Changes In MHPG Research Articles

Salivary 3‐methoxy‐4‐hydroxyphenylglycol increases after awakening in healthy young adults

Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) may reflect central noradrenergic activity. In this study, we investigated salivary MHPG changes after awakening, and explored their relationships with cortisol and peripheral autonomic activity. The participants were 25 college students. Saliva samples were collected on awakening and 30 min after awakening to determine MHPG and cortisol. Ambulatory electrocardiograms were obtained to assess heart rate, cardiac sympathetic index (CSI), and cardiac vagal index (CVI) before and after awakening. MHPG levels increased significantly during the first 30 min after awakening. Similarly, cortisol, heart rate, and CSI increased during the 30 min after awakening, but changes in MHPG did not correlate with changes in cortisol, heart rate, CSI, and CVI during that period. This study demonstrated that salivary MHPG levels increase after awakening, in common with cortisol, heart rate, and cardiac sympathetic activity.

A Possible Paradigm Shift

This month, guest editors Laura N. Antar, MD, PhD, and Eric Hollander, MD, and colleagues examine hypotheses about the relationship between inflammation and psychiatric illness. Their articles focus on a possible mechanism of psychiatric disorders that could constitute a major paradigm shift. As a psychiatry resident in the 1960s, I was taught that depression was caused by “anger turned inward,” rather than the humoral theories based on early Greek and Chinese medicine. About the same time, the effectiveness of antipsychotics was becoming realized with the use of chlorpromazine. This, taken together with the antidepressant effects of imipramine and iproniazid, led to the psychopharmacologic revolution and a marked increase in neurobiologic research. Following my residency, I was a fellow at the National Institute of Mental Health (NIMH), also in the mid-1960s, where I was focused on the norepinephrine depletion theory of depression. Also at that time, the NIMH was investigating the role of serotonin. We discovered changes in MHPG (a metabolite of norepinephrine) in patients with depression and our excitement grew. Had we established a biochemical basis for depression? My excitement was immense. The development of fluoxetine in the midto late-1980s shifted the attention to selective serotonin reuptake inhibitors (SSRIs). It was a new twist on the neurotransmitter theme, ultimately becoming the dominant truth. For a while, norepinephrine was nearly forgotten, as was dopamine, despite the fact that it is key in hedonic functions (one of the primary dysfunctions in depression). Maybe the avoidance of developing more potent dopaminergic medications was due to the fear of developing addictive substances. As the therapeutic limitations of the new-generation antidepressants that were more specific in their effect became evident, the field started to realize that the “dirtier” the drug (meaning it affected more neurotransmitters), the more effective it might be for treatment-resistant patients. (Tricyclic antidepressants and monoamine oxidase inhibitors are in this category.)

Chronological Changes of Plasma Homovanillic Acid (HVA) and 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG) Levels in 4 Patients with Temporal Lobe Epilepsy who Developed Psychosis‐Like Symptoms (Hallucination and Delusion) During Zonisamide (ZNS) Administration.

Purpose: Zonisamide (ZNS) is a relatively new antiepileptic drug with an extensive therapeutic spectrum. However, ZNS can produce psychiatric side effects. In this study, we serially measured plasma hoinovaniliic acid (HVA) and 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG) levels in 4 patients with epilepsy who developed psychosis‐like symptoms (hallucinations and delusions) during ZNS administration. Methods: Subjects comprised 4 patients (3 males and 1 female) with temporal lobe epilepsy ranging in age from 18 to 28 years. Intervals from the start of ZNS administration to the appearance of psychiatric symptoms ranged from 36 to 707 days. Intervals from achievement of the maximal dose to the appearance of psychiatric symptoms ranged from 2 to 240 days. In these 4 patients, the maximal doses of ZNS ranged from 300 to 600 mg/day. In 3 cases, serum ZNS levels were within the effective therapeutic concentration range wlicn syinptoms appeared. However, in 1 case, the serum ZNS level exceeded thc therapeutic level. In all cases, psychiatric symptoms disappeared after ZNS was switched to other antiepileptic drugs and anti‐psychotic agents (2‐5 mg/day of haloperidol or 10 mg/day of thioridazine) were added. In these cases, we serially measured plasma HVA and MHPG concentrations. Results: Case 1 was a 28‐year‐old male. Delusions of persecution appeared 190 days after ZNS administration was started. HVA levels at the appearance of psychiatric symptoms were 12.7 ng/ml and HVA levels at the disappearance of psychiatric symptoms were 7.4 ng/ml. MHPG levels at the appearance of psychiatric symptoms were 14.5 ng/ml and MHPG levels at the disappearance of psychiatric symptoms were 6. I ng/ml. When psychiatric symptoms appeared, the plasma HVA level was increased, whereas the MHPG level was slightly increased.Case 2 was an 18‐year‐old female. Auditory hallucinations appeared 320 days after ZNS first was administered. HVA levels at the appearance of psychiatric symptoms were 9.6‐ 10.0 nghl and HVA levels at the disappearance of psychiatric symptoms were 5.3–6.1 ng/ml. MHPG levcls at the appearance of psychiatric symptoms were 4.14.2 ng/ml and MHPG levels at the disappearance of psychiatric symptoms were 3.1 ng/ml. When psychiatric symptoms appeared, the plasma HVA level was increased, but there was no increase in MHPG.Case 3 was an 18‐year‐old male. Delusion of persecution appeared 707 days after ZNS administration was started. HVA levels at the appearance of psychiatric symptoms were 10.6 ng/ml and HVA levels at the disappearance of psychiatric symptoms were 7.2 ngiml. MHPG levels at the appearance of psychiatric symptoms were 5.3 ng/ml and MHPG levels at the disappearance of psychiatric symptoms were 3.9 ng/ml. When psychiatric symptoms appeared, plasma HVA level was increased, while the MHPG level was slightly increased.Case 4 was a 20‐year‐old male. Auditory hallucination appeared 36 days after ZNS was administered. HVA levels at the appearance of psychiatric symptoms were 13.6 ng/ml and HVA levels at the disappearance of psychiatric symptoms were 7.2 ng/ml. MHPG levels at the appearance of psychiatric symptoms were 5.4 ng/ml and MHPG levels at the disappearance of psychiatric symptoms were 6. I ng/ml. When psychiatric symptoms appeared, the plasma HVA level was increased, but there was no increase in MHPG. Conclusions: In all patients, the plasma HVA levels at the appearance of psychiatric symptoms was higher than the corresponding level at time of disappearance of psychiatric symptoms. Psychiatric symptoms may have been associated with activation of dopaniine by ZNS. MHPG levels were slightly increased in 2 cases. However, in thc other 2 cases, there were no changes in MHPG. The influence of ZNS on neurotransmitter metabolites should be further investigated in a larger nuniber of patients.

Endocrine and amine responses to D,L-fenfluramine in normal subjects

To investigate indirectly the central neurotransmitter mechanisms of d,l-fenfluramine-induced hormone release, prolactin, adrenocorticotropic hormone, cortisol, growth hormone, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) responses to d,l-fenfluramine (60 mg, oral) were examined in a single-blind, placebo-controlled trial in 14 normal subjects. As compared with placebo, d,l-fenfluramine significantly increased both prolactin and cortisol. There was a significant correlation between the cortisol and prolactin responses. HVA levels were also significantly increased, but there were no changes in MHPG or 5HIAA. The elevation in HVA significantly correlated with increases in both prolactin and cortisol. These findings are consistent with recent animal studies suggesting that d,l-fenfluramine-induced prolactin and cortisol release may be mediated, at least in part, by catecholaminergic systems.

Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and growth hormone responses to yohimbine in panic disorder patients and normal controls

Eleven patients with a DSM-III diagnosis of panic disorder and seven normal controls received yohimbine (20 mg) or placebo orally in a double-blind paradigm on two separate days. Compared to normal control subjects, the panic disorder patients had similar behavioral responses to placebo but a greater anxiogenic response to yohimbine. Compared to placebo, yohimbine produced a significant increase in plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) levels ( p<0.02), with a trend toward greater MHPG rises in the panic disorder patients compared to the normal controls. In the patients, but not in the controls, there was a significant positive correlation between yohimbine-induced peak changes in MHPG and increased ratings of panic anxiety. Yohimbine had no effect on plasma growth hormone (GH) levels in either patients or controls. These results are discussed within the context of the noradrenergic theory of panic disorder.

Modulation by corticotropin-releasing factor of monoamine metabolism in the lateral hypothalamus

Corticotropin-releasing factor (CRF) was injected into the lateral hypothalamus of conscious unrestrained rats and the local concentration of monoamines in the vicinity of the microinjection monitored by microdialysis. The concentration of norepinephrine and MHPG in the dialysis fluid from the lateral hypothalamic areas of rats fasted for 24 h was nearly 4 times higher than in fed rats. Following the injection of 2 μg of CRF into the lateral hypothalamus of fasted rats there was a rapid decline in levels of both norepinephrine and 3-methoxy-4-hydroxyphenylglycol (MPHG) to the level in fed rats after 60–90 min. The changes in MHPG and norepinephrine in the fed rats were not significant. There was no difference in serotonin concentration between fasted and fed animals, although the mean value for 5-hydroxyindoleacetic acid (5-HIAA) was slightly increased. Following the injection of CRF, there was a fall in serotonin in the fed rats but not in the fasted animals. There was a fall in the concentration of 5-HIAA in both the fasted and fed rats so that at 30, 60 and 90 min their concentrations were not significantly different. The concentration of DOPAC in the lateral hypothalamus was twice as high in the fasted as in the fed rats. Following injection of CRF there was a rapid decline in DOPAC concentrations in the fasted rats and a small decline in the fed rats. By the end of 30 min after the injection of CRF, concentrations of DOPAC were similar in fed and fasted rats. The studies are consistent with the hypothesis that CRF may depress feeding by altering monoamine metabolism in the lateral hypothalamus to the pattern of a fed rat.

The effects of carbon dioxide inhalation of plasma MHPG, plasma hormones respiratory rate, and behavior in the Rhesus monkey

The effects of inhalation of air and 3 concentrations of carbon dioxide (CO2) on plasma levels of the norepinephrine metabolite, MHPG, plasma hormones, and behavioral activation were assessed in eight chair-adapted Rhesus monkeys (Macaca mulatta). In comparison to air, inhalation of 5%, 7.5% and 10% CO2 for 180 minutes produced significant dose-dependent increases in respiratory rate, plasma MHPG, cortisol, growth hormone and prolactin. CO2 at the 7.5% concentration produced peak changes in behavior at 15, growth hormone at 30, and cortisol and MHPG at 180 minutes without producing changes in prolactin. The lack of previously reported CO2 induced changes in MHPG, growth hormone and prolactin in humans exposed to 7.5% CO2 for only 15 minutes, may therefore relate to the relatively short duration of CO2 exposure.

Source and physiological significance of plasma 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol

To elucidate the source and physiological significance of plasma 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) as metabolites of noradrenaline (NA), unlabeled and tritium-labeled NA ([ 3H]NA) were infused into conscious rats and the formation of labeled and unlabeled DHPG and MHPG examined. Animals were pretreated with clorgyline to determine the effects of inhibiting monoamine oxidase type A (MAO-A), with desipramine to determine the effects of blockade of NA neuronal uptake, or with reserpine to determine the effects of interference with vesicular translocation of NA. Inhibition of neuronal uptake prevented the formation of DHPG from exogenous NA and halved the formation of MHPG, indicating that DHPG is derived from NA metabolized intraneuronally and that MHPG is derived from NA metabolized extraneuronally and from DHPG produced intraneuronally. Blockade of vesicular translocation of NA with reserpine increased DHPG formation from exogenous NA by 300% and MHPG formation by 70%, consistent with enhanced availability of NA in the neuronal cytoplasm for metabolism by MAO-A. About 74% of NA recaptured by sympathetic nerves was estimated to be sequestered into storage vesicles. Endogenous DHPG and MHPG were derived mainly (60–70%) from leakage of NA from storage vesicles and to a smaller extent (30–40%) from NA recaptured after exocytotic release. An increased plasma DHPG to NA ratio with no change in the MHPG to NA ratio during infusions of physiologically active NA demonstrated that changes in plasma MHPG do not necessarily follow changes in DHPG. Consideration of the intra- and extraneuronal sources of plasma DHPG and MHPG, their main derivation from NA directly released into the neuronal cytoplasm and the influences of neuronal uptake and translocation of NA into storage vesicles is essential for the correct interpretation of plasma concentrations of these metabolites in the evaluation of sympathetic nervous function.

The effect of lithium on urinary MHPG in unipolar and bipolar depressed patients.

Twenty-four hour urinary excretion of 3-methoxy-4-hydroxphaeylglycol (MHPG), the metabolite thought best to reflect brain norepinephrine metabolism, was studied longitudinally in ten depressed patients before and during the acute and chronic phases of lithium treatment. Five of the patients were identified as bipolar I (prior history of mania), 3 as bipolar II (history of hypomania) and 2 as unipolar (history of depression). During acute lithium administration (first week) there was no consistent pattern of change in MHPG. Comparing the predrug period with the third and fourth week of treatment, all of the responders showed an increase in MHPG, while the non-responders showed no change or a decrease. It is concluded that the change in clinical state is the most important variable contributing to MHPG changes in these patients. There was a tendency for the pretreatment MHPG excretion to be low in the patients who went on to show a clear-cut antidepressant response to lithium compared to those who were unequivocal non-responders. The predrug MHPG for the bipolar patients (prior history of mania) was significantly lower than the unipolar patients, a difference which apparently contributes to the lower MHPG in the lithium responders, all of whom were in the bipolar group.