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Learned helplessness: In vivo biogenic amine release in hypothalamus
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THURSDAE, MAY 18
BIOL PSYCHIATRY 1995:37:593 683
57. LEARNED HELPLESSNESS: IN VIVO BIOGENIC AMINE RELEASE IN HYPOTHALAMUS F. Petty 1,2 & G.L. Krarner I 1Department o f Veterans Affairs Medical Center, Dallas, T X 75216; 2University of Texas S o u t h w e s t e r n Medical School, Dallas, T X 75235 Learned helplessness (LH) is a behavioral depression caused by inescapable stress that models some aspects of human depression. We are developing a neuronal map of learned helplessness, which involves multiple neurotransmitters in several limbic regions. In frontal cortex, dopamine (DA), serotonin (5-HT), and GABA modulate the development and maintenance of LH, while in hippocampus interactions between GABA and norepinephrine (NE) play the major role. In hypothalamus, other investigators have reported decreased 5-HT uptake into synaptosomes and decreased basal and K+-stimulated 5-HT release from tissue slices of LH rats, as well as decreased paroxetine and unchanged [3-receptor binding. We have now applied in vivo microdialysis to measuring DA, NE, and 5-HT simultaneously in hypothalamus or caudate of conscious, freely moving rats in a LH paradigm. Rats received 100 trials of inescapable tailshock stress, and after testing for LH, microdialysis probes were implanted into either caudate or lateral hypothalamus. One day later, perfusion was maintained with Ringer's solution until a stable baseline was obtained, then switched to high K +. In caudate, no differences were found in DA or 5-HT among any of the three experimental groups--LH, non-helpless (NH), or unstressed tested controls (TC). In hypothalamus, no differences were observed among experimental groups for DA or 5-HT; however, NE showed significantly higher levels of basal release in LH rats, compared to NH or TC. Interestingly, NH rats had significantly higher K+-stimulated NE release compared to the other two groups. For all the stressed rats, there was a significant positive correlation between shuttlebox escape latencies and basal NE release. These data suggest that the caudate may not be involved in the biogenic amine neurochemistry of LH, and that in the lateral hypothalamus, NE mechanisms predominate in this animal model of depression.
58. PLASMA GABA IN CHILDREN AND ADOLESCENTS WITH MOOD AND BEHAVIOR DISORDERS F. Petty 1,2, J. Prosser 2,3, S. Sheikha 3, R. Kowatch 2, G.L. Kramer j, N. Rosenbarger 3, J. Trent 3, & C.W. Hughes 2"3 1Department o f Veterans Affairs Medical Center, Dallas, T X 75216; 2University o f Texas S o u t h w e s t e r n Medical School, Dallas, T X 75235; 3Terrell State Hospital, Terrell, T X 7 5 1 6 0 Plasma GABA, which is a peripheral index of brain GABA activity, is low in a subset of about 40% of adults with major depressive and bipolar disorders. It is not known whether this biological marker of mood disorder is a consequence or "scar" of illness or represents an antecedent vulnerability. We measured plasma GABA in 14 healthy control adolescents with no history of psychiatric disorder in first-degree family members, and found these levels to be generally in the range of 100-150 pmol/ml, similar to previously reported levels in adult controls. In children and adolescent patients with mood disorders (n = 38) and comorbid mood plus behavior disorders (n = 48), mean plasma GABA levels were similar to controls; however, 15% of these patients had plasma GABA levels below 100 pmol/ml, the lowest level of any controls. Children and adolescents with behavior disorders and no comorbid mood disorder (n = 29) had
plasma GABA levels that were significantly higher than the other study groups. There was an inverse correlation between plasma GABA and age for the patients. These data suggest that low plasma GABA may characterize a subset of patients with mood disorders early in the course of illness. Therefore, at least in some cases, low plasma GABA may not be a consequence or "scar" of illness. Finding elevated plasma GABA levels in children and adolescents with behavior disorders was interesting, particularly since behavior disorder patients on medication had lower plasma GABA levels than those not on medication. Further research is needed on the GABA system in children and adolescents.
59. SENILE PLAQUES IN THE LOCUS COERULEUS OF YOUNG PATIENTS WITH DEPRESSION M.R. Issidorides, S. Havaki, & M. Chrysanthou-Piterou D e p a r t m e n t o f Psychiatry, U n i v e r s i t y o f A t h e n s , Eginition Hospital, A t h e n s , Greece Although senile plaques (SP) are a marker of Alzheimer's disease and advanced age, they have been found, using antibodies to ~-amyloid, in temporal Iobotomy specimen of young epileptics. Thus, the deposition of [3-amyloid within the brain is not a property uniquely of the aged. In a study of monoamine neurons in the brains of young suicides with a diagnosis of major depression, a high incidence of SP was found in the locus coeruleus (LC) with the use of the anamoniacal silver reaction (ASR) of Black and Ansley (1966). Observations of the resin-embedded, semithin sections in the light microscope showed a high concentration of diffuse and primitive SP, but an absence of mature SP. In the matched controls, only rare, atypical black deposits were encountered. In the LC of the patients, SP were seen in contact with neuronal cell bodies and glial nuclei, around capillaries, next to dendrites, and interconnected in long assemblies. The texture of the SP appeared fibrillar, a fact which was confirmed by studying the thin sections in the electron microscope. The ASR produced dense black deposits in all cell nuclei in the sections of both controis and patients. In view of the involvement of the norepinephrine pathway from the LC in the pathogenesis of major depression, the presence of SP in this area is important. Although its significance is unclear, it suggests that some aspect of major depression has an inducing influence on the formation of SP in young individuals. (Supported by grants from the Ministry of Research & Technology, Greece and the Theodor Tbeohari Cozzika Research Foundation.)
60. 31pHOSPHOROUS MRSI OF THE FRONTAL LOBES IN BIPOLAR DISORDER R.F. Deicken 1,2,3, M.W Weiner 1,4,5, & G. Fein 2,3 IMagnetic R e s o n a n c e Unit a n d 2Psychiatry Service, San Francisco D e p a r t m e n t o f Veterans Affairs M e d i c a l Center S F V A M C ; D e p a r t m e n t s o f 3psychiatry, 4Radiology, and 5Medicine, University o f California, San Francisco The objective of this study was to determine if there were alterations in brain high-energy phosphorous and phospholipid metabolism in the frontal lobes of patients with bipolar disorder using in vivo 31phosphorous (31p) Magnetic Resonance Spectroscopic Imaging (MRSI). Twelve unmedicated, euthymic bipolar patients and 16 control subjects underwent 31p MRSI using a Philips Gyroscan MRI/MRS system at the SFVAMC Magnetic Resonance Unit. The bipolar patients met DSM-III-R criteria and had been euthymic for at least 2 months prior to study by clinical
THURSDAE, MAY 18
BIOL PSYCHIATRY 1995:37:593 683
57. LEARNED HELPLESSNESS: IN VIVO BIOGENIC AMINE RELEASE IN HYPOTHALAMUS F. Petty 1,2 & G.L. Krarner I 1Department o f Veterans Affairs Medical Center, Dallas, T X 75216; 2University of Texas S o u t h w e s t e r n Medical School, Dallas, T X 75235 Learned helplessness (LH) is a behavioral depression caused by inescapable stress that models some aspects of human depression. We are developing a neuronal map of learned helplessness, which involves multiple neurotransmitters in several limbic regions. In frontal cortex, dopamine (DA), serotonin (5-HT), and GABA modulate the development and maintenance of LH, while in hippocampus interactions between GABA and norepinephrine (NE) play the major role. In hypothalamus, other investigators have reported decreased 5-HT uptake into synaptosomes and decreased basal and K+-stimulated 5-HT release from tissue slices of LH rats, as well as decreased paroxetine and unchanged [3-receptor binding. We have now applied in vivo microdialysis to measuring DA, NE, and 5-HT simultaneously in hypothalamus or caudate of conscious, freely moving rats in a LH paradigm. Rats received 100 trials of inescapable tailshock stress, and after testing for LH, microdialysis probes were implanted into either caudate or lateral hypothalamus. One day later, perfusion was maintained with Ringer's solution until a stable baseline was obtained, then switched to high K +. In caudate, no differences were found in DA or 5-HT among any of the three experimental groups--LH, non-helpless (NH), or unstressed tested controls (TC). In hypothalamus, no differences were observed among experimental groups for DA or 5-HT; however, NE showed significantly higher levels of basal release in LH rats, compared to NH or TC. Interestingly, NH rats had significantly higher K+-stimulated NE release compared to the other two groups. For all the stressed rats, there was a significant positive correlation between shuttlebox escape latencies and basal NE release. These data suggest that the caudate may not be involved in the biogenic amine neurochemistry of LH, and that in the lateral hypothalamus, NE mechanisms predominate in this animal model of depression.
58. PLASMA GABA IN CHILDREN AND ADOLESCENTS WITH MOOD AND BEHAVIOR DISORDERS F. Petty 1,2, J. Prosser 2,3, S. Sheikha 3, R. Kowatch 2, G.L. Kramer j, N. Rosenbarger 3, J. Trent 3, & C.W. Hughes 2"3 1Department o f Veterans Affairs Medical Center, Dallas, T X 75216; 2University o f Texas S o u t h w e s t e r n Medical School, Dallas, T X 75235; 3Terrell State Hospital, Terrell, T X 7 5 1 6 0 Plasma GABA, which is a peripheral index of brain GABA activity, is low in a subset of about 40% of adults with major depressive and bipolar disorders. It is not known whether this biological marker of mood disorder is a consequence or "scar" of illness or represents an antecedent vulnerability. We measured plasma GABA in 14 healthy control adolescents with no history of psychiatric disorder in first-degree family members, and found these levels to be generally in the range of 100-150 pmol/ml, similar to previously reported levels in adult controls. In children and adolescent patients with mood disorders (n = 38) and comorbid mood plus behavior disorders (n = 48), mean plasma GABA levels were similar to controls; however, 15% of these patients had plasma GABA levels below 100 pmol/ml, the lowest level of any controls. Children and adolescents with behavior disorders and no comorbid mood disorder (n = 29) had
plasma GABA levels that were significantly higher than the other study groups. There was an inverse correlation between plasma GABA and age for the patients. These data suggest that low plasma GABA may characterize a subset of patients with mood disorders early in the course of illness. Therefore, at least in some cases, low plasma GABA may not be a consequence or "scar" of illness. Finding elevated plasma GABA levels in children and adolescents with behavior disorders was interesting, particularly since behavior disorder patients on medication had lower plasma GABA levels than those not on medication. Further research is needed on the GABA system in children and adolescents.
59. SENILE PLAQUES IN THE LOCUS COERULEUS OF YOUNG PATIENTS WITH DEPRESSION M.R. Issidorides, S. Havaki, & M. Chrysanthou-Piterou D e p a r t m e n t o f Psychiatry, U n i v e r s i t y o f A t h e n s , Eginition Hospital, A t h e n s , Greece Although senile plaques (SP) are a marker of Alzheimer's disease and advanced age, they have been found, using antibodies to ~-amyloid, in temporal Iobotomy specimen of young epileptics. Thus, the deposition of [3-amyloid within the brain is not a property uniquely of the aged. In a study of monoamine neurons in the brains of young suicides with a diagnosis of major depression, a high incidence of SP was found in the locus coeruleus (LC) with the use of the anamoniacal silver reaction (ASR) of Black and Ansley (1966). Observations of the resin-embedded, semithin sections in the light microscope showed a high concentration of diffuse and primitive SP, but an absence of mature SP. In the matched controls, only rare, atypical black deposits were encountered. In the LC of the patients, SP were seen in contact with neuronal cell bodies and glial nuclei, around capillaries, next to dendrites, and interconnected in long assemblies. The texture of the SP appeared fibrillar, a fact which was confirmed by studying the thin sections in the electron microscope. The ASR produced dense black deposits in all cell nuclei in the sections of both controis and patients. In view of the involvement of the norepinephrine pathway from the LC in the pathogenesis of major depression, the presence of SP in this area is important. Although its significance is unclear, it suggests that some aspect of major depression has an inducing influence on the formation of SP in young individuals. (Supported by grants from the Ministry of Research & Technology, Greece and the Theodor Tbeohari Cozzika Research Foundation.)
60. 31pHOSPHOROUS MRSI OF THE FRONTAL LOBES IN BIPOLAR DISORDER R.F. Deicken 1,2,3, M.W Weiner 1,4,5, & G. Fein 2,3 IMagnetic R e s o n a n c e Unit a n d 2Psychiatry Service, San Francisco D e p a r t m e n t o f Veterans Affairs M e d i c a l Center S F V A M C ; D e p a r t m e n t s o f 3psychiatry, 4Radiology, and 5Medicine, University o f California, San Francisco The objective of this study was to determine if there were alterations in brain high-energy phosphorous and phospholipid metabolism in the frontal lobes of patients with bipolar disorder using in vivo 31phosphorous (31p) Magnetic Resonance Spectroscopic Imaging (MRSI). Twelve unmedicated, euthymic bipolar patients and 16 control subjects underwent 31p MRSI using a Philips Gyroscan MRI/MRS system at the SFVAMC Magnetic Resonance Unit. The bipolar patients met DSM-III-R criteria and had been euthymic for at least 2 months prior to study by clinical