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A calcium channel antagonist enhances ethanol's antiseizure efficacy
Basic and Clinical Studies
64
BIOL PSYCHIATRY
1990;27:41A-!79A
69A
TESTING THE HYPOTHESIS THAT Y-CHROMOSOMAL HAPLOTYPE IS ASSOCIATED WITH IMPULSIVE BEHAVIOR Annabel Bolos, M.D., Markku Linnoila, M.D., Ph.D., Matti Virkkunen, M.D., David Goldman, M.D. National Institute on Alcohol Abuse and Alcoholism, Bet,~csda, MD 20892. The paternal pattern of inherit~ce of aggression in mice (Selmanoff et al. Nature 1975; 253:529) and the correlation between an extended Yq and human criminal behavior (l'/ieisen and Henriksen. Acta Psychiatrica Scand 1972; 48:87) led to the hypothesis that a locus for impulsivi~y may exist on Se Y chromosome. We therefore analyzed genomic DNA of 40 Finnish violent males and racially matched controls by Southern hybridization. Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA), a sel,Jtonin metabolite that shows a strong negative correlation with impulsivity, w~t, .measured in the impulsive/violent males and in s¢me of the controls. Exceptionally low CSF 5-HIAA levels were noted in several members of this extreme impulsive/violent group. Y chromosome-specific polymorphisms were identified with the use of probes 49F, pDP61, and pDPI32 after restriction digestion of genomic DNA with Taq I. Five polymorphic fragments, several in linkage disequilibrium in this Finnish population, ~ r e ,evealed with probe 49F, and one of these alleles (a fragment of 8.6 kb) was novel. The distribution of Y hap!otypes i~ imp~iisive and control males was compared.
65
A CALCIUM CHANNEL ANTAGONIST ENHANCES ETHANOL'S ANTISEIZURE EFFICACY James A. Huntzinger, M.D., Mohini Kaushik, M.D., Truc-Mai Phelps, B.S., John Mastropaolo, Ph.D., Stephen I. Deutsch, M.D., Ph.D. Psychiatry Service, Department of Veterans Affairs Medical Center, Washington, D.C. 20422. Acute exposure to ethanol inhibits depolarization-dependt,'nt calcium ion uptake through the L-type voltageseas~tive channel. Moreover, tolerance to the effects of chronic ethanol exposure and the alcehol withdrawal .~yndrome seem to involve up regulation of the binding site for the dihydropyridine class of voltage-sensitive calcium channel aatagonist and to involve altered depolarization-dependent calcium ion flux. The present ex~riment examined t'.,,, a~.ate interaction of nimodipine, a centrally effective calcium chdnnel antagonist, and ethanol in altering seizure thresholds in mice. Seizures were induced with an incremental dectroconvulsive shock (IECS) procedure. In this procedure, 0.3 sec of voltage ~s applied by means of earclips, beginning at 70 V and increasing in 10 V i~crements until a seizure occurs (maximal tonic hindlimb extension) or 170 V is reached. Groups of mice (n - 12/group) were injected (ip) with either vehicle or one of several doses (0.56--1.8 g/kg body weight) of ethanol 20 min before the IECS procedure. Separate groups of mice were injected (ip) with nimodipine (18 mg/kg) 20 min before the ethanol or vehicle injection. A two-way ANOVA revealed two main effects. Ethanol alone significantly increased the threshold voltage for seizure production (F5.126 - 46.991, p < 0.0001). An'imals pretreated with aimodipine and ethanol had significantly higher seizure thresholds than animals given ethanol alone (F1.126 "- 4.284, p < 0.05). These data show that pharmacological manipulations that attenuate voltage-sensitive calcitm3 ion flux can enhance some of ethanol's pharmacological properties. This finding may |lave relevance to an underst~ding of eth~ol's a~ute intoxicational effects.
64
BIOL PSYCHIATRY
1990;27:41A-!79A
69A
TESTING THE HYPOTHESIS THAT Y-CHROMOSOMAL HAPLOTYPE IS ASSOCIATED WITH IMPULSIVE BEHAVIOR Annabel Bolos, M.D., Markku Linnoila, M.D., Ph.D., Matti Virkkunen, M.D., David Goldman, M.D. National Institute on Alcohol Abuse and Alcoholism, Bet,~csda, MD 20892. The paternal pattern of inherit~ce of aggression in mice (Selmanoff et al. Nature 1975; 253:529) and the correlation between an extended Yq and human criminal behavior (l'/ieisen and Henriksen. Acta Psychiatrica Scand 1972; 48:87) led to the hypothesis that a locus for impulsivi~y may exist on Se Y chromosome. We therefore analyzed genomic DNA of 40 Finnish violent males and racially matched controls by Southern hybridization. Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA), a sel,Jtonin metabolite that shows a strong negative correlation with impulsivity, w~t, .measured in the impulsive/violent males and in s¢me of the controls. Exceptionally low CSF 5-HIAA levels were noted in several members of this extreme impulsive/violent group. Y chromosome-specific polymorphisms were identified with the use of probes 49F, pDP61, and pDPI32 after restriction digestion of genomic DNA with Taq I. Five polymorphic fragments, several in linkage disequilibrium in this Finnish population, ~ r e ,evealed with probe 49F, and one of these alleles (a fragment of 8.6 kb) was novel. The distribution of Y hap!otypes i~ imp~iisive and control males was compared.
65
A CALCIUM CHANNEL ANTAGONIST ENHANCES ETHANOL'S ANTISEIZURE EFFICACY James A. Huntzinger, M.D., Mohini Kaushik, M.D., Truc-Mai Phelps, B.S., John Mastropaolo, Ph.D., Stephen I. Deutsch, M.D., Ph.D. Psychiatry Service, Department of Veterans Affairs Medical Center, Washington, D.C. 20422. Acute exposure to ethanol inhibits depolarization-dependt,'nt calcium ion uptake through the L-type voltageseas~tive channel. Moreover, tolerance to the effects of chronic ethanol exposure and the alcehol withdrawal .~yndrome seem to involve up regulation of the binding site for the dihydropyridine class of voltage-sensitive calcium channel aatagonist and to involve altered depolarization-dependent calcium ion flux. The present ex~riment examined t'.,,, a~.ate interaction of nimodipine, a centrally effective calcium chdnnel antagonist, and ethanol in altering seizure thresholds in mice. Seizures were induced with an incremental dectroconvulsive shock (IECS) procedure. In this procedure, 0.3 sec of voltage ~s applied by means of earclips, beginning at 70 V and increasing in 10 V i~crements until a seizure occurs (maximal tonic hindlimb extension) or 170 V is reached. Groups of mice (n - 12/group) were injected (ip) with either vehicle or one of several doses (0.56--1.8 g/kg body weight) of ethanol 20 min before the IECS procedure. Separate groups of mice were injected (ip) with nimodipine (18 mg/kg) 20 min before the ethanol or vehicle injection. A two-way ANOVA revealed two main effects. Ethanol alone significantly increased the threshold voltage for seizure production (F5.126 - 46.991, p < 0.0001). An'imals pretreated with aimodipine and ethanol had significantly higher seizure thresholds than animals given ethanol alone (F1.126 "- 4.284, p < 0.05). These data show that pharmacological manipulations that attenuate voltage-sensitive calcitm3 ion flux can enhance some of ethanol's pharmacological properties. This finding may |lave relevance to an underst~ding of eth~ol's a~ute intoxicational effects.