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Catecholamine metabolism and affective disorders
cxl
Frontiers in Catecholamine R e s e a r c h
It is noteworthy that despite the fact that both pharmacological and mechanical lesions of the dopamine system lead to a large increase in the endogenous levels of DA the rate of DA synthesis both in vivo and in v i t r o after establishment of this new increased steadyostate level of DA is not significantly different from the rate of DA synthesis in untreated control animals. However, if endogenous levels of DA are increased by treatment with MAO inhibitors the synthesis of DA is markedly retarded. This may in part be explained by the intemeuronal distribution of the increased DA. Possible mechanisms by which dopaminergic neurons control synthesis and release will be discussed.
CATECHOLAM1NE METABOLISM AND AFFECTIVE DISORDERS
Joseph J. Schildkraut Harvard Medical School, Boston, Massaehusets, U.S.A. This paper will summarize aspects of our research on cateeholamine metabolism in affective disorders (depressions and manias), focusing on recent studies of the urinary excretion of 3-methoxy-4~hydroxyphenylglycol (MHPG), a metabolite of norepinephrine which may provide some index of the synthesis and metabolism of norepinephrine in the brain. In one aspect of our research we have examined the changes in MHPG excretion which were asociated with changes in affective state. The findings from our longitudinal studies of patients with naturally occurring or amphetamine-induced manic-depressive episodes indicate that levels of urinary MHPG are relatively lower during depressions and higher during manic or hypomanic episodes than after clinical remissions. However, all depressed patients do not excrete comparably low levels of MHPG ; and recent findings have suggested that MHPG excretion may provide a biological criterion for classifying depressive disorders and for predicting the responses to specific forms of antidepressant pharmacotherapy. In a preliminary study of a small group of depressed patients, favorable responses to treatment with amitriptyline were observed in patients with relatively high levels of urinary MHPG but not in patients with lower levels of MHPG. Differences in physical activity or stress could conceivably account for the differences in MHPG excretion observed in patients with affective disorders. Moreover, the relationship between urinary MHPG excretion and central noradrenergic activity remains an unresolved issue, and one may question whether MHPG (or any biogenic amine metabolite) measured in urine can provide meaningful information about the activity of the central nervous system. In order to explore these issues, we recently compared the urinary excretion of
Frontiers in Catecholamine Research
cxli
MHPG in a small group of patients with various clinically defined subtypes of depressive disorders studied during drug-free periods, and examined our findings for possible relationships between urinary MHPG excretion and clinical measures of motor activity and anxiety as well as electroencephalographic measures of central nervous system activity. MHPG excretion was significantly lower in 5 patients with manic-depressive depressions (i.e. bipolar disorders with histories of hypomanias or manias) than in 5 patients with chronic characterological depressions (i.e. disphoric depressive syndromes with no history of hypomania or mania). In a patient with a schizoaffective depression, MHPG excretion was lower than the mean for manicdepressive depressions, while in a patient with a recurrent endogenous depression (but no history of hypomania or mania) MHPG excretion fell between the means for manic-depressive and chronic chatacterological depressions. These differences in MHPG excretion could not be explained by differences in retardation, agitation and psychic or somatic anxiety as reflected by scores on a modified Hamilton Depression Rating Scale, but may be related to the recent observations of other investigators that platelet monoamine oxidase activity was decreased in patients with bipolar affective disorders as well as schizophrenias but relatively elevated in other types of depressive disorder. In collaboration with Dr. Ernest Hartmann, we also attempted to relate MHPG excretion to certain aspects of central nervous system activity as reflected by all-night electroencephalographic sleep recordings. When data from the total group of 12 depressed patients were examined, there was no correlation between MHPG excretion and total sleep time or slow-wave sleep time. However, a statistically significant inverse correlation was observed between MHPG excretion and the amount of time spent in desynchronized, i.e. REM, sleep (D-time). When the subgroups of depressive disorders were examined separately the inverse correlation between MHPG excretion and Dotime was high and significant in the subgroup with relatively lower MHPG excretion (i.e. the manic~depressive and schizoaffective depressions). MHPG excretion was higher and D-time was lower in two patients studied during hypomanic episodes than during any of the depressive episodes in patients with manicdepressive disorders. Taken in conjunction with pharmacological findings which have suggested an inverse relationship between D-time and central catecholaminergic activity, these findings appear to support the view that MHPG excretion may reflect central noradrenergic activity, particularly an patients with manic~depressive disorders. In summary our studies have showr/: 1. MHPG excretion is higher during hypomanias or manias, intermediate
cxlii
Frontiers in Catecholamine Research
during well intervals, and lower during depressions in patients with naturally occurring or amphetamine-induced manic-depressive disorders; 2. MHPG excretion is significantly lower in patients with manic*depressive depressions than in patients with chronic characterological depressions; 3. Depressed patients with higher MHPG excretion may respond better to treatment with amitriptyline than patients with lower MHPG excretion ; 4. There is an inverse correlation between MHPG excretion and D4ime (i.e. REM sleep time) in patients with affective disorders, particularly in the manicdepressive disorders.
BEHAVIORAL PHARMACOLOGY OF 6-HYDROXYDOPAMINI~
R. I. Schoenfeld and M. J. Zigmond Departments of Psychiatry and Pharmacology, Children's Hospital Medical Center and tlarvard Medical School, Departments of Biology and Psychology, University of Pittsburgh, U.S.A. The ability of 6~hydroxydopamine (6-HDA) to produce a specific degeneration of central catecholamine (CA)-containing neurons offers a unique opportunity to extend our knowledge of the involvement of these neurons in the performance of a conditioned response. At the same time we are provided with an experimental tool useful for testing present theories ~f the mechanism of action of drugs thought to act on CA neurons. The present report will discuss several experiments, utilizing 6-HDA treated rats, which were designed with this dual significance in mind. 6-HDA AND OPERANT BEHAVIOR Administration of 250/ag of 6-HDA into alternate lateral ventricles (with a 48 hour delay between injections) produces an 80-.90% decrease in brain norepinephrine (NE) and a 70-80% decrease in brain dopamine (DA). We have studied the effect of this dosage regimen on the performance of rats trained to lever-press for a water reinforcement. Different schedules of reinforcement were utilized to generate a variety of control response rates and pattbrns. 1. Fixed Ratio (FR)'. This schedule generates a high response rate that is maintained throughout the behavioral test session. Administration of f~HDA to animals trained on this schedule produced a decrease in responding which was apparent after each injection. By the third day after injection, however, 6-HDA treated rats were responding at control levels which were maintained for several
Frontiers in Catecholamine R e s e a r c h
It is noteworthy that despite the fact that both pharmacological and mechanical lesions of the dopamine system lead to a large increase in the endogenous levels of DA the rate of DA synthesis both in vivo and in v i t r o after establishment of this new increased steadyostate level of DA is not significantly different from the rate of DA synthesis in untreated control animals. However, if endogenous levels of DA are increased by treatment with MAO inhibitors the synthesis of DA is markedly retarded. This may in part be explained by the intemeuronal distribution of the increased DA. Possible mechanisms by which dopaminergic neurons control synthesis and release will be discussed.
CATECHOLAM1NE METABOLISM AND AFFECTIVE DISORDERS
Joseph J. Schildkraut Harvard Medical School, Boston, Massaehusets, U.S.A. This paper will summarize aspects of our research on cateeholamine metabolism in affective disorders (depressions and manias), focusing on recent studies of the urinary excretion of 3-methoxy-4~hydroxyphenylglycol (MHPG), a metabolite of norepinephrine which may provide some index of the synthesis and metabolism of norepinephrine in the brain. In one aspect of our research we have examined the changes in MHPG excretion which were asociated with changes in affective state. The findings from our longitudinal studies of patients with naturally occurring or amphetamine-induced manic-depressive episodes indicate that levels of urinary MHPG are relatively lower during depressions and higher during manic or hypomanic episodes than after clinical remissions. However, all depressed patients do not excrete comparably low levels of MHPG ; and recent findings have suggested that MHPG excretion may provide a biological criterion for classifying depressive disorders and for predicting the responses to specific forms of antidepressant pharmacotherapy. In a preliminary study of a small group of depressed patients, favorable responses to treatment with amitriptyline were observed in patients with relatively high levels of urinary MHPG but not in patients with lower levels of MHPG. Differences in physical activity or stress could conceivably account for the differences in MHPG excretion observed in patients with affective disorders. Moreover, the relationship between urinary MHPG excretion and central noradrenergic activity remains an unresolved issue, and one may question whether MHPG (or any biogenic amine metabolite) measured in urine can provide meaningful information about the activity of the central nervous system. In order to explore these issues, we recently compared the urinary excretion of
Frontiers in Catecholamine Research
cxli
MHPG in a small group of patients with various clinically defined subtypes of depressive disorders studied during drug-free periods, and examined our findings for possible relationships between urinary MHPG excretion and clinical measures of motor activity and anxiety as well as electroencephalographic measures of central nervous system activity. MHPG excretion was significantly lower in 5 patients with manic-depressive depressions (i.e. bipolar disorders with histories of hypomanias or manias) than in 5 patients with chronic characterological depressions (i.e. disphoric depressive syndromes with no history of hypomania or mania). In a patient with a schizoaffective depression, MHPG excretion was lower than the mean for manicdepressive depressions, while in a patient with a recurrent endogenous depression (but no history of hypomania or mania) MHPG excretion fell between the means for manic-depressive and chronic chatacterological depressions. These differences in MHPG excretion could not be explained by differences in retardation, agitation and psychic or somatic anxiety as reflected by scores on a modified Hamilton Depression Rating Scale, but may be related to the recent observations of other investigators that platelet monoamine oxidase activity was decreased in patients with bipolar affective disorders as well as schizophrenias but relatively elevated in other types of depressive disorder. In collaboration with Dr. Ernest Hartmann, we also attempted to relate MHPG excretion to certain aspects of central nervous system activity as reflected by all-night electroencephalographic sleep recordings. When data from the total group of 12 depressed patients were examined, there was no correlation between MHPG excretion and total sleep time or slow-wave sleep time. However, a statistically significant inverse correlation was observed between MHPG excretion and the amount of time spent in desynchronized, i.e. REM, sleep (D-time). When the subgroups of depressive disorders were examined separately the inverse correlation between MHPG excretion and Dotime was high and significant in the subgroup with relatively lower MHPG excretion (i.e. the manic~depressive and schizoaffective depressions). MHPG excretion was higher and D-time was lower in two patients studied during hypomanic episodes than during any of the depressive episodes in patients with manicdepressive disorders. Taken in conjunction with pharmacological findings which have suggested an inverse relationship between D-time and central catecholaminergic activity, these findings appear to support the view that MHPG excretion may reflect central noradrenergic activity, particularly an patients with manic~depressive disorders. In summary our studies have showr/: 1. MHPG excretion is higher during hypomanias or manias, intermediate
cxlii
Frontiers in Catecholamine Research
during well intervals, and lower during depressions in patients with naturally occurring or amphetamine-induced manic-depressive disorders; 2. MHPG excretion is significantly lower in patients with manic*depressive depressions than in patients with chronic characterological depressions; 3. Depressed patients with higher MHPG excretion may respond better to treatment with amitriptyline than patients with lower MHPG excretion ; 4. There is an inverse correlation between MHPG excretion and D4ime (i.e. REM sleep time) in patients with affective disorders, particularly in the manicdepressive disorders.
BEHAVIORAL PHARMACOLOGY OF 6-HYDROXYDOPAMINI~
R. I. Schoenfeld and M. J. Zigmond Departments of Psychiatry and Pharmacology, Children's Hospital Medical Center and tlarvard Medical School, Departments of Biology and Psychology, University of Pittsburgh, U.S.A. The ability of 6~hydroxydopamine (6-HDA) to produce a specific degeneration of central catecholamine (CA)-containing neurons offers a unique opportunity to extend our knowledge of the involvement of these neurons in the performance of a conditioned response. At the same time we are provided with an experimental tool useful for testing present theories ~f the mechanism of action of drugs thought to act on CA neurons. The present report will discuss several experiments, utilizing 6-HDA treated rats, which were designed with this dual significance in mind. 6-HDA AND OPERANT BEHAVIOR Administration of 250/ag of 6-HDA into alternate lateral ventricles (with a 48 hour delay between injections) produces an 80-.90% decrease in brain norepinephrine (NE) and a 70-80% decrease in brain dopamine (DA). We have studied the effect of this dosage regimen on the performance of rats trained to lever-press for a water reinforcement. Different schedules of reinforcement were utilized to generate a variety of control response rates and pattbrns. 1. Fixed Ratio (FR)'. This schedule generates a high response rate that is maintained throughout the behavioral test session. Administration of f~HDA to animals trained on this schedule produced a decrease in responding which was apparent after each injection. By the third day after injection, however, 6-HDA treated rats were responding at control levels which were maintained for several