Dopamine-beta-hydroxylase deficits in the brains of schizophrenic patients.

Postmortem brain specimens from 18 schizophrenic patients and 12 normal controls were assayed for dopamine-beta-hydroxylase (DBH), the enzyme responsible for the final step in norepinephrine biosynthesis. There was a significant reduction in the DBH activity of the schizophrenic group in all brain regions examined. Enzyme deficits in hippocampus and diencephalon were somewhat larger than that in pons-medulla. Since various extraneous factors, such as non-specific deterioration, drug treatment, duration of hospitalization, cause of death, sex, and age could be ruled out, the deficits in DBH mnay be associated with the schizophrenic disease process. These findings are consistent with the hypothesis that noradrenergic "reward" pathways are damaged in schizophrenia.

Possible etiology of schizophrenia: progressive damage to the noradrenergic reward system by 6-hydroxydopamine.

Single or repeated intraventricular injections of 6-hydroxydopamine caused marked and long-lasting deficits in brain self-stimulation and other rewarded behaviors in the rat. The behavioral deficits, as well as the depletion of brain norepinephrine induced by 6-hydroxydopamine, were prevented by prior treatment with chlorpromazine. Episodic or continuous formation of endogenous 6-hydroxydopamine in man as a result of a genetically determined enzymatic error could selectively damage the binding capacity and, eventually, the structural integrity of the noradrenergic reward mechanism. Such damage might cause the fundamental symptoms and long-term downhill course of schizophrenia.

Facilitation of brain self-stimulation by central administration of norepinephrine.

Rats with electrodes implanted in the medial forebrain bundle stimulated their own brains at sharply reduced rates after systemic administration of disulfiram or intraventricular administration of diethyldithiocarbamate. Both drugs inhibit dopamine-beta-hydroxylase, the enzyme responsible for the final step in the biosynthesis of norepinephrine. The suppressed behavior was reinstated by intraventricular injections of 1-norepinephrine, but not by injection of its biologically inactive isomer, d-norepinephrine. Intraventricular administration of dopamine and serotonin did not restore self-stimulation. The rewarding effect of medial forebrain bundle stimulation may depend on the availability of norepinephrine as a transmitter, but not on dopamine or serotonin.

Nerve growth factor: enhanced recovery of feeding after hypothalamic damage.

A single intraventricular injection of nerve growth factor (NGF). given at the time of brain damage, facilitated the course of recovery from the lateral hypothalamic anorexic syndrome in male rats. In the second and third weeks after the trauma, NGF-treated rats ate more food, regained body weight more rapidly, and fed more vigorously in response to intraventricular administration of norepinephrine than untreated controls. After full recovery, rats that had been treated with NGF were resistant to reinstatement of the hypothalamic syndrome by 6-hydroxydopamine. NGF may facilitate behavioral recovery by promoting the development of supersensitivity to norepinephrine and possibly also by stimulating the growth of regenerating noradrenergic neurons in the brain.

Benzodiazepines: anxiety-reducing activity by reduction of serotonin turnover in the brain.

The anxiety-reducing effects of minor tranquilizers in the rat conflict test were mimicked by serotonin antagonists and by p-chlorophenylalanine, an inhibitor of serotonin synthesis; the depressant effects of the minor tranquilizers were mimicked by norepinephrine antagonists. Intraventricular injections of serotonin led to a suppression of behavior, and also antagonized the anxiety-reducing action of benzodiazeprines. Intraventricular injections of norepinephrine led to a release of punished behavior from suppression, and also antagonized the depressant action of benzodiazepines. The anxiety-reducing activity, and the decrease in serotonin turnover induced by benzodiazepines, were maintained over repeated doses, whereas depressant activity, and the decrease induced in norepinephrine turnover, both rapidly underwent tolerance. Tranquilizers may exert their anxiety-reducing effects by a reduction of serotonin activity in a behaviorally suppressive punishment system, and they may exert their depressant effects by a reduction of norepinephrine activity in a behaviorally facilitatory reward system.

Norepinephrine: reversal of anorexia in rats with lateral hypothalamic damage.

Injection of norepinephrine in the lateral ventricles of rats recovering from lateral hypothalamic anorexia caused immediate feeding and, frequently, overeating. Intraventricular administration of the alpha-noradrenergic blocker, phentolamine, suppressed feeding in both normal rats and rats that had recovered from lateral hypothalamic lesions. Feeding is reinforced by ascending medial forebrain bundle fibers that form alpha-noradrenergic synapses in the hypothalamus and forebrain. Damage to these fibers suppresses feeding by reducing noradrenergic transmission and, hence, the rewarding value of food. Recovery of feeding after hypothalamic lesions coincides with the recovery of noradrenergic reward function.

Dopamine-beta-hydroxylase, monoamine oxidase, and schizophrenia.

Plasma dopamine-beta-hydroxylase (DBH) activity was studied in two different populations of chronic schizophrenic patients and assayed by two independent laboratories. No significant difference between schizophrenic patients and normal controls was found although in both groups chronic undifferentiated schizophrenics with paranoid features had a trend towards lower DBH activity than the other patients and controls. In addition, DBH and monoamine oxidase (MAO) activities were studied in 13 schizophrenic patients and available first degree-relatives. There was no association of low MAO and low DBH activities within the schizophrenic families.

Benzodiazepines: behavioral and neurochemical mechanisms.

The therapeutic effects of benzodiazepines in psychoneurosis may depend in part on their ability to release or disinhibit a patient's anxiety-suppressed gratification-seeking behavior. Benzodiazepines may disinhibit behavior by reducing the activity of serotonin (and possibly acetylcholine) neurons in the brain's "punishment" system. Reduction of serotonin transmission may be due to a facilitation of gamma-aminobutyric acid (GABA)-mediated presynaptic inhibition at the serotonin nerve terminal.

Lymphocyte monoamine oxidase and plasma prolactin and growth hormone in tardive dyskinesia.

Twelve elderly women with tardive dyskinesia were matched with 12 patients without dyskinesia. Lymphocyte monoamine oxidase (MAO) activity and plasma prolactin and growth hormone concentrations were determined "blind" in these 12 pairs of patients. Chronic schizophrenic patients with tardive dyskinesia had significantly lower lymphocyte MAO activity as compared to controls. Organic brain syndrome patients with dyskinesia did not differ from controls in the lymphocyte MAO activity. These results with lymphocyte MAO parallel our earlier findings on platelet MAO. No significant differences were found between dyskinesia group and controls in the plasma prolactin and growth hormone concentrations. Possible implications of our findings are discussed.

Inhibition of neuroleptic binding by human brain extracts--an effect of endogenous dopamine?

Extracts of autopsied human brain tissue exhibited a specific inhibition of [3H]spiroperidol binding, in support of previous reports. The extent of binding inhibition varied depending upon the brain region from which the tissue was taken. We observed two peaks of inhibition binding from extracts of caudate or putamen placed on a Sephadex G10 column. Results of experiments to characterize the extract in the second peak indicate a correlation between inhibition of spiroperidol binding and dopamine content of the tissue. The content of the first peak could not be definitively identified but indirect evidence indicates that it may be a high molecular weight conjugate of dopamine that is formed at low concentrations. No evidence was obtained to suggest the existence of previously undetected neuroleptic-like material in human brain.

Monoamine oxidase in schizophrenia: an overview.

A brief history and summary of studies designed to elucidate the role of monoamine oxidase (MAO) in schizophrenia are presented. The majority of these studies have reported a decrease in the platelet enzyme activity of chronic schizophrenic patients when compared to controls. Difficulties encountered when comparing MAO activity measured in different patient populations are also considered. Finally, the significance of decreased platelet MAO activity is discussed with respect to its possible etiological role in some forms of schizophrenia.

Platelet monoamine oxidase: studies on the rate of heat inactivation in normal and in paranoid and nonparanoid chronic schizophrenic groups.

The heat inactivation curves for platelet monoamine oxidase (MAO) in chronic schizophrenic and normal subjects were virtually identical. There were also no differences found when schizophrenic patients were subgrouped into paranoid and nonparanoid types. However, the MAO from one of the normal subjects showed a substantially greater thermolability than that of any other control or schizophrenic subject.

A probable neuroleptic effect on platelet monoamine oxidase in chronic schizophrenic patients.

Platelet monoamine oxidase activity (MAO) was studied serially over time in 16 chronic schizophrenic patients when medication free and then when medicated. Thirteen of the 16 patients had significant decreases in platelet MAO activity following neuroleptic drug treatment. The change in MAO activity was found to be correlated with response to treatment and to dose of medication.

Some kinetic parameters of platelet monoamine oxidase in chronic schizophrenia.

The michaelis constants (Vmax and Km) for platelet monoamine oxidase (MAO) with tyramine as substrate are found to be significantly lower in chronic schizophrenic patients than in normal controls. Furthermore, these kinetic parameters for the MAO of paranoid chronic schizophrenics are significantly lower than those for nonparanoid chronic schizophrenics. Paranoid chronic schizophrenia may be a separate biochemical disorder from other chronic schizophrenias.

Schizophrenic outcome in late life: symptom state and platelet monoamine oxidase activity.

Reported here are the results of a study of symptom state, platelet monoamine oxidase (MAO) activity, and demographic variables in a group of elderly neuroleptic-free schizophrenics. Analyzed by both bivariate and multivariate techniques, the data from this sample indicate that after the effects of demographic variables upon the variance of enzyme activity have been controlled for, the patients most likely to continue to manifest schizophrenic symptomatology in the senium are those with low platelet MAO activity. The results are discussed with respect to other studies of platelet MAO and prognosis in schizophrenia and with respect to future studies.

A biochemical study of tardive dyskinesia in young male patients.

Based on specific criteria, tardive dyskinesia was diagnosed in 6 out of 29 young schizophrenic male inpatients. We compared several biochemical parameters in these six dyskinesia patients with those in six matched controls. The patients with dyskinesia had significantly lower platelet monoamine oxidase activity and significantly higher plasma dopamine-beta-hydroxylase activity as compared with the controls, thus confirming our previous findings in a population of elderly female inpatients. The dyskinetic and nondyskinetic groups did not differ from each other in mean whole blood serotonin concentration and mean serum neuroleptic concentration as measured with a radioreceptor binding assay. Possible significance of our results is discussed.

Possible role of dopamine-beta-hydroxylase in the regulation of norepinephrine biosynthesis in rat brain.

In Experiment 1, the dose-response effects of three dopamine-beta-hydroxylase (DBH) inhibitors (diethyldithiocarbamate, FLA-63 and U-14, 624) on the endogenous levels of norepinephrine and dopamine in pons-medulla of rat brain were determined. In Experiment 2, the effect of low doses of diethylithiocarbamate (2.5 to 120 mg/kg) on the level of norepinephrine-3H produced from dopamine-H3 was determined. The data obtained by extrapolation of the curves in both experiments provided an estimation of the in vivo level of DBH activity and suggested that it was not present in excess. Finally, in Experiment 3, the three DBH inhibitors reduced self-stimulation (a behavior dependent upon catecholamines) in a dose-related manner and intraventricular injections of 1-norepinephrine reinstated normal rates of self-stimulation. The results from the three experiments are consistent with the idea that DBH is involved in the regulation of norepinephrine biosynthesis. The relationship of this finding to our earlier report of a deficit of DBH in post-mortem brains of schizophrenics is discussed.