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Clinical, neuroendocrine and treatment studies of impulsive aggression
Abstracts
pcl'5on:aIHy, distinguishing four dimensions of temperament that are 50% heritable and indeplmdent of one another. This genetic architecture for pcrsomdil)' has now been independently replicmcd also. In tum, Pc I'll on· ailly was n:lated to sllsceptibility to a!c:oholism and to underlying variation in monoaminergic neurotronsmission. Recent results predicting susceptibility to alcoholism and other psychopathology wlll be described in terms of the non-llneardyn.amics of personality development, which is relevant to both hum:an and .animal research. Finally, current findings about Ihe neurobiological correlates of personality in the general popu· 13tion and in a alcoholics will be summarized.
212. MOLECULAR GENETICS OF IMPAIRED IMPULSE CONTROL AND EARLY ONSET ALCOHOLISM D. Goldman I D. Nielsen~ M. Okada. M. Adamsoll~ J. Lappnlninen, N. Malhotra, U. Pesonen, M. Koulu, M. Eggert, M. Virkkunen, N. Ozaki, & M. Linnoila. l..ab. of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism. Rockville, MD 20&52. We have directly sc.anned coding regions of cllndidate for variants Ihllt could increase vulne,Jbllity to alcoholism, panicularly early onset alcoholism associatcd with impulsive behavior. The focus of the direct gene analysis was genes involved in serotonin fUllctian. Previously. we also evaluated the known DRD4 16 amino acid repeat varinnt recently implicnted in impulsivity and DRD2 dopamine Taq I variants for llssociation with .alcoholism or nltcred CSF monoamine metabolite levcls. Neither was n.~sociiltcd. However. we have replicated the association of the TPH intron 7 polymorphism to suicide attempts in 11 second populalion of 88 Finnish alcoholic offenders. who arc all impulsive. By ssep :mtl direct sequencing, amino llcid substitutions were found in 5HT 1A (Gly22Ser and tle28Val), SHT::!A (Aln439Vnl and His444Tyr). 5HT2C (Cys23Scr), and 5HT, (Pro279Leu) serotonin receptors. and in the serotonin transporter (SHIT). 5HT2C Cys23 lind Se~23 (allele frcquency = 0.13) were expressed in Cos·7 cells llnd found to differ in affinity for several ligands. SHT7 Pro279Lcu alters tl conserved residue in the third intracellular loop of the receptor. Lcu279 was observed in six subjects from >400 pmients and controls. Five of the six had antisocial personality and/or history of su icide allcmpt and the sixth was a COnlrol (from among 232 controls, Chi-square ""'7.879. DF = 2, p
213. A NONHUMAN PRIMATE MODEL OF TYPE II EXCESSIVE ALCOHOL CONSUMPTION J.D. Higley, P. Mehlman, S.J. Suomi, & M. Linnoila Labof'Jtol)' of Clinical Studies· Primate Unit, NIH Animal Center, NIAAA, Poole~ville, MD 20837 Cloninger's Neurogelletic theory proposes two sUbtypes of alcoholism (Type I and 11), each with n unique etiology that Is corrcl31ed with
DlOL PSYCUIATRY 1996;39:500-666
561
different symptomology. In our symposium presentation. we will discuss recent findings lhllt show some nonhuman primates' behavior. p3ttcrns of alcohol consumption. and neurohiology p.amllcl Cloninger's description or Type II alcoholism. Similar to humans. Ilmong nOnhUm:lll primates there is a wide range of interindividual diffcrences in alcohol consumption, with some subjects consuming alcohol at high ratcs producing body sway. clumsy movements, and in some ca.~es, stupor. As predicted by Cloninger's model, subjects th:lt consume alcohol at high roles exhibit low eNS serotonin and norepinephrine activity (as measured by low cerebrospinal nuid concentrations of S-HIAA and MHPG). Paralleling the behavior problems of humans with Type II alcoholism, nonhull1an primatcs with reduced eNS serotonin activity, e1l:hibit impaired impUlse control. For example, they exhibit llnpro\'oked, long dangerous leaps bClween tree· tops :and arc troppcd more often than subjects with high CSF 5·HIAA. This impaired impulse control leads to aggression that frequently escalmes into severe levels that pIlice subjects at risk for physical trauma and wounds, As a result. they nre prematurely expelled from their social grcups, 3nd suffer early mortatity. Animals with low CSF 5·HIAA that remain with their social groups. exhibit reduced socinl competence ami arc subject 10 social ostracism. Other studies have shown that during their first exposure to alcohol. subjects with low CSF 5·HIAA e"hibh high levels of tolerance to alcohol, showing minimal signs of intoxication to a 2 gramfl,;g IV dose ofaleohol. Unlike hum3ns, however. in nonhuman primates the Type II patlem of behavior .and alcohol consumption is not n131e limited. suggesting possible species influences an the phenotypic expression of Type II-like 3lcohol abuse. As etiologicilt factors have been delineated. both genetic and early adverse rearing experiences h:lve been shawn to be faClOrs producing excessive alcohol consumption in nonhuman prim3te subjects with fC3Iures of Type II 'lleoholism.
214. CLINICAL, NEUROENDOCRINE AND TREATMENT STUDIES OF IMPULSIVE AGGRESSION E.F. Coccaro Clinical Neuroscience Research Unit. Department of Psychiatry. Medical College of Pcnnsylvnnia ilt Eastern Pennsylvania Psychiatric InstilUle, Phillldelphia, PA ! 9129 RelJuccd central serotonin (S-HT) system function rellected by reduced concentrations of lumbar cerebrospinal nuid S-hydroxyindolacetic acid or by altered honnonal responses to S·HT challenge agents, has been a!;:mciated with suicidal and impUlsive nggressive bch:lViors in a variety of psychiatric p3tients, p.articu]nrly those with personality disorders. In addition, there is emerging evillenee of rel3tionships between other neurotransmitter and these behaviol'll as well as their Interaction with the 5-HT system. This presentation will review data from Il variety of neurochemical. neurocmlocrine. nnd clinical trial stutlics in psychiatric patients in which history of suicidallindior impulsive 3ggressive bch:lvior were used as independent variables. Among the variables whieh have been reponed a~ correlating with suicidal lind/or impulsive aggressive behavior are: a) CSF S·HIAA. b) PRL Response to Fennurnmine Challenge, c) Platelet S·HT Tl'l1llsporterl5-lIT·2a Receptors; d) pMHPG lind GH Response to Clonidine Challenge (Alpha.2 NE); e) CSF Vasopressin. While 5·HT ilppears to have Iln inhibitins innucncc on suicidal and impulsive llssressive behaviors, other neurotransmitter systems may playa role in f3dlitating these behaviors. An undcrslandi ns of [his more complex view of the biology of impUlsive aggICssiveness is important if one is to design phllnnacologic treatment strategies.
pcl'5on:aIHy, distinguishing four dimensions of temperament that are 50% heritable and indeplmdent of one another. This genetic architecture for pcrsomdil)' has now been independently replicmcd also. In tum, Pc I'll on· ailly was n:lated to sllsceptibility to a!c:oholism and to underlying variation in monoaminergic neurotronsmission. Recent results predicting susceptibility to alcoholism and other psychopathology wlll be described in terms of the non-llneardyn.amics of personality development, which is relevant to both hum:an and .animal research. Finally, current findings about Ihe neurobiological correlates of personality in the general popu· 13tion and in a alcoholics will be summarized.
212. MOLECULAR GENETICS OF IMPAIRED IMPULSE CONTROL AND EARLY ONSET ALCOHOLISM D. Goldman I D. Nielsen~ M. Okada. M. Adamsoll~ J. Lappnlninen, N. Malhotra, U. Pesonen, M. Koulu, M. Eggert, M. Virkkunen, N. Ozaki, & M. Linnoila. l..ab. of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism. Rockville, MD 20&52. We have directly sc.anned coding regions of cllndidate for variants Ihllt could increase vulne,Jbllity to alcoholism, panicularly early onset alcoholism associatcd with impulsive behavior. The focus of the direct gene analysis was genes involved in serotonin fUllctian. Previously. we also evaluated the known DRD4 16 amino acid repeat varinnt recently implicnted in impulsivity and DRD2 dopamine Taq I variants for llssociation with .alcoholism or nltcred CSF monoamine metabolite levcls. Neither was n.~sociiltcd. However. we have replicated the association of the TPH intron 7 polymorphism to suicide attempts in 11 second populalion of 88 Finnish alcoholic offenders. who arc all impulsive. By ssep :mtl direct sequencing, amino llcid substitutions were found in 5HT 1A (Gly22Ser and tle28Val), SHT::!A (Aln439Vnl and His444Tyr). 5HT2C (Cys23Scr), and 5HT, (Pro279Leu) serotonin receptors. and in the serotonin transporter (SHIT). 5HT2C Cys23 lind Se~23 (allele frcquency = 0.13) were expressed in Cos·7 cells llnd found to differ in affinity for several ligands. SHT7 Pro279Lcu alters tl conserved residue in the third intracellular loop of the receptor. Lcu279 was observed in six subjects from >400 pmients and controls. Five of the six had antisocial personality and/or history of su icide allcmpt and the sixth was a COnlrol (from among 232 controls, Chi-square ""'7.879. DF = 2, p
213. A NONHUMAN PRIMATE MODEL OF TYPE II EXCESSIVE ALCOHOL CONSUMPTION J.D. Higley, P. Mehlman, S.J. Suomi, & M. Linnoila Labof'Jtol)' of Clinical Studies· Primate Unit, NIH Animal Center, NIAAA, Poole~ville, MD 20837 Cloninger's Neurogelletic theory proposes two sUbtypes of alcoholism (Type I and 11), each with n unique etiology that Is corrcl31ed with
DlOL PSYCUIATRY 1996;39:500-666
561
different symptomology. In our symposium presentation. we will discuss recent findings lhllt show some nonhuman primates' behavior. p3ttcrns of alcohol consumption. and neurohiology p.amllcl Cloninger's description or Type II alcoholism. Similar to humans. Ilmong nOnhUm:lll primates there is a wide range of interindividual diffcrences in alcohol consumption, with some subjects consuming alcohol at high ratcs producing body sway. clumsy movements, and in some ca.~es, stupor. As predicted by Cloninger's model, subjects th:lt consume alcohol at high roles exhibit low eNS serotonin and norepinephrine activity (as measured by low cerebrospinal nuid concentrations of S-HIAA and MHPG). Paralleling the behavior problems of humans with Type II alcoholism, nonhull1an primatcs with reduced eNS serotonin activity, e1l:hibit impaired impUlse control. For example, they exhibit llnpro\'oked, long dangerous leaps bClween tree· tops :and arc troppcd more often than subjects with high CSF 5·HIAA. This impaired impulse control leads to aggression that frequently escalmes into severe levels that pIlice subjects at risk for physical trauma and wounds, As a result. they nre prematurely expelled from their social grcups, 3nd suffer early mortatity. Animals with low CSF 5·HIAA that remain with their social groups. exhibit reduced socinl competence ami arc subject 10 social ostracism. Other studies have shown that during their first exposure to alcohol. subjects with low CSF 5·HIAA e"hibh high levels of tolerance to alcohol, showing minimal signs of intoxication to a 2 gramfl,;g IV dose ofaleohol. Unlike hum3ns, however. in nonhuman primates the Type II patlem of behavior .and alcohol consumption is not n131e limited. suggesting possible species influences an the phenotypic expression of Type II-like 3lcohol abuse. As etiologicilt factors have been delineated. both genetic and early adverse rearing experiences h:lve been shawn to be faClOrs producing excessive alcohol consumption in nonhuman prim3te subjects with fC3Iures of Type II 'lleoholism.
214. CLINICAL, NEUROENDOCRINE AND TREATMENT STUDIES OF IMPULSIVE AGGRESSION E.F. Coccaro Clinical Neuroscience Research Unit. Department of Psychiatry. Medical College of Pcnnsylvnnia ilt Eastern Pennsylvania Psychiatric InstilUle, Phillldelphia, PA ! 9129 RelJuccd central serotonin (S-HT) system function rellected by reduced concentrations of lumbar cerebrospinal nuid S-hydroxyindolacetic acid or by altered honnonal responses to S·HT challenge agents, has been a!;:mciated with suicidal and impUlsive nggressive bch:lViors in a variety of psychiatric p3tients, p.articu]nrly those with personality disorders. In addition, there is emerging evillenee of rel3tionships between other neurotransmitter and these behaviol'll as well as their Interaction with the 5-HT system. This presentation will review data from Il variety of neurochemical. neurocmlocrine. nnd clinical trial stutlics in psychiatric patients in which history of suicidallindior impulsive 3ggressive bch:lvior were used as independent variables. Among the variables whieh have been reponed a~ correlating with suicidal lind/or impulsive aggressive behavior are: a) CSF S·HIAA. b) PRL Response to Fennurnmine Challenge, c) Platelet S·HT Tl'l1llsporterl5-lIT·2a Receptors; d) pMHPG lind GH Response to Clonidine Challenge (Alpha.2 NE); e) CSF Vasopressin. While 5·HT ilppears to have Iln inhibitins innucncc on suicidal and impulsive llssressive behaviors, other neurotransmitter systems may playa role in f3dlitating these behaviors. An undcrslandi ns of [his more complex view of the biology of impUlsive aggICssiveness is important if one is to design phllnnacologic treatment strategies.