David E. Sternberg

Assessment of α2 adrenergic autoreceptor function in humans: Effects of oral yohimbine

Administration of three oral doses of yohimbine (10 mg, 15 mg, 20 mg) to eight healthy subjects resulted in significant increases in plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG). The 15 mg and 20 mg yohimbine doses induced modest increases in systolic blood pressure and autonomic symptoms such as piloerection and rhinorrhea. Marked behavioral effects such as anxiety were not observed. These results indicate that determination of the plasma MHPG response to yohimbine may be of value in assessing alpha 2 adrenergic autoreceptor function in humans.

The effect of intravenous L-tryptophan on prolactin and growth hormone and mood in healthy subjects

In order to assess the effects of increased central nervous system serotonergic function in humans on prolactin (PRL), growth hormone (GH) and mood, intravenous L-tryptophan (TRP) was administered to ten healthy subjects. The TRP infusion induced robust increases in PRL in all ten subjects. A significant increase in GH concentration was also observed, although the response was more variable. The subjects reported feeling significantly more high, mellow, and drowsy following the TRP infusion in comparison to placebo. These findings indicate an important role for serotonin in PRL and GH secretion, as well as in mood regulation. The intravenous TRP challenge may be of use in the study of serotonergic function in a variety of neurologic and psychiatric diseases.

Plasma homovanillic acid as an index of brain dopamine metabolism: Enhancement with debrisoquin

Plasma levels of the dopamine (DA) metabolite homovanillic acid (HVA) may be a useful measure of brain HVA production by central DA systems. Even though there is a significant peripheral contribution to plasma HVA, experimental manipulations that alter brain HVA produce parallel changes in plasma HVA levels. This study was designed to assess whether the ability of plasma HVA to reflect haloperidol induced increases in brain HVA could be strengthened by reducing the contribution to plasma HVA from peripheral sources. Debrisoquin sulfate, a monoamine oxidase inhibitor that does not enter the brain, was given in a low dose schedule to rats and lowered the peripheral contribution to plasma HVA by between 42 and 68%, resulting in a situation where between 62 and 87% of plasma HVA derived from brain. Using this dose schedule, rats pretreated with debrisoquin displayed a significant increase in plasma HVA following a lower dose of haloperidol than that required in the vehicle pretreated rats. In the debrisoquin pretreated group, a 71% increase in brain HVA was accompanied by a significant 60% increase in plasma HVA, whereas the vehicle pretreated group required a 136% increase in brain HVA to display a significant 50% increase in plasma. These findings indicate that debrisoquin pretreatment improves the reliability of plasma HVA to reflect changes in brain DA metabolism. Plasma HVA samples obtained from humans following debrisoquin may provide a clinically applicable method for assessing brain DA systems in neurologic and psychiatric illness.

Plasma MHPG in depression: Effects of acute and chronic desipramine treatment

The effects of acute and chronic desmethylimipramine (DMI) administration on 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in plasma and urine were examined in eight depressed inpatients. DMI treatment induced an immediate and continuous highly significant reduction in plasma MHPG throughout the 30-day treatment period. This effect was not related to treatment response. In contrast to plasma MHPG, there was no uniform effect of DMI treatment on urinary MHPG. Chronic DMI treatment increased or did not change urinary MHPG in the three treatment responders and decreased urinary MHPG in five nonresponders. The correlation between plasma and urinary MHPG during the placebo period was not significant, and the effect of DMI treatment on the two measures differed markedly.

The effect of IV l-tryptophan on prolactin, growth hormone, and mood in healthy subjects

In order to assess the effects of increased CNS serotonergic function in humans on prolactin (PRL), growth hormone (GH), and mood, IV l-tryptophan (TRP) was administered to ten healthy subjects. The TRP infusion induced robust increases in PRL in all ten subjects. A significant increase in GH concentration was also observed, although the response was more variable. The subjects reported feeling significantly more ‘high’, ‘mellow’, and ‘drowsy’ following the TRP infusion in comparison to placebo. These findings indicate an important role for serotonin in PRL and GH secretion, as well as in mood regulation. The IV TRP challenge may be of use in the study of serotonergic function in a variety of neurologic and psychiatric diseases.

Failure of chronic antidepressant treatment to alter growth hormone response to clonidine

The effect of 4 to 6 weeks of treatment with the antidepressants, desmethylimipramine and amitriptyline, on the growth hormone response to clonidine was studied in 12 depressed patients. In contrast to the reported effects of clonidine in healthy subjects, clonidine did not significantly increase growth hormone secretion in the depressed patients before treatment. The antidepressant treatments did not alter the growth hormone response to clonidine in either treatment responders or nonresponders.

Lithium prevents adaptation of brain dopamine systems to haloperidol in schizophrenic patients

To evaluate the effect of lithium treatment on haloperidol-induced changes of brain dopamine systems, cerebrospinal fluid homovanillic acid (HVA) was assessed in nine patients during a sequential treatment protocol with placebo, lithium, lithium plus acute haloperidol, and lithium plus chronic haloperidol. None of the patients developed tolerance to the rise in HVA during treatment with haloperidol and lithium. Concurrent treatment with lithium appears to prevent the development of tolerance in dopamine metabolism during chronic haloperidol treatment. These data provide the first evidence in man that lithium may prevent neuroleptic-induced functional supersensitivity of brain dopamine systems.

Cerebrospinal fluid hydroxylase cofactor in schizophrenia

Cerebrospinal fluid levels of pterin cofactor were measured in off-medication schizophrenic patients and normal control subjects as one aspect of monoamine physiology in schizophrenia. Pterin cofactor is essential for the hydroxylation of several substances including tyrosine, the rate-limiting step in the synthesis of dopamine and norepinephrine. No significant differences were found. Platelet monoamine oxidase activity correlated significantly with pterin levels in male schizophrenic and in female control subjects.

Schizophrenia: Low spinal fluid GABA levels?

Abstract Cerebrospinal fluid (CSF) GABA levels were determined in the spinal fluid of 17 drug-free schizophrenic patients and of 40 normal volunteers. Following lumbar puncture in fasting patients maintained at bed rest, CSF from the 16th to the 20th cc was collected, placed on ice immediately and frozen at −70°C within one hour. CSF GABA was measured by a modified cation exchange chromatography. Schizophrenic patients showed significantly lower CSF GABA levels (191 ± 9 pmol / ml ) compared to normal controls (233 ± 13 pmol / ml ; p r =0.54) and number of hospitalizations ( r =0.50), but not with severity of psychosis or age of onset. A negative correlation with CSF glucose levels was observed ( r =−0.61). These data suggest that if a GABA deficit is present it only will be observed early in the illness and may disappear with chronicity.

SPINAL FLUID GABA LEVELS IN SCHIZOPHRENIA

Cerebrospinal fluid (CSF) GABA levels were determined in the spinal fluid of 17 drug-free schizophrenic patients and normal volunteers. CSF GABA was measured by a modified cation exchange chromatography method. Schizophrenic patients showed significantly lower CSF GABA levels compared to normal controls (p <. 01). This difference was observed particularly in the women (p <. 005). CSF GABA levels were significantly correlated with the number of hospitalizations (r =. 50) but not with severity of psychosis or age of onset. These data suggest that if a GABA deficit is present it only will be observed early in the illness and may disappear with chronic neuroleptic use. Further studies are necessary.