic regions in a dose dependent manner. A significant increase in the number of immunoreactive cells was observed in the shell of the nucleus accumbens after injection of YM-436 I I (10.0 mglkg) or either of two other drugs. On the other hand. there were some differences noticed between the drugs. Specifically, haloperidol elevated the number of positive cells in the striatum and the core of the nucleus accumbens, while YM-436 I I ( 1.0. 10.0 mglkg) and clozap ine did not. YM-43611 (10.0 mg/kg) and clozapine produced marked increases of Fos-like immunoreactive cells located in the lateral septal nucleus and the limbic cortex. Although the distribution of the target cell bodies were not identical, these findings demonstrated that YM-4361 1 and clozapine have similar characteristics on the regional c-fos expression in the rat forebrain.
I P-9-3 ! Similar Effects of Chronic Clozapine and 'Seroquel'
IP-9-5'
(ICI 204,636) Administration on l.FosB Expression in the Forebrain
a.s. Robertson I . 1 Dept. of Pharmacology; University of Ottawa. Ottawa, Ontario. Canada; 2 Dept. of Biochemistry. Medical Institute ofBioregulation, Kyushu University, Fukuoka, Japan
F. Ansari I, Y. Nakabeppu ~.
We have recently demonstrated that the immediate-early gene product ~FosB is a marker of chronic neuronal activation. This observation suggests that repeated administration of typical and atypical neuroleptics may produce distinct patterns of tiFosB expression that can be used to identify such compounds and their neuronal targets. To test this hypothesis, we compared the effects of chronic haloperidol, clozapine and 'Ser oquel' rrcr 204,636) administration on ~ Fos B - l ike immunoreactivity (L'> FosBLI) in the rodent forebrain. Administration of haloperidol (2 mglkg/day) for 19 days induced a homogeneou s elevation of neurons which displayed tiFosB-LI in the ventral. medial and dorsolateral aspects of the striatum. Chronic haloperidol administration did not enhance L'>FosB-LI in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapine (20 mglkg/day) and leI 204.636 (20 rug/kg/day) for 19 days elevated L'> FosB-LI not only in the ventral striatum but also in the prefrontal cortex and lateral septal nucleus. However, these compounds had weak effects on L'>FosB-LI in the dorsolateral striatum. These findings suggest that a preferential action on limbic structures such as the prefrontal cortex, ventral striatum and lateral septal nucleus may account for the unique ability of chronic clozapine and ICI 204,636 administration to reduce both the negative and positive symptoms of schizophrenia without generating extrapyramidal side effects. Results from studies on the phenotypical and connecti onal identity of neurons which display haloperidol-, cJozapine and ICI 204.636-induced ti FosB-LI will also be presented. "Seroquel" is a trademark, the propert y of Zeneca Limited.
[I] Hidaka et al., J. Neurochem. 65: (1995) S165.
Receptor Mechanisms Mediating Clozapine-Induced c-tos Expression H.C. Fibiger. Division ofNeurological Sciences, Department of Psychiatry, University ofBritish Columbia, Vancouver, Canada
The atypical antipsychotic clozapine has activity at many neurotransmitter receptors (including dopaminergic, noradrenergic, serotonergic , muscarinic and histaminergic) and at present. the key mechanisms by which this compound produces its unique pattern of clinical effects are not established. Clozapine also increases regional c-fos expression in a unique manner, being highly active in medial prefrontal cortex. nucleus accumbens and lateral septal nucleus. In contrast to typical neuroleptics which consistently increase c-fos expression in the dorsolateral striatum. recent studies suggest that the antimuscarinic actions of clozapine may contribute to its failure to be active in this brain region, Other studies suggest that its actions a a I noradrenergic and 5HT~ serotonergic receptors do not explain the effects of clozapine on regional c-fos expression. In contrast, a combination of in situ hybridization and immunohistochemical techniques have shown that clozapine increases Fos immunoreactivity in dopamine D3 expressing neurons in the nucleus accumbens and lateral septal nucleus. This contrasts with haloperidol which increases c-fos expression in these regions in neurons that do not express D3 receptors, These results indicate that clozapine and haloperidol target different populations of neurons in the nucleus accumbens and lateral septal nucleus. They also implicate muscarinic and D3 receptors in the unique actions of clozapine.
Ip-9-s l Differential Roles of D2, D3 and 04 Receptors in Dopamine-Related Behaviors as Assessed With a Novel 03/04 Antagonist YM-43611 K. Koshiya, K. Nakatoh, H. Hattori, S. Usuda. Institutefor Drug
Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan Dopamine D2, D3 and D4 receptors which belong to the D2 receptor subfamily are differentially distributed in the brain and therefore supposed to have distinct physiological functions as well. In this study, we assessed the involvement of these receptors in various behaviors related to dopaminergic system by using haloperidol (HAL ). a typical D2 antag-