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Naltrexone in the treatment of anorexia and bulimia nervosa
SATURDAY, MAY 21
Biomedical Sciences,
BIOL PSYCHIATRY 735 1994;35:615-747
Tampere, Finland
Different stressful conditions are known to alter biochemical parameters of [3H]-GABA and [3H]-bonzodiazepine binding. Thus the effects of handling stress alone and combined with phencyclidine (I~P) treatment on GABAergic neumtransmission were studied in Sprague-Dawley rats. The animal material consisted of handling-habituated (HH, for 11 days), acutely handled (naive, N), handling-habituated and PCP-treated (10 rag/ kg i.p., HH+PCP) and acutely handled (naive) PCP-treated (N+PCP) rats. The binding of [3H]-GABA and [3H]-flunitrazepam (FLU) was studied in membranes and the release of [3H]-GABA with slices prepared from the striatum and the frontal cortex. The maximal binding capacity (Bmu) and the binding constant (K D) of [3H]-GABA were in both brain areas the same in N and HH rats, but in the frontal cortex, however, KD was lower in N rats. KD constants of 3H-FLU were significantly lower in both brain areas in N rats than in HH rats. After PEP treatment both Bu and KD for [3HI-FLU increased in these two brain areas in handling-habituated rats, whereas Brow of [3H/-GABA diminished. Neither handling nor PCP had any effect on [3H]-GABA release from striatal and frontal cortical slices. Handling prior to killing thus affects differently the GABAergic parameters studied end modulates the PCP-induced effects.
433. GLUTAMATE RECEPTOR AUTORADIOGRAPHY OF POSTMORTEM BASAL GANGLIA IN SCHIZOPHRENIA J. 1'. Noga, T. M. Hyde, M. Herman, L. L. Bigelow, D.R. Weinberger, & J.E. Kleinman
in (animal) brains, especially in glial cells, and white matter structures like the corpus callosum (CC) and optic chiasm (Celotti F et ai. Frontier Neuroendocrino11992; 163-215). Suprachiasmatic nucleus, and splenium of the CC (Allen L & Gorski R. Proc Natnl Acad Sci USA ! 992; 89: 7199-202.), are enlarged in gay men. These two "non-sexual" neuroanatomical changes in gay men could quite possibly be determined by changes in 5-red'se in those sites. Marian Diamond (Enriching Heredity, New York, Free Press, 1988, pp. 40 50) studied Einstein's Brain, and found that the number of glial cells per neuron was substantially higher, in all the areas she studied, than that in comparably aged male brains. She also noted more glial cells per neuron in the prefrontal cortex than in the inferior parietal cortex, and suggested that the ratio between neurons to glial cells may decrease in regions that are more highly evolved, or the more active, or both. Body hair growth is determined more by 5-red'se activity in the skin than by blood androgen levels (see Lookingbill DP et al .J Clin EndMetab 1991; 72: 1242-8). $-red'se deficiency 46 XY sub. jects who are often born and raised as girls dramatically turn around towards puberty, usually to become highly muscular, heterosexual men with negligible tendency for body hair growth (Peterson RE et al. Am J Mud. 1977; 62: 170-91). ! have consistently noted, in several samples of gay men, another "non-specific" finding that they were more hirsute but much less muscular, and that there were positive correlations between intelligence and body hair growth in several groups of men in different races (manuscript in preparation). Interestingly, the incidence of male homosexuality somewhat steadily increases with the years of their education (Fay RE et al. Science 1989; 243:338-48 ). However, too many gay men are glabrous, so also was Einstein. An explanation for this apparent paradox will be presented. All these findings, if confirmed, can tie in together, and may also be a reflection of a "continuum model," e.g. Kinsey !-6, for sexual orientation (see Wortis J. Biol Psychiat 1993; 34: 505-6).
NIH/NIMH/DIRP/Clinicai Brain Disorders Branch, Washington, DC 20032 A variety of disturbances of the glutamatergic receptor system have been reported in schizophrenia. We compared the binding densities of radioligands aimed at glutamate uptake sites (with [3H]-D-aspartate) and AMPA sites (with [3H]-CNQX in the basal ganglia (BG) of 7 schizophrenia (DSM3-R criteria), 8 normal, 8 neuroleptic control, and 8 suicide victim brains. Schizophrenia subjects were neuroleptic free by toxicology at autopsy. Two fourteen-micron frozen sections were taken from the basal ganglia of each brain at the level of the nucleus aocumbens, mounted, and Incubated in 50 nM [3H]-CNQX for 45 minutes at 4°C, pH 7.2- 100 mM L-glutamate was used with an adjacent section to determine nonspecific binding. After apposing to film/with radioactive standards and developing, the anturadiographic images were optically scanned and NIH Image software used for quantitative analysis. A similar procedure was followed for labeling the glutamate uptake sites with [3H]-D-aspartate. Preliminary comparison of groups was done by two-tailed t-tests. These data suggest an increase in density of AMPA receptor sites in the caudate in schizophrenia, providing further support for a glutamatergic abnormality in this disorder. Further details of analysis, including results of study of NMDA and kainic acid sites in these postmortem brains, will also be presented.
434. 5¢x-REDUCTASE IN GLIAL CELLS, SEXUAL ORIENTATION, AND FLUID INTELLIGENCE A. G. Alias Chester Mental Health Center, Chester, IL 62233 Steroid 50a-reductase (5-red'se), which converts testosterone to dihydrotestosterone, and also acts on certain other steroids, is widely distributed
435. NALTREXONE IN THE TREATMENT OF ANOREXIA AND BULIMIA NERVOSA M.A. Marrazzi, J. Kinzie & E.D. Luby Wayne State University School of Medicine & Harper-Grace Hospitals, Detroit, MI 48201 Our auto-addiction model suggests that opiate blockade may be therapeutically useful in both anorexia and bulimia nervosa. Naltrexone, the longacting, orally active narcotic antagonist, was administered to out-patient subjects in controlled double blind clinical trials with randomized crossover designs. Reduction in binge - purge symptomatology was evident in the naitrexone period over placebo for 21 out of 22 subjects with either bulimia, anorexia nervosa of the bulimic subtype, or binge eating disorder. in every case, the decoding of drug or placebo double blinding confirmed the assessments of both the investigator and the subjects, based on the blind analysis of the data and on their therapeutic response, respectively. Statistical analysis done on the total population and two diagnostic subgroups was highly significant. The diagnostic subgroups did not show statistically significant differences in either the distributions during the placebo period or in the interaction with the effect of the chug. The results will also be illustrated by the detailed extended longitudinal analysis of a subject. All subjects are required to be in concomitant weekly psychotherapy. The drug interrupts the binge purge addictive cycle, thus facilitating psychotherapy. The primary chug effect is to enhance the patients' sense of control over her relevant behaviors, rather than directly i~tcrease or decrease food intake or body weight. Accordingly, when changes in food intake or body weight did occur, they tended to normalize - i.e. decreasing in overweight bulimics and increasing or stabilizing in underweight anorexic~, in normal weight subjects, body weight fluctuated around normal.
Biomedical Sciences,
BIOL PSYCHIATRY 735 1994;35:615-747
Tampere, Finland
Different stressful conditions are known to alter biochemical parameters of [3H]-GABA and [3H]-bonzodiazepine binding. Thus the effects of handling stress alone and combined with phencyclidine (I~P) treatment on GABAergic neumtransmission were studied in Sprague-Dawley rats. The animal material consisted of handling-habituated (HH, for 11 days), acutely handled (naive, N), handling-habituated and PCP-treated (10 rag/ kg i.p., HH+PCP) and acutely handled (naive) PCP-treated (N+PCP) rats. The binding of [3H]-GABA and [3H]-flunitrazepam (FLU) was studied in membranes and the release of [3H]-GABA with slices prepared from the striatum and the frontal cortex. The maximal binding capacity (Bmu) and the binding constant (K D) of [3H]-GABA were in both brain areas the same in N and HH rats, but in the frontal cortex, however, KD was lower in N rats. KD constants of 3H-FLU were significantly lower in both brain areas in N rats than in HH rats. After PEP treatment both Bu and KD for [3HI-FLU increased in these two brain areas in handling-habituated rats, whereas Brow of [3H/-GABA diminished. Neither handling nor PCP had any effect on [3H]-GABA release from striatal and frontal cortical slices. Handling prior to killing thus affects differently the GABAergic parameters studied end modulates the PCP-induced effects.
433. GLUTAMATE RECEPTOR AUTORADIOGRAPHY OF POSTMORTEM BASAL GANGLIA IN SCHIZOPHRENIA J. 1'. Noga, T. M. Hyde, M. Herman, L. L. Bigelow, D.R. Weinberger, & J.E. Kleinman
in (animal) brains, especially in glial cells, and white matter structures like the corpus callosum (CC) and optic chiasm (Celotti F et ai. Frontier Neuroendocrino11992; 163-215). Suprachiasmatic nucleus, and splenium of the CC (Allen L & Gorski R. Proc Natnl Acad Sci USA ! 992; 89: 7199-202.), are enlarged in gay men. These two "non-sexual" neuroanatomical changes in gay men could quite possibly be determined by changes in 5-red'se in those sites. Marian Diamond (Enriching Heredity, New York, Free Press, 1988, pp. 40 50) studied Einstein's Brain, and found that the number of glial cells per neuron was substantially higher, in all the areas she studied, than that in comparably aged male brains. She also noted more glial cells per neuron in the prefrontal cortex than in the inferior parietal cortex, and suggested that the ratio between neurons to glial cells may decrease in regions that are more highly evolved, or the more active, or both. Body hair growth is determined more by 5-red'se activity in the skin than by blood androgen levels (see Lookingbill DP et al .J Clin EndMetab 1991; 72: 1242-8). $-red'se deficiency 46 XY sub. jects who are often born and raised as girls dramatically turn around towards puberty, usually to become highly muscular, heterosexual men with negligible tendency for body hair growth (Peterson RE et al. Am J Mud. 1977; 62: 170-91). ! have consistently noted, in several samples of gay men, another "non-specific" finding that they were more hirsute but much less muscular, and that there were positive correlations between intelligence and body hair growth in several groups of men in different races (manuscript in preparation). Interestingly, the incidence of male homosexuality somewhat steadily increases with the years of their education (Fay RE et al. Science 1989; 243:338-48 ). However, too many gay men are glabrous, so also was Einstein. An explanation for this apparent paradox will be presented. All these findings, if confirmed, can tie in together, and may also be a reflection of a "continuum model," e.g. Kinsey !-6, for sexual orientation (see Wortis J. Biol Psychiat 1993; 34: 505-6).
NIH/NIMH/DIRP/Clinicai Brain Disorders Branch, Washington, DC 20032 A variety of disturbances of the glutamatergic receptor system have been reported in schizophrenia. We compared the binding densities of radioligands aimed at glutamate uptake sites (with [3H]-D-aspartate) and AMPA sites (with [3H]-CNQX in the basal ganglia (BG) of 7 schizophrenia (DSM3-R criteria), 8 normal, 8 neuroleptic control, and 8 suicide victim brains. Schizophrenia subjects were neuroleptic free by toxicology at autopsy. Two fourteen-micron frozen sections were taken from the basal ganglia of each brain at the level of the nucleus aocumbens, mounted, and Incubated in 50 nM [3H]-CNQX for 45 minutes at 4°C, pH 7.2- 100 mM L-glutamate was used with an adjacent section to determine nonspecific binding. After apposing to film/with radioactive standards and developing, the anturadiographic images were optically scanned and NIH Image software used for quantitative analysis. A similar procedure was followed for labeling the glutamate uptake sites with [3H]-D-aspartate. Preliminary comparison of groups was done by two-tailed t-tests. These data suggest an increase in density of AMPA receptor sites in the caudate in schizophrenia, providing further support for a glutamatergic abnormality in this disorder. Further details of analysis, including results of study of NMDA and kainic acid sites in these postmortem brains, will also be presented.
434. 5¢x-REDUCTASE IN GLIAL CELLS, SEXUAL ORIENTATION, AND FLUID INTELLIGENCE A. G. Alias Chester Mental Health Center, Chester, IL 62233 Steroid 50a-reductase (5-red'se), which converts testosterone to dihydrotestosterone, and also acts on certain other steroids, is widely distributed
435. NALTREXONE IN THE TREATMENT OF ANOREXIA AND BULIMIA NERVOSA M.A. Marrazzi, J. Kinzie & E.D. Luby Wayne State University School of Medicine & Harper-Grace Hospitals, Detroit, MI 48201 Our auto-addiction model suggests that opiate blockade may be therapeutically useful in both anorexia and bulimia nervosa. Naltrexone, the longacting, orally active narcotic antagonist, was administered to out-patient subjects in controlled double blind clinical trials with randomized crossover designs. Reduction in binge - purge symptomatology was evident in the naitrexone period over placebo for 21 out of 22 subjects with either bulimia, anorexia nervosa of the bulimic subtype, or binge eating disorder. in every case, the decoding of drug or placebo double blinding confirmed the assessments of both the investigator and the subjects, based on the blind analysis of the data and on their therapeutic response, respectively. Statistical analysis done on the total population and two diagnostic subgroups was highly significant. The diagnostic subgroups did not show statistically significant differences in either the distributions during the placebo period or in the interaction with the effect of the chug. The results will also be illustrated by the detailed extended longitudinal analysis of a subject. All subjects are required to be in concomitant weekly psychotherapy. The drug interrupts the binge purge addictive cycle, thus facilitating psychotherapy. The primary chug effect is to enhance the patients' sense of control over her relevant behaviors, rather than directly i~tcrease or decrease food intake or body weight. Accordingly, when changes in food intake or body weight did occur, they tended to normalize - i.e. decreasing in overweight bulimics and increasing or stabilizing in underweight anorexic~, in normal weight subjects, body weight fluctuated around normal.