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Cerebral cortex β-adrenoceptor binding in bipolar affective disorder
Journal of AffectiLe Disorders, 30 (1994) 89-92
89
© 1994 Elsevier Science B.V. All rights reserved 0165-0327/94/$07.00
JAD 1057
Cerebral cortex/3-adrenoceptor binding in bipolar affective disorder L. T r e v o r Y o u n g
*, P e t e r P. Li, S t e p h e n J. K i s h a n d J e r r y J. W a r s h
Section of Biochemical Psychiatry, Clarke Institute of Psychiatry, and the Departments of Psychiatry, Pharmacology, and Institute of Medical Sciences, Unicersity of Toronto, Toronto, Ontario, Canada (Received 22 July 1993) (Revision received and accepted 26 August 1993)
Summary /3-Adrenoceptor density was measured in cerebral cortex membranes obtained postmortem from age-matched controls and subjects with bipolar disorder (BD). [~25I]Iodopindolol (PIN) binding performed using a single point concentration was not different in frontal, occipital or temporal cortex in BD. Scatchard analysis of [125I]PIN binding in temporal cortex confirmed the lack of differences in binding density and no changes in K D between these two subject groups. These findings do not support alterations in the density or affinity of/3-adrenoceptor binding in cerebral cortex in BD.
Key words: Cerebral cortex; /3-Adrenoceptor; Bipolar affective disorder
Introduction Substantial evidence implicates disturbances in norepinephrine (NE) neurotransmission in the pathophysiology of bipolar affective disorder (BD) (for reviews see Post and Ballenger, 1985; Horton and Katona, 1991; Goodwin and Jamison, 1991). Results of earlier studies of NE turnover and metabolism implicated possible disturbances in presynaptic NE function in affective disorders (for reviews see Warsh et al., 1988; Goodwin and
* Corresponding author. L. Trevor Young, Clarke Institute of Psychiatry, 250 College Street, Toronto, Canada M5T 1R8. Tel: 416-979-6918; Fax: 416-979-7871.
SSD1 0 1 6 5 - 0 3 2 7 ( 9 3 ) E 0 0 8 0 - E
Jamison, 1991). More recent investigations of receptors and postreceptor mechanisms, however, point to possible alterations in receptor-activated transmembrane signal transduction and postreceptor signalling in BD (Young et al., 1991; 1993). The exact nature and extent of alterations in the receptor signalling chain, however, are still obscure. Studies of /3-adrenoceptors, the first component in the receptor-effector signalling chain, in postmortem brain from patients who died of suicide are inconclusive (Cheetham et al., 1991), with reports of increased (Mann et al., 1986; Biegon and Israeli, 1988; Arango et al., 1990) or unchanged (Meyerson et al., 1982; Crow et al., 1984; De Paermentier et al., 1990) frontal cortical /3-adrenoceptor density. One study of patients
90
with major depressive disorder ( M D D ) who died from natural causes failed to detect any differences in frontal cortical /3-adrenoceptor density compared to controls (Ferrier et al., 1986). The status of/3-adrenoceptors, however, has not been directly examined in postmortem BD brain. Thus, we measured the binding of [125I]iodopindolol (PIN) to cerebral cortical m e m b r a n e s in subjects with BD compared with age-matched controls to determine whether /3-adrenoceptors are altered in postmortem BD brain. Methods
Autopsied brains were obtained from subjects (n = 10) with a diagnosis of BD ( D S M - I I I R ) confirmed by independent review of medical records by two research psychiatrists. Seven out of 10 cases met full criteria for BD, whereas three met all criteria including major depressive episodes, except that length of manic episodes could not be established with certainty due to incomplete records. In one case, the differential diagnosis of schizoaffective disorder could not be ruled out and in another case the diagnosis of bipolar disorder type II could not be excluded with certainty. In one patient (a 40-year-old male) comorbidity with alcohol abuse was evident from review of medical records. Neurological disorder was ruled out by neuropathological examination and chart review. Patients with other concurrent major psychiatric disorders were excluded. Controls (n - 10) had no history of neurologic, psychiatric or substance use disorder, or suicide. Details of patients histories have been reported elsewhere (Young et al., 1991) and are summarized in "Fable I. Autopsied brains were frozen ( - 8 0 ° C ) within 24 h after death in all but one BD subject (33 h). Brain p H was determined as previously described (Butterworth et al., 1989) to provide an index of postmortem agonal state and delay. M e m b r a n e /3-adrenoceptor radioligand binding assays were performed using [12Sl]iodopindolol (PIN) ( N E N Dupont, spec. act. 2200 C i / m m o l ) as described by Arango et al. (1990). Nonspecific binding was determined in the presence of 1 /.tM isoproterenol. Single [125I]PIN concentrations (80 pmol/1) were used to determine binding in
TABLE 1 Subject characteristics A. B i p o l a r
B. C o n t r o l s
Age/Sex
Lithium treatment
Suicide
Age/Sex
28F 71M 88M 70F 40M 37M 27F 70F 94F 42F
yes no no unknown yes yes no yes no yes
yes no 11o no no yes yes no no yes
28F 71M 92F 74F 48M 51M 30M 66F 86M 58F
60.4_+7.2
(mean + SEM)
56.7+8.3
frontal, temporal and occipital cortical regions. Saturation binding (4-200 p m o l / l PIN) and Scatchard analysis was performed on temporal cortical membranes to confirm the findings obtained with single point assays and to ensure similar affinities ( K D) of/3-adrenoceptors in BD and control subjects. Protein was determined by the method of Bradford et al. (1976). Differences between group means were evaluated statistically using Student's two-tailed t-tests with P < 0.05 considered significant. Results
There were no significant differences ( P > 0.1) between the mean age of control (60.4 +_ 7.2 years, mean + SEM) and BD subjects (56.7 _+ 8.3 years), in the time from death to autopsy (i.e., postmortem delay) (16.1 + 1.6 h compared with 17.9 _+ 2.4) or in brain pH, as an index of agonal status (6.37 _+ 0.09 vs. 6.49 + 0.06), respectively. No significant differences ( P > 0.1) were found between control and BD subjects (Fig. 1A) in specific [lZSI]P1N binding (determined at 80 p m o l / l ) in frontal, 66 + 7.0(10) (mean _+ SEM(n)) f m o l / m g protein vs. 68 +_3.9(10); or occipital cortex, 57 +_ 5.7(7) vs. 54 _+ 7.9(7). A trend toward a decrease in specific PIN binding of temporal cortex, 30_+ 8.5(6) vs. 23 + 6.0(7) also did not reach statistical significance ( P > 0.1). Additionally, Scatchard analysis of [125I]PIN binding in
91
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Fig. 1. (A) Plot of individual data points for [125I]PINbinding to cerebral cortex membranes from frontal, temporal and occipital cortex in controls (o) and BD subjects (e). Mean + SEM are indicated with horizontal bars. (B) Mean + SEM affinity (K D) and density (Bm~~) determined by Scatchard analysis are shown for temporal cortex membranes. Open bars indicate controls and filled bars indicate BD subjects.
temporal cortex also failed to reveal any significant differences ( P > 0 . 1 ) between either K D, (49 _+ 7.3(6) pM vs. 53 _+ 11(6)); or density (B .... ), (54 _+ 11(6) f m o l / m g protein vs. 48 ± 14(6)); between control and BD subjects (Fig. 1B), respectively. In temporal cortex, single point binding data and Bmax values gave good agreement (r = 0.62, P < 0.05). Finally, no differences were apparent in frontal cortical []25I]PIN binding (the region with the largest n) when patients were subgrouped on the basis of death by suicide (56 ± 3.3(4)) vs. death by natural causes (49 ± 2.5(6)); or by a history of lithium treatment (53.3 ± 3.0(5) vs. 49.4 ± 3.3(5)).
Discussion The present findings do not support the occurrence of changes in cerebral cortical /3-adrenoceptor density in BD. In addition, no changes in receptor binding were evident when BD subjects were subdivided on the basis of history of suicide or lithium treatment. Although increased NE turnover ( M H P G / N E ratio) was found in these same cortical regions in the same subject group compared with controls (Young et al., submitted) there was no signficant correlation between these estimates and either density or affinity of PIN binding (data not shown). The estimates of /3-
adrenoceptor density and affinity using [~25I]PIN in the current study agree well with values reported by Arango et al. (1990) who employed the same methodology. Analysis of binding density and affinity in temporal cortex confirmed the lack of significant difference between BD and control subjects obtained by measurement at a single concentration in the same region. The present results concur with the postmortem brain findings of Ferrier et al. (1986) of unchanged/3-adrenoceptor densities in major depressive disorder. In addition, these findings agree with results of several studies in which /3-adrenoceptor binding was measured in transformed lymphoblasts obtained from BD patients. Berrettini et al. (1987) and Kay et al. (1993) found no differences in /3-adrenoceptor densities in lymphoblastoid cells in BD whereas Wright et al. (1984) reported decreased /3-adrenoceptor densities. Furthermore, decreased /3-adrenoceptor stimulation of adenylyl cyclase in mononuclear leukocytes was found to occur in the absence of changes in /3-adrenoceptor density (Mann et al., 1985) suggesting that adrenoceptor-effector response is reduced at postreceptor sites without long-term changes in adrenoceptor number. The findings of increased stimulatory guanine nucleotide binding protein a-subunit levels and adenylyl cyclase activity reported earlier (Young
92
et al., 1991; 1993) in postmortem BD brain together with the lack of differences in brain /3adrenoceptor number reported here, support a defect in transmembrane signal transduction distal to the /3-adrenoceptor in this disorder.
Acknowledgements Supported by grants from Ontario Mental Health Foundation (LTY), MRC of Canada (LTY and J J W ) and the Stanley Foundation ( J J W and LTY). LTY and SJK are Career Scientists of the Ontario Ministry of Health. Thanks are due to K.P. Siu for technical assistance. Thanks are also due to the Canadian Brain Tissue Bank (Toronto), the Brain Resource Centre (Boston), and the National Neurological Research Bank (Los Angeles) for post mortem specimens.
References Arango, V., Ernsberger, P., Reis, D.J. and Mann, J.J. (19901 Demonstration of high- and low-affinity /3-adrenergic receptors in slide-mounted sections of rat and human brain. Brain Res. 516, 113-121. Berrettini, W.H., Cappellari, C.B., Nurnberger, J.I. and Gershon, E.S. (1987a) Beta-adrenergic receptor on lymphoblasts: a study of manic-depressive illness. Neuropsychobiology 17, 15-18. Biegon, A. and Israeli, M. (1988) Regionally selective increases in /3-adrenergic receptor density in the brains of suicide victims. Brain Res. 442,199-203. Bradford, M.M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-252. Butterworth, J. and Tennant, M.C. (1989) Postmortem human brain pH and lactate in sudden infant death syndrome. J. Neurochem. 53, 1494-1499. Cheetham, S.C., Katona, C.L.E. and Horton, R.W. (19911 Postmortem studies of neurotransmitter biochemistry in depression and suicide. In: R. Horton and C. Katona (Eds.), Biological Aspects of Affective Disorders. London: Academic Press, pp. 191-221. Crow, T.J., Cross, A.J., Cooper, S.J., Deakin, J.F.W., Ferrier, I.N., Johnson J.A., Joseph, M.H., Owen, F., Poulter, M., Lofthouse, R., Corsellis, J.A.N., Chambers, D.R., Blessed, G., Perry, E.K., Perry, R.H. and Tomlinson, B.E. (1984) Neurotransmitter receptors and monoamine metabolites
in the brains of patients with Alzheimer-type dementia and depression, and suicides. Neuropharmacology 23, 1561-1569. De Paermentier, F., Cheetham, S.C., Crompton, M.R., Katona, C.L.E. and Horton, R.W. (1990) Brain /3-adrenoceptor binding sites in antidepressant-free depressed suicide victims. Brain Res. 525, 71-77. Ferrier, I.N., McKeith, I.G., Cross, A.J., Perry, E.K., Candy, J.M. and Perry, R.H. (1986) Postmortem neurochemical studies in depression. Ann. NY Acad. Sci. 487, 128 142. Goodwin, F.K. and Jamison, K.R. (1990) Biochemical and pharmacological studies. In: Manic-Depressive Illness. Oxford University Press, Oxford, pp. 416 574. Horton, R. and Katona, C. (1991) Biological Aspects of Affective Disorders. Academic Press, London. Kay, G., Sargeant, M., McGuffin, P., Whatley, S., Marchbanks, R., Baldwin, D., Montgomery, S. and Elliott, J.M. (1993) The lymphoblast /3-adrenergic receptor in bipolar depressed patients: characterization and down-regulation. J. Affect. Disord. 27, 163 172. Mann, J.J., Brown, R.P., Halper, J.P., Brown, R.P., Johnson, K.S., Kocsis, J.H. and Chen, J.S. (19851 Reduced sensitivity of lymphocyte beta-adrenergic receptors in patients with endogenous depression and psychomotor agitation. N. Engl. J. Med. 313, 715 720. Mann, J.J., Stanley, M., McBride, A. and McEwen, B.S. (19861 Increased serotonin 2 and /3-adrenergic receptor binding in the frontal cortices of suicide victims. Arch. Gen. Psychiatry 43, 954 959. Meyerson, L.R., Wennogte, L.P., Abel, M.S., Coupet, J., Lippa, A.S,, Rauh, C.E. and Beer, B. (19821 Human brain receptor alterations in suicide victims. Pharmacol. Biochem. Behav. 17, 159-163. Post, R.M. and Ballenger, J.C. (1984) Neurobiology of Mood Disorders. Baltimore: Williams&Wilkins. Warsh, J.J., Chiu, A.S. and Li, P.P. (1988) Noradrenergic mechanisms in affective disorders: contributions of receptor research. In: A.D. Sen (Ed.), Receptors and Ligands in Psychiatry and Neurology. Cambridge: Cambridge University Press, pp. 271-302. Wright, A.F., Crichton, D.N., Loudon, J.B., Morten, J.E. and Steel, C.M. (1984)/3-Adrenoceptor binding defects in cell lines from families with manic-depressive disorder. Ann. Hum. Genet. 48, 2(11-214. Young, L.T., Li, P.P., Kish, S.J., Siu, K.P. and Warsh, J.J. (1991) Postmortem cerebral cortex G~ alpha-subunit levels are elevated in bipolar affective disorder. Brain Res. 553, 323-326. Young, L.T., Li, P.P., Kish, S.J., Siu, K.P., Kamble, A., Hornykiewicz, O. and Warsh, J.J. (1993) Cerebral cortex Gsa protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J. Neurochem. 61, 89(/-898.
89
© 1994 Elsevier Science B.V. All rights reserved 0165-0327/94/$07.00
JAD 1057
Cerebral cortex/3-adrenoceptor binding in bipolar affective disorder L. T r e v o r Y o u n g
*, P e t e r P. Li, S t e p h e n J. K i s h a n d J e r r y J. W a r s h
Section of Biochemical Psychiatry, Clarke Institute of Psychiatry, and the Departments of Psychiatry, Pharmacology, and Institute of Medical Sciences, Unicersity of Toronto, Toronto, Ontario, Canada (Received 22 July 1993) (Revision received and accepted 26 August 1993)
Summary /3-Adrenoceptor density was measured in cerebral cortex membranes obtained postmortem from age-matched controls and subjects with bipolar disorder (BD). [~25I]Iodopindolol (PIN) binding performed using a single point concentration was not different in frontal, occipital or temporal cortex in BD. Scatchard analysis of [125I]PIN binding in temporal cortex confirmed the lack of differences in binding density and no changes in K D between these two subject groups. These findings do not support alterations in the density or affinity of/3-adrenoceptor binding in cerebral cortex in BD.
Key words: Cerebral cortex; /3-Adrenoceptor; Bipolar affective disorder
Introduction Substantial evidence implicates disturbances in norepinephrine (NE) neurotransmission in the pathophysiology of bipolar affective disorder (BD) (for reviews see Post and Ballenger, 1985; Horton and Katona, 1991; Goodwin and Jamison, 1991). Results of earlier studies of NE turnover and metabolism implicated possible disturbances in presynaptic NE function in affective disorders (for reviews see Warsh et al., 1988; Goodwin and
* Corresponding author. L. Trevor Young, Clarke Institute of Psychiatry, 250 College Street, Toronto, Canada M5T 1R8. Tel: 416-979-6918; Fax: 416-979-7871.
SSD1 0 1 6 5 - 0 3 2 7 ( 9 3 ) E 0 0 8 0 - E
Jamison, 1991). More recent investigations of receptors and postreceptor mechanisms, however, point to possible alterations in receptor-activated transmembrane signal transduction and postreceptor signalling in BD (Young et al., 1991; 1993). The exact nature and extent of alterations in the receptor signalling chain, however, are still obscure. Studies of /3-adrenoceptors, the first component in the receptor-effector signalling chain, in postmortem brain from patients who died of suicide are inconclusive (Cheetham et al., 1991), with reports of increased (Mann et al., 1986; Biegon and Israeli, 1988; Arango et al., 1990) or unchanged (Meyerson et al., 1982; Crow et al., 1984; De Paermentier et al., 1990) frontal cortical /3-adrenoceptor density. One study of patients
90
with major depressive disorder ( M D D ) who died from natural causes failed to detect any differences in frontal cortical /3-adrenoceptor density compared to controls (Ferrier et al., 1986). The status of/3-adrenoceptors, however, has not been directly examined in postmortem BD brain. Thus, we measured the binding of [125I]iodopindolol (PIN) to cerebral cortical m e m b r a n e s in subjects with BD compared with age-matched controls to determine whether /3-adrenoceptors are altered in postmortem BD brain. Methods
Autopsied brains were obtained from subjects (n = 10) with a diagnosis of BD ( D S M - I I I R ) confirmed by independent review of medical records by two research psychiatrists. Seven out of 10 cases met full criteria for BD, whereas three met all criteria including major depressive episodes, except that length of manic episodes could not be established with certainty due to incomplete records. In one case, the differential diagnosis of schizoaffective disorder could not be ruled out and in another case the diagnosis of bipolar disorder type II could not be excluded with certainty. In one patient (a 40-year-old male) comorbidity with alcohol abuse was evident from review of medical records. Neurological disorder was ruled out by neuropathological examination and chart review. Patients with other concurrent major psychiatric disorders were excluded. Controls (n - 10) had no history of neurologic, psychiatric or substance use disorder, or suicide. Details of patients histories have been reported elsewhere (Young et al., 1991) and are summarized in "Fable I. Autopsied brains were frozen ( - 8 0 ° C ) within 24 h after death in all but one BD subject (33 h). Brain p H was determined as previously described (Butterworth et al., 1989) to provide an index of postmortem agonal state and delay. M e m b r a n e /3-adrenoceptor radioligand binding assays were performed using [12Sl]iodopindolol (PIN) ( N E N Dupont, spec. act. 2200 C i / m m o l ) as described by Arango et al. (1990). Nonspecific binding was determined in the presence of 1 /.tM isoproterenol. Single [125I]PIN concentrations (80 pmol/1) were used to determine binding in
TABLE 1 Subject characteristics A. B i p o l a r
B. C o n t r o l s
Age/Sex
Lithium treatment
Suicide
Age/Sex
28F 71M 88M 70F 40M 37M 27F 70F 94F 42F
yes no no unknown yes yes no yes no yes
yes no 11o no no yes yes no no yes
28F 71M 92F 74F 48M 51M 30M 66F 86M 58F
60.4_+7.2
(mean + SEM)
56.7+8.3
frontal, temporal and occipital cortical regions. Saturation binding (4-200 p m o l / l PIN) and Scatchard analysis was performed on temporal cortical membranes to confirm the findings obtained with single point assays and to ensure similar affinities ( K D) of/3-adrenoceptors in BD and control subjects. Protein was determined by the method of Bradford et al. (1976). Differences between group means were evaluated statistically using Student's two-tailed t-tests with P < 0.05 considered significant. Results
There were no significant differences ( P > 0.1) between the mean age of control (60.4 +_ 7.2 years, mean + SEM) and BD subjects (56.7 _+ 8.3 years), in the time from death to autopsy (i.e., postmortem delay) (16.1 + 1.6 h compared with 17.9 _+ 2.4) or in brain pH, as an index of agonal status (6.37 _+ 0.09 vs. 6.49 + 0.06), respectively. No significant differences ( P > 0.1) were found between control and BD subjects (Fig. 1A) in specific [lZSI]P1N binding (determined at 80 p m o l / l ) in frontal, 66 + 7.0(10) (mean _+ SEM(n)) f m o l / m g protein vs. 68 +_3.9(10); or occipital cortex, 57 +_ 5.7(7) vs. 54 _+ 7.9(7). A trend toward a decrease in specific PIN binding of temporal cortex, 30_+ 8.5(6) vs. 23 + 6.0(7) also did not reach statistical significance ( P > 0.1). Additionally, Scatchard analysis of [125I]PIN binding in
91
B.
A. 120
..............................................
80
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80
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Fig. 1. (A) Plot of individual data points for [125I]PINbinding to cerebral cortex membranes from frontal, temporal and occipital cortex in controls (o) and BD subjects (e). Mean + SEM are indicated with horizontal bars. (B) Mean + SEM affinity (K D) and density (Bm~~) determined by Scatchard analysis are shown for temporal cortex membranes. Open bars indicate controls and filled bars indicate BD subjects.
temporal cortex also failed to reveal any significant differences ( P > 0 . 1 ) between either K D, (49 _+ 7.3(6) pM vs. 53 _+ 11(6)); or density (B .... ), (54 _+ 11(6) f m o l / m g protein vs. 48 ± 14(6)); between control and BD subjects (Fig. 1B), respectively. In temporal cortex, single point binding data and Bmax values gave good agreement (r = 0.62, P < 0.05). Finally, no differences were apparent in frontal cortical []25I]PIN binding (the region with the largest n) when patients were subgrouped on the basis of death by suicide (56 ± 3.3(4)) vs. death by natural causes (49 ± 2.5(6)); or by a history of lithium treatment (53.3 ± 3.0(5) vs. 49.4 ± 3.3(5)).
Discussion The present findings do not support the occurrence of changes in cerebral cortical /3-adrenoceptor density in BD. In addition, no changes in receptor binding were evident when BD subjects were subdivided on the basis of history of suicide or lithium treatment. Although increased NE turnover ( M H P G / N E ratio) was found in these same cortical regions in the same subject group compared with controls (Young et al., submitted) there was no signficant correlation between these estimates and either density or affinity of PIN binding (data not shown). The estimates of /3-
adrenoceptor density and affinity using [~25I]PIN in the current study agree well with values reported by Arango et al. (1990) who employed the same methodology. Analysis of binding density and affinity in temporal cortex confirmed the lack of significant difference between BD and control subjects obtained by measurement at a single concentration in the same region. The present results concur with the postmortem brain findings of Ferrier et al. (1986) of unchanged/3-adrenoceptor densities in major depressive disorder. In addition, these findings agree with results of several studies in which /3-adrenoceptor binding was measured in transformed lymphoblasts obtained from BD patients. Berrettini et al. (1987) and Kay et al. (1993) found no differences in /3-adrenoceptor densities in lymphoblastoid cells in BD whereas Wright et al. (1984) reported decreased /3-adrenoceptor densities. Furthermore, decreased /3-adrenoceptor stimulation of adenylyl cyclase in mononuclear leukocytes was found to occur in the absence of changes in /3-adrenoceptor density (Mann et al., 1985) suggesting that adrenoceptor-effector response is reduced at postreceptor sites without long-term changes in adrenoceptor number. The findings of increased stimulatory guanine nucleotide binding protein a-subunit levels and adenylyl cyclase activity reported earlier (Young
92
et al., 1991; 1993) in postmortem BD brain together with the lack of differences in brain /3adrenoceptor number reported here, support a defect in transmembrane signal transduction distal to the /3-adrenoceptor in this disorder.
Acknowledgements Supported by grants from Ontario Mental Health Foundation (LTY), MRC of Canada (LTY and J J W ) and the Stanley Foundation ( J J W and LTY). LTY and SJK are Career Scientists of the Ontario Ministry of Health. Thanks are due to K.P. Siu for technical assistance. Thanks are also due to the Canadian Brain Tissue Bank (Toronto), the Brain Resource Centre (Boston), and the National Neurological Research Bank (Los Angeles) for post mortem specimens.
References Arango, V., Ernsberger, P., Reis, D.J. and Mann, J.J. (19901 Demonstration of high- and low-affinity /3-adrenergic receptors in slide-mounted sections of rat and human brain. Brain Res. 516, 113-121. Berrettini, W.H., Cappellari, C.B., Nurnberger, J.I. and Gershon, E.S. (1987a) Beta-adrenergic receptor on lymphoblasts: a study of manic-depressive illness. Neuropsychobiology 17, 15-18. Biegon, A. and Israeli, M. (1988) Regionally selective increases in /3-adrenergic receptor density in the brains of suicide victims. Brain Res. 442,199-203. Bradford, M.M. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-252. Butterworth, J. and Tennant, M.C. (1989) Postmortem human brain pH and lactate in sudden infant death syndrome. J. Neurochem. 53, 1494-1499. Cheetham, S.C., Katona, C.L.E. and Horton, R.W. (19911 Postmortem studies of neurotransmitter biochemistry in depression and suicide. In: R. Horton and C. Katona (Eds.), Biological Aspects of Affective Disorders. London: Academic Press, pp. 191-221. Crow, T.J., Cross, A.J., Cooper, S.J., Deakin, J.F.W., Ferrier, I.N., Johnson J.A., Joseph, M.H., Owen, F., Poulter, M., Lofthouse, R., Corsellis, J.A.N., Chambers, D.R., Blessed, G., Perry, E.K., Perry, R.H. and Tomlinson, B.E. (1984) Neurotransmitter receptors and monoamine metabolites
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