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A polymorphism in tryptophan hydroxylase and irritable aggression in personality disorders
506
Abstracts
DIOL PSYCHIATRY 1996:39:500-G66
KJ) was91 % higherthnn in theage matched controls while the Bm J • was not changed. In contrast, the old schizophrenics had II 263% lower Ko ami a 197% lower Bm... Ihan the old controls, Furthermore, there Wa.s a significant negative correlation between the duration of illness and the binding constants: B~ rSO.58, p-=Q.03; K D rS-= 0.62;p-=O.02. Duration of illness was directly proportional to the age at death with a correlation coefflclent of o.aa, p=O.OOOI. Since the reduction in DAT receptors (DATR) is only present in old sehlzophrenks with a long duration of the dlsease.the datu indictlto that the loss of DATR is progressively related to nge and the duration of the disease;
23. EFFECT OF CHRONIC ETHANOL TREATMENT ON HIPPOCAMPAL CA3 NEURONS RL. Ownby & B.J, Mason Alcohol Disorders Research Unit, University [If Miami School of Medicine, Miami. FL BUl'!aing is an important properly of certainmammallau neurons, related to long-term potentiation and osclllatory interactions in small networks. Abnormalities in bursting may underlie neurological and psychiatric disorders. Chronic ethanol exposure increases the number of calcium channels in several animal tissues (Dolin ct :1.1 1987) including rat hippocampus (Docherty & Brown 1986). Since calcium channels arc intimately related to inherent bursting in neurons, chronic ethanol exposure may affect this behavior. Such a change would have implications for theories of relnforccmeru and l.:amil'Z in persons !".'ilh alcohol use disorders (Charness '992). The olJjectivC' of this study was. to decide whetherethanol-related increases in calcium channels affect bursting in CA3 hippocampal neurons. A neural model of the mammalian CA3 hippocampal neuron was previously developed. Chronic ethanol exposure increases calcium condueunccs by 50 to 100 percent, and calcium conductances in the model were increased by 50 percent throughout the neuron to simulate Ihis effect. Changes in calcium conductance profoundly affected the neuron's behavior. Action potentials related to calcium conductances were prolonged tlnd had greater nmplltudcs. Bursting was prolonged. These results show thai changes in eulclum conductances induced by chronic ethanol exposure haw important effects 011 the behaviorof the CA3 hippocampal neuron. These findings have implications forthe roleof the hippocampus in cpilcptogenesis, The inherent rhythmicity of the neuron isdisrupted as well. a change thut may affect the behaviorof both the small and largernetworks comprising the hippocampus. Disruption of these networks may have implications for other ncuropsychlatric phenomena, including learning, memory, ami the regulation of level of consciousness,
24, A POLYMORPHISM IN TRYPTOPHAN HYDROXYLASE AND IRRITABLE AGGRESSION IN PERSONALITY DISORDERS A.S. NewI, J. Gelernter', R.L. TrestmanI , V. Mitropoulou 1. & LJ. Siever' IMt, Sinal & Bronx VA Mcdiclli CeIUCI1i, New York. NY 10029: ~Yale Unlv, & West Haven VA Medical Center, West Haven.
cr 06516
As decreased serotonerglc activity has been assoclatcd with irritable or Impulsive aggression in pailems with personality disorders. and there is
evidence 10 suggest a partially heritable basis for irritllblc aggression, it is logical to investigate the possibility of genetic differences in the determinants or serotoncrgic activity. A biallellc polymorphism in the gene for tryptophan hydroxylase (TPH), the rate limitingenzyme in the synthesis of serotonin, has been identified using the single strand conformationul polymorphism method. The "L" allele has been associated with reduced CSF S-HIAA and a history suicide attempt in a cohort of Finnish alcoholic offenders (Nielsen et a1 1994). We assessed TPH genotype in 0. sample of 40 Caucuslan patients with personality dlsurder, investigating a possible association between allelic status and degree of impulsive aggression as measured by the Buss-Durkee Hostility Inventory {DOH!). We also developed new criteria for impulsivity which idcl1tify the extremes of highly impulsive and non-impulslve patients. Twenty-one male parlents with the "LL" genotype had significantly higher totsl ODHI scores (45.3:9.8) compared lO males with the "UL" or "UU" genotypes (32.9± 13.5; t=2.38, df= 19: p
or
25, ABNORMAL D3 pre-mRNA PROCESSING IN CHRONIC SCHIZOPHRENIA C. Schmauss Mount Slnui School of Medicine. New York, NY 10029 We have previously reponed that the dopamine OJ-receptor mRNA is lost in certain cortical regions of brains obtained postmortem from long-term hospitalized patients withchronic schizophrenia. However. the expression of u truncated D.l-like mRNA, named Djnf' was found to be unaltered in these anatomlcal regions (Schmauss er nl, 1993, PNAS 90: 8942-8946). Results from ill vitro splicing experiments will now be presented thut demonstrate that Dj nr mRNA derives from the D-cncoded pre~mRNA vln removal of an alternative splieeosomal huron thai ha.s an atypical 3' splice-site and branchpoint sequence. Despite the unusual d.r-actingclements of the Djnr'lipecific splicing activity, DJnr mRNA and protein are obund:mtly expressed in human bruin (Liu et ul, 1994. JDC 269: 29220-29226), A more quantitative analysis (with RNase protecHon assays) of the relatlve abundance of OJ and DJnr mRNA expression in the eingulatc cortex of schizophrenics showed a decreased expression of OJ mRNA and an increased expression of D.1nr mRNA compared to controls. This finding suggests thal enhunced Djn('spccific nhernatlve splicing of the Dj-encoded pre-mRNA is the underlying reason for the observed decreased (or abolished) expression of OJ-encoded mRNA in brains of patients with chronic psychosis. Furthermore, preliminary results from ill vitro splicing experiments, performed with nuclear extracts of Hcl,a and SY5Y cells, indicate that the efficiency of
Abstracts
DIOL PSYCHIATRY 1996:39:500-G66
KJ) was91 % higherthnn in theage matched controls while the Bm J • was not changed. In contrast, the old schizophrenics had II 263% lower Ko ami a 197% lower Bm... Ihan the old controls, Furthermore, there Wa.s a significant negative correlation between the duration of illness and the binding constants: B~ rSO.58, p-=Q.03; K D rS-= 0.62;p-=O.02. Duration of illness was directly proportional to the age at death with a correlation coefflclent of o.aa, p=O.OOOI. Since the reduction in DAT receptors (DATR) is only present in old sehlzophrenks with a long duration of the dlsease.the datu indictlto that the loss of DATR is progressively related to nge and the duration of the disease;
23. EFFECT OF CHRONIC ETHANOL TREATMENT ON HIPPOCAMPAL CA3 NEURONS RL. Ownby & B.J, Mason Alcohol Disorders Research Unit, University [If Miami School of Medicine, Miami. FL BUl'!aing is an important properly of certainmammallau neurons, related to long-term potentiation and osclllatory interactions in small networks. Abnormalities in bursting may underlie neurological and psychiatric disorders. Chronic ethanol exposure increases the number of calcium channels in several animal tissues (Dolin ct :1.1 1987) including rat hippocampus (Docherty & Brown 1986). Since calcium channels arc intimately related to inherent bursting in neurons, chronic ethanol exposure may affect this behavior. Such a change would have implications for theories of relnforccmeru and l.:amil'Z in persons !".'ilh alcohol use disorders (Charness '992). The olJjectivC' of this study was. to decide whetherethanol-related increases in calcium channels affect bursting in CA3 hippocampal neurons. A neural model of the mammalian CA3 hippocampal neuron was previously developed. Chronic ethanol exposure increases calcium condueunccs by 50 to 100 percent, and calcium conductances in the model were increased by 50 percent throughout the neuron to simulate Ihis effect. Changes in calcium conductance profoundly affected the neuron's behavior. Action potentials related to calcium conductances were prolonged tlnd had greater nmplltudcs. Bursting was prolonged. These results show thai changes in eulclum conductances induced by chronic ethanol exposure haw important effects 011 the behaviorof the CA3 hippocampal neuron. These findings have implications forthe roleof the hippocampus in cpilcptogenesis, The inherent rhythmicity of the neuron isdisrupted as well. a change thut may affect the behaviorof both the small and largernetworks comprising the hippocampus. Disruption of these networks may have implications for other ncuropsychlatric phenomena, including learning, memory, ami the regulation of level of consciousness,
24, A POLYMORPHISM IN TRYPTOPHAN HYDROXYLASE AND IRRITABLE AGGRESSION IN PERSONALITY DISORDERS A.S. NewI, J. Gelernter', R.L. TrestmanI , V. Mitropoulou 1. & LJ. Siever' IMt, Sinal & Bronx VA Mcdiclli CeIUCI1i, New York. NY 10029: ~Yale Unlv, & West Haven VA Medical Center, West Haven.
cr 06516
As decreased serotonerglc activity has been assoclatcd with irritable or Impulsive aggression in pailems with personality disorders. and there is
evidence 10 suggest a partially heritable basis for irritllblc aggression, it is logical to investigate the possibility of genetic differences in the determinants or serotoncrgic activity. A biallellc polymorphism in the gene for tryptophan hydroxylase (TPH), the rate limitingenzyme in the synthesis of serotonin, has been identified using the single strand conformationul polymorphism method. The "L" allele has been associated with reduced CSF S-HIAA and a history suicide attempt in a cohort of Finnish alcoholic offenders (Nielsen et a1 1994). We assessed TPH genotype in 0. sample of 40 Caucuslan patients with personality dlsurder, investigating a possible association between allelic status and degree of impulsive aggression as measured by the Buss-Durkee Hostility Inventory {DOH!). We also developed new criteria for impulsivity which idcl1tify the extremes of highly impulsive and non-impulslve patients. Twenty-one male parlents with the "LL" genotype had significantly higher totsl ODHI scores (45.3:9.8) compared lO males with the "UL" or "UU" genotypes (32.9± 13.5; t=2.38, df= 19: p
or
25, ABNORMAL D3 pre-mRNA PROCESSING IN CHRONIC SCHIZOPHRENIA C. Schmauss Mount Slnui School of Medicine. New York, NY 10029 We have previously reponed that the dopamine OJ-receptor mRNA is lost in certain cortical regions of brains obtained postmortem from long-term hospitalized patients withchronic schizophrenia. However. the expression of u truncated D.l-like mRNA, named Djnf' was found to be unaltered in these anatomlcal regions (Schmauss er nl, 1993, PNAS 90: 8942-8946). Results from ill vitro splicing experiments will now be presented thut demonstrate that Dj nr mRNA derives from the D-cncoded pre~mRNA vln removal of an alternative splieeosomal huron thai ha.s an atypical 3' splice-site and branchpoint sequence. Despite the unusual d.r-actingclements of the Djnr'lipecific splicing activity, DJnr mRNA and protein are obund:mtly expressed in human bruin (Liu et ul, 1994. JDC 269: 29220-29226), A more quantitative analysis (with RNase protecHon assays) of the relatlve abundance of OJ and DJnr mRNA expression in the eingulatc cortex of schizophrenics showed a decreased expression of OJ mRNA and an increased expression of D.1nr mRNA compared to controls. This finding suggests thal enhunced Djn('spccific nhernatlve splicing of the Dj-encoded pre-mRNA is the underlying reason for the observed decreased (or abolished) expression of OJ-encoded mRNA in brains of patients with chronic psychosis. Furthermore, preliminary results from ill vitro splicing experiments, performed with nuclear extracts of Hcl,a and SY5Y cells, indicate that the efficiency of