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The effect of adrenalectomy on immediate early genes induction by electroconvulsive shock in rat brain
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from patients meeting the DSM-IIIR criteria for schizophrenia and healthy volunteers. Plasma from drug-naive schizophrenic patients caused significantly more inhibition of platelet NOS activity than that from healthy subjects. These results suggest raised circulating levels of an inhibitory substance in these patients. Previously we have found raised NOS activities in platelets from drug-naive schizophrenic patients compared to healthy subjects. It is likely that plasma levels of the NOS inhibitor(s) may have increased as a compensatory mechanism to overcome the raised NOS activity.
THE EFFECT OF ADRENALECTOMY ON IMMEDIATE EARLY GENES INDUCTION BY ELECTROCONVULSIVE SHOCK IN RAT BRAIN K.S. Ha, U.G. Kang, H.Y. Jung, J.B. Park, I.W. Chung, Y.S. Kim*
Department of Psychiatry, Seoul National University, College of Medicine, Yongon-dong, Chongno-gu, Seou1110-744, South Korea The adrenal hormones are known to be related with the pathogenesis of mental disorders and individual vulnerability to stress. To evaluate the influences of adrenal hormones on the signal transduction system in rat brain, the authors observed the effect of bilateral adrenalectomy (ADX) on the induction of c-fos, junB and TIS1 (NGFI-B) by electroconvulsive shock (ECS). The young (70g) and adult (200g) male SpragueDawley rats were treated by ECS (130 V, 0.5 s) at 3 days after ADX. The rats were sacrificed at 0, 15, 30, 45 and 60 min after ECS. The induction of immediate early genes (lEGs) were assessed by Northern blot analysis. ECS clearly induced lEGs in cerebral cortex, hippocampus and cerebellum of both ADX and sham-operated groups but ADX altered the pattern of lEGs induction by ECS. The c-fos, junB and TIS1 in cerebral cortex of the young and the adult rats were induced earlier and disappeared earlier by ADX. The tendency of earlier disappearance of lEGs was more prominent in adult ADX rats compared to young ADX rats. However, the lEGs induction by ECS in hippocampus and cerebellum were not influenced by ADX. These results show that adrenal hormones have some influences on the signal transduction system in the brain.
DISTRIBUTION OF DOPAMINE D2, D3 AND D4 RECEPTORS IN HUMAN POST-MORTEM BRAIN SECTIONS R.A. Lahti*, R. Conley, L. G r u b o w s k i , C.A. T a m m i n g a
Maryland Psychiatric Research Center, Baltimore, MD 21228, USA There are three dopamine D2-type receptors; the D2, D3 and D4 receptors (Bunzow, 1988; Sokoloff, 1990; Van Tol,
1991). The mRNA for the D2 receptor is primarily located in the caudate-putamen-accumbens areas, the D3 receptor is in the nuc. accumbens and the Isle of Caljia, and the D4 receptor is in the cortex and hippocampus. Most neuroleptics are selective for the D2 receptor yet have high affinity for the D4 receptor; clozapine is selective for the D4 receptor. It is possible that (Lahti, 1993) D2 receptor occupancy may be related to EPS activity and D4 receptor occupancy may be related to antipsychotic activity. The distribution of the receptors were studied in human post-mortem brain sections using autoradiographic techniques. The ligands used were [3H]-raclopride for D2/D3; [3H]-YM09151 2 for D2/D3/D4; and [3H]-(+)-7-OH-DPAT for the D3 receptor. The difference between [3H]-raclopride and [3H]-(+)7-OH-DPAT is taken as D2 distribution and between [3H]YM-09151-2 and [3H]-raclopride is taken as the D4 distribution. D2 receptors are most dense in putamen, caudate and nuc. accumbens; D3 receptors in nuc. accumbens. D4 receptors are most dense in cortical areas, as well as the hippocampus, with little evident in the caudate-putamen. The D4 receptor localization in extrastriatal areas and clozapine's selectivity highten its interest in a role in schizophrenia.
INTRINSIC AGONISTS
ACTIVITY OF DOPAMINE AND PARTIAL AGONISTS
THE CLONED
DOPAMINE
AT
D4. 4 R E C E P T O R
R o b e r t A. Lahti*, Alex M u t i n , E r i k a Cochrane, Carol A. T a m m i n g a
Maryland Psychiatric Research Center, Baltimore, MD 21228, USA The dopamine D 4 receptor was cloned and clozapine found to be selective for the D4 vs the Dz receptor (Van Tol et al., 1991 ). Others (Lahti et al., 1993) suggested that antipsychotic activity may reside in D 4 receptor occupancy whereas EPS effects reside in D: receptor occupancy. Dopamine agonists and partial agonists have been evaluated in the treatment of schizophrenia (Tamminga et al., 1978, 1986, 1992). Their intrinsic activity was determined at the D2 receptor, not at the D 4 receptor. Using receptor state (high- and low-affinity agonist states) binding affinities (Lahti et al., 1992) and hD4. 4 m e m b r a n e s (courtesy H. Van Tol) the intrinsic activity of dopamine agonists, partial agonists, was determined. Affinity at the low-affinity agonist state was determined using [3H]-YM09151-2+GTP and affinity for the high-affinity agonist state was determined using [3H]-N-0437. Quinpirole, dopamine and N-0437 have high intrinsic activity, such as SDZ-208-912 and chlorpromazine are the same at both receptors. (-)-3-PPP (Tamminga et al., 1994) appears to have higher intrinsic activity at the D4. 4 receptor than the D2. ( - ) - and (+)-Apomorphine may exhibit similar levels of intrinsic activity at the D4.4, compared to differences at the D z. The findings may be of interest in the treatment of schizophrenia.
from patients meeting the DSM-IIIR criteria for schizophrenia and healthy volunteers. Plasma from drug-naive schizophrenic patients caused significantly more inhibition of platelet NOS activity than that from healthy subjects. These results suggest raised circulating levels of an inhibitory substance in these patients. Previously we have found raised NOS activities in platelets from drug-naive schizophrenic patients compared to healthy subjects. It is likely that plasma levels of the NOS inhibitor(s) may have increased as a compensatory mechanism to overcome the raised NOS activity.
THE EFFECT OF ADRENALECTOMY ON IMMEDIATE EARLY GENES INDUCTION BY ELECTROCONVULSIVE SHOCK IN RAT BRAIN K.S. Ha, U.G. Kang, H.Y. Jung, J.B. Park, I.W. Chung, Y.S. Kim*
Department of Psychiatry, Seoul National University, College of Medicine, Yongon-dong, Chongno-gu, Seou1110-744, South Korea The adrenal hormones are known to be related with the pathogenesis of mental disorders and individual vulnerability to stress. To evaluate the influences of adrenal hormones on the signal transduction system in rat brain, the authors observed the effect of bilateral adrenalectomy (ADX) on the induction of c-fos, junB and TIS1 (NGFI-B) by electroconvulsive shock (ECS). The young (70g) and adult (200g) male SpragueDawley rats were treated by ECS (130 V, 0.5 s) at 3 days after ADX. The rats were sacrificed at 0, 15, 30, 45 and 60 min after ECS. The induction of immediate early genes (lEGs) were assessed by Northern blot analysis. ECS clearly induced lEGs in cerebral cortex, hippocampus and cerebellum of both ADX and sham-operated groups but ADX altered the pattern of lEGs induction by ECS. The c-fos, junB and TIS1 in cerebral cortex of the young and the adult rats were induced earlier and disappeared earlier by ADX. The tendency of earlier disappearance of lEGs was more prominent in adult ADX rats compared to young ADX rats. However, the lEGs induction by ECS in hippocampus and cerebellum were not influenced by ADX. These results show that adrenal hormones have some influences on the signal transduction system in the brain.
DISTRIBUTION OF DOPAMINE D2, D3 AND D4 RECEPTORS IN HUMAN POST-MORTEM BRAIN SECTIONS R.A. Lahti*, R. Conley, L. G r u b o w s k i , C.A. T a m m i n g a
Maryland Psychiatric Research Center, Baltimore, MD 21228, USA There are three dopamine D2-type receptors; the D2, D3 and D4 receptors (Bunzow, 1988; Sokoloff, 1990; Van Tol,
1991). The mRNA for the D2 receptor is primarily located in the caudate-putamen-accumbens areas, the D3 receptor is in the nuc. accumbens and the Isle of Caljia, and the D4 receptor is in the cortex and hippocampus. Most neuroleptics are selective for the D2 receptor yet have high affinity for the D4 receptor; clozapine is selective for the D4 receptor. It is possible that (Lahti, 1993) D2 receptor occupancy may be related to EPS activity and D4 receptor occupancy may be related to antipsychotic activity. The distribution of the receptors were studied in human post-mortem brain sections using autoradiographic techniques. The ligands used were [3H]-raclopride for D2/D3; [3H]-YM09151 2 for D2/D3/D4; and [3H]-(+)-7-OH-DPAT for the D3 receptor. The difference between [3H]-raclopride and [3H]-(+)7-OH-DPAT is taken as D2 distribution and between [3H]YM-09151-2 and [3H]-raclopride is taken as the D4 distribution. D2 receptors are most dense in putamen, caudate and nuc. accumbens; D3 receptors in nuc. accumbens. D4 receptors are most dense in cortical areas, as well as the hippocampus, with little evident in the caudate-putamen. The D4 receptor localization in extrastriatal areas and clozapine's selectivity highten its interest in a role in schizophrenia.
INTRINSIC AGONISTS
ACTIVITY OF DOPAMINE AND PARTIAL AGONISTS
THE CLONED
DOPAMINE
AT
D4. 4 R E C E P T O R
R o b e r t A. Lahti*, Alex M u t i n , E r i k a Cochrane, Carol A. T a m m i n g a
Maryland Psychiatric Research Center, Baltimore, MD 21228, USA The dopamine D 4 receptor was cloned and clozapine found to be selective for the D4 vs the Dz receptor (Van Tol et al., 1991 ). Others (Lahti et al., 1993) suggested that antipsychotic activity may reside in D 4 receptor occupancy whereas EPS effects reside in D: receptor occupancy. Dopamine agonists and partial agonists have been evaluated in the treatment of schizophrenia (Tamminga et al., 1978, 1986, 1992). Their intrinsic activity was determined at the D2 receptor, not at the D 4 receptor. Using receptor state (high- and low-affinity agonist states) binding affinities (Lahti et al., 1992) and hD4. 4 m e m b r a n e s (courtesy H. Van Tol) the intrinsic activity of dopamine agonists, partial agonists, was determined. Affinity at the low-affinity agonist state was determined using [3H]-YM09151-2+GTP and affinity for the high-affinity agonist state was determined using [3H]-N-0437. Quinpirole, dopamine and N-0437 have high intrinsic activity, such as SDZ-208-912 and chlorpromazine are the same at both receptors. (-)-3-PPP (Tamminga et al., 1994) appears to have higher intrinsic activity at the D4. 4 receptor than the D2. ( - ) - and (+)-Apomorphine may exhibit similar levels of intrinsic activity at the D4.4, compared to differences at the D z. The findings may be of interest in the treatment of schizophrenia.