Leslie F. Major

Dopamine-β-hydroxylase in cerebrospinal fluid and plasma: Effects of α-adrenergic agents

Dopamine-beta-hydroxylase (DBH) and norepinephrine are both localized in noradrenergic storage vesicles. When noradrenergic nerves fire, both norepinephrine and DBH are released by exocytosis. DBH released from the peripheral nervous system and the adrenal medullae is found in blood, while DBH in cerebrospinal fluid (CSF) is presumably of central origin. This study was designed to: (1) investigate the effect of drugs which alter central noradrenergic activity on DBH activity in CSF; and (2) compare the effects of these drugs on DBH in CSF and plasma in cats. Phenoxybenzamine was given subcutaneously at 6 mg/kg and DBH was measured 8 h later. This treatment significantly increased DBH activity in CSF (n = 10,P less than 0.005). There were no consistent changes in plasma DBH, although there was a tendency for DBH to increase from low basal levels and to decrease from high basal levels. Clonidine was administered in 4 subcutaneous injections (100, 50, 50, 50 microgram/kg) over a 19-h period, and blood and CSF were taken 5 h after the last injection. This treatment caused a significant decrease in CSF DBH activity (P less than 0.05, n = 8). The effect of clonidine on plasma DBH was strongly dependent on the basal enzyme level. The 3 lowest DBH values increased and the 5 highest DBH values decreased on drug treatment. These results are discussed with respect to the theory that changes in CSF DBH may reflect central noradrenergic activity.

The central noradrenergic system and affective response to MAO inhibitors

1. In humans, norepinephrine (NE) has been postulated to be involved in the regulation of mood and behavior and to be altered in patients with manic-depressive illness. 2. Recent methodological advances have made possible a more direct assessment of central noradrenergic activity by the accurate measurement of the small amounts of NE and of the enzyme responsible for the conversion of dopamine to NE, dopamine-beta-hydroxylase (DBH), found in cerebrospinal fluid (CSF). 3. Cerebrospinal fluid samples were obtained from depressed patients both before and after treatment with two monoamine oxidase-inhibiting antidepressant drugs, clorgyline and pargyline. 4. Patients were rated twice daily by nursing staff on a modified 15-point scale for severity of global depression and anxiety. Patients were also rated using the Hamilton depression rating scale. 5. High negative correlations were observed between the drug-related changes in CSF NE and the changes in depression ratings on both the global ratings (r = -.95, p less than .001) and the Hamilton rating scale (r = -.81, p less than .01). Changes in NE were also highly correlated with changes in global anxiety ratings (r = -.85, p less than .01) calculated on the basis of changes from baseline for each measurement. Drug-related changes in CSF DBH similarly showed negative correlations with clinical response (r = -.79, r = -.38, r = -.68 respectively). In contrast, no significant correlations were found when drug-related changes in CSF MHPG were compared to changes in clinical state.

Central noradrenergic adaptation to long-term treatment with imipramine in rhesus monkeys

Rhesus monkeys were treated with the antidepressant drug imipramine; cerebrospinal fluid norepinephrine and dopamine-beta-hydroxylase were measured to assess central noradrenergic activity. Large changes occurred after short-term, but not long-term, treatment. Biochemical stabilization occurs at the time when therapeutic effects are seen in patients.

Dopamine-β-hydroxylase activity and ethanol-induced sleep time in selectively bred and heterogeneous stock mice

Dopamine-β-hydroxylase (DBH), the enzyme responsible for the conversion of dopamine to norepinephrine, was measured in the plasma of two lines of mice selectively bred for differential sensitivity to hypnotic doses of ethanol. Plasma levels of DBH were measured by radioenzymatic assay in long sleep (LS) and short sleep (SS) male and female mice which had no prior exposure to ethanol. LS mice had significantly higher plasma DBH activity than did SS mice, although no significant sex difference was found. Fusaric acid, an inhibitor of both central and peripheral DBH, attenuated sleep time induced by either 3 or 4 g/kg ethanol in mice of a heterogeneous genetic stock. The results of these experiments may further implicate noradrenergic systems in mediating some of the depressed effects of ethanol.

Elevated cerebrospinal fluid histidine in alcohol withdrawal

Cerebrospinal fluid (CSF) histidine concentration was significantly elevated in seven patients early in the alcohol withdrawal syndrome (206.3 +/- 74.4 (SEM) nanomols/ml CSF). When these same patients were restudied an average of six days later when alcohol withdrawal was clinically resolved, their mean CSF histidine concentration continued to be significantly elevated (164.7 +/- 24.7) when compared to normal (12.0 +/- 0.5 nanomols/ml CSF). Other amino acids (aspartic acid, serine, alanine, methionine, leucine, tyrosine, phenylalanine, lysine and arginine) showed no definite changes from normal, and no change during the course of alcohol withdrawal. Possible reasons for these high concentrations and the extreme variability (especially early in alcohol withdrawal) are discussed.

Adrenergic nervous system alteration and ethanol-induced narcosis in long-sleep and short-sleep mice.

Long-sleep (LS) and short-sleep (SS) mice were pretreated with either propranolol or phentolamine, followed by a hypnotic dose of ethanol. Pretreatment with propranolol, but not phentolamine, significantly reduced ethanol sleep time in LS mice. The SS mice were not affected. In a second study propranolol pretreatment was given subsequent to ethanol at various doses, different for each line, that produced similar sleep time durations in both lines. Under these conditions, propranolol decreased sleep time in both LS and SS mice. These data lend support to the idea that noradrenergic mechanisms play a role in the mediation of the hypnotic effects of ethanol.

Dopamine-β-Hydroxylase in Cerebrospinal Fluid

Dopamine-β-hydroxylase (DBH), the biosynthetic enzyme for norepinephrine, is unique among enzymes in that it is localized with a neurotransmitter in storage vesicles and is released with the transmitter during nerve firing. After release, norepinephrine binds to a receptor on a postsynaptic or effector cell, but the released DBH has no known physiological function. Although the exocytotic release of DBH has no readily apparent value to the cell, its release is potentially of great value for neuroscientists. DBH released from noradrenergic tissue can be measured in plasma and cerebrospinal fluid (CSF), and such measurements may give a chemical evaluation for noradrenergic activity in vivo.80a This chapter reviews and evaluates studies on DBH in CSF, with special reference to the theory that DBH activity in CSF may reflect central noradrenergic activity.