Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics.

BACKGROUND: Impulsive violence, suicide, and depression are strongly associated with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA). Increased suicide and trauma reported in some cholesterol-lowering trials may be related to altered concentrations of polyunsaturated fatty acids rather than cholesterol, a possible surrogate marker. METHODS: CSF 5-HIAA and homovanillic acid (HVA), total cholesterol, and plasma fatty acid concentrations were examined in 176 subjects, including 49 healthy volunteers, and 88 early- and 39 late-onset alcoholics. RESULTS: Among each group, polyunsaturated fatty acids predicted both CSF 5-HIAA and CSF HVA concentrations, but total cholesterol was unrelated to either neurotransmitter metabolite. The relationships between plasma 22: 6n3 and CSF 5-HIAA were significantly different when healthy volunteers (r = .35) were compared to early-onset alcoholics (r = -.38) (p < .0002). CONCLUSIONS: Dietary studies are indicated to determine if essential fatty acid supplementation can influence central nervous system serotonin and dopamine metabolism and modify impulsive behaviors related to these neurotransmitters.

Effects of morphine administration on catecholamine levels in rat brain; specific reduction of epinephrine concentration in hypothalamus.

The effects of morphine administration on concentrations of epinephrine, norepinephrine and dopamine were examined in the rat brain. Morphine injection reduced the epinephrine level only in the hypothalamus, while the norepinephrine level was reduced in the hypothalamus, medulla, and locus coeruleus. The dopamine concentration was elevated in all regions examined. These changes were blocked by administration of naloxone. Repeated injection of morphine for 14 days did not affect any catecholamine level. In naloxone-induced withdrawal, epinephrine was most markedly depleted in hypothalamus. These observations suggest that the epinephrine level in hypothalamus is affected by morphine acting on opioid receptors.

Modification of gonadectomy-induced increases in brain monoamine metabolism by steroid hormones in male and female rats.

Concentrations of monoamines (dopamine, DA; serotonin, 5-HT) and their major metabolites (homovanillic acid--HVA; dihydroxyphenylacetic acid--DOPAC; 5-hydroxyindolacetic acid--5-HIAA) were measured in selected brain areas of chronically gonadectomized, steroid- or oil-treated male and female rats. Concentrations of DOPAC and HVA were markedly increased in the hypothalamus (male, female), striatum (male, female) and brainstem (male) following gonadectomy, whereas the levels of DA remained unaltered in most of the brain areas examined. Most of the changes were reversed or attenuated by chronic estradiol (EB) substitution. In contrast, chronic treatment with physiological concentrations of testosterone (TP) reduced indexes of DA turnover only in the striatum of ovariectomized (OVX) and brainstem of orchidectomized (ORDX) rats. ORDX-related increases in striatal levels of DOPAC and HVA were not reversed by either EB or TP. ORDX increased the levels of 5-HIAA (hypothalamus, striatum) and decreased those of 5-HT (hypothalamus, hippocampus). These changes were reversed by chronic treatment with either TP or EB. Brain metabolism of 5-HT remained unaltered following OVX. Gonadectomy and chronic steroid replacement therapy appear to alter brain monoamine metabolism in a brain region and sex-dependent manner. Our data demonstrate that gonadectomy-related increases in the activity of brain monoaminergic neurons in both male and female rats was attenuated more effectively with physiological concentrations of estradiol than with testosterone. Insensitivity of monoaminergic neurons in a number of brain areas (e.g., hypothalamus, striatum) to the action of testosterone was evident in both sexes.

Low affinity hypothalamic [3H]mazindol binding: a probe for hypothalamic body weight regulation?

It has been previously suggested that low affinity [3H]mazindol binding in the hypothalamus correlates with body weight and obesity. Low affinity [3H]mazindol binding in hypothalamic crude synaptosome preparations was carried out in normoglycemic obese mice (C57 B1/6J ob/ob) as well as in their lean littermates (C57 B1/6J +/?). NIH Swiss mice were used as additional controls. Furthermore the effect on this binding site of repeated electroconvulsive shock (ECS), a treatment known to change body weight gain, was studied in rats. Neither Bmax nor Kd were altered in obese mice compared with their lean littermates or NIH Swiss mice. The obese mice had a significantly greater body weight and weight gain than either control group. Once-daily ECS over 10 days (which significantly reduced weight gain in rats) did not change binding parameters for [3H]mazindol in hypothalami. The present data do not appear to support the hypothesis that this low affinity binding site has a physiological function in the control of body weight and obesity, at least in the examined paradigm.

Diabetes-induced changes in monoamine concentrations of rat hypothalamic nuclei.

Streptozotocin-induced diabetes produced marked alterations of monoamine concentrations in several hypothalamic nuclei of male and female rats. Norepinephrine (NE) concentrations were significantly elevated in the median eminence (ME), supraoptic nucleus (SON) and periventricular nucleus (PEVN) in both sexes of diabetic rats. NE concentrations in the suprachiasmatic nucleus (SCN) and ventromedial nucleus (VMN) of male and female diabetic animals remained unaltered. Serotonin (5-HT) concentrations were increased in PEVN of male and female diabetic rats. No significant changes in hypothalamic dopamine (DA) concentrations were observed. Insulin treatment reversed the diabetes-related changes in monoamine concentrations in most of the nuclei. The significance of these biochemical changes relative to the endocrine and behavioral abnormalities in diabetes is discussed.

Serotonin turnover in discrete hypothalamic nuclei and mesencephalic raphe nuclei of young and adult spontaneously hypertensive rats.

Serotonin levels and turnover were analyzed in discrete forebrain and mesencephalic nuclei of young (4-week-old) and adult (14-week-old) spontaneously hypertensive rats and age-matched normotensive control Wistar Kyoto rats. Most changes observed were age-dependent, and occurred only in young, early hypertensive rats. Both serotonin levels and the accumulation rate of 5-hydroxy-tryptophan after L-amino acid decarboxylase inhibition were higher in the nuclei periventricularis and paraventricularis of the hypothalamus of young hypertensive rats than in controls. In addition, 4-week-old spontaneously hypertensive rats showed higher 5-hydroxytryptophan accumulation rates in the nuclei supraopticus and dorsomedialis of the hypothalamus than controls. The only difference in serotonin metabolism found in adult hypertensive rats was high serotonin concentration in the median eminence of the hypertensive animals. Our results suggest the presence of anatomically specific, age-dependent alterations in serotonin metabolism, localized to selected hypothalamic nuclei in young hypertensive rats. These data support a role for the hypothalamic serotonin in the development of the spontaneous (genetic) hypertension in the rat.

Serotonin and 5-hydroxyindoleacetic acid in brains of suicide victims. Comparison in chronic schizophrenic patients with suicide as cause of death.

Serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations were determined in various brain areas of nonschizophrenic suicide victims, chronic schizophrenic patients with or without suicide as the cause of death, and normal control subjects without psychiatric or neurologic disorders. Serotonin concentrations in the basal ganglia were significantly elevated in suicide victims and chronic schizophrenic patients, as were 5-hydroxyindoleacetic acid concentrations in the occipital cortex. These differences were not specific to either patient group and may have been caused by neuroleptic or antidepressant treatment. A decreased 5-HT concentration was found in the hypothalamus of nonschizophrenic suicide victims. Among the chronic schizophrenic patients, there was no significant difference in the hypothalamic 5-HT content between the suicide victims and others, indicating that low 5-HT levels in the hypothalamus are not characteristic of schizophrenic patients who died of suicide.

Simultaneous determination of histamine and N tau-methylhistamine with high-performance liquid chromatography using electrochemical detection.

We have developed a liquid chromatographic method which uses electrochemical detection for the simultaneous quantitation of histamine and N tau-methylhistamine in rat brain. The amines are derivatized with the water-soluble Bolton-Hunter reagent (sulfo B-H). Perchloric acid extracts of rat brains are chromatographed on a strong cation-exchange resin. The eluate is evaporated and allowed to react with sulfo B-H at pH 9.8 at room temperature. The derivatization is complete after 30 s vortexing. The derivatives are purified using a cellulose-phosphate fibrous cation exchanger. They are quantified with an electrochemical detector at a potential of 0.56 V after preoxidizing the sample at 0.47 V. The derivatives of histamine, N tau-methylhistamine, and N alpha-methylhistamine are completely separated without interfering peaks. Since no N alpha-methylhistamine was detected in rat brain it was used as an internal standard. The detection limits are 0.1 pmol of histamine and 0.2 pmol of N tau-methylhistamine. The precision of this method is high, with within-run and between-run coefficients of variation of 2-7% and linearity of 0.999. Both histamine and N tau-methylhistamine peak heights increased significantly and selectively after treatment with pargyline. Because of the high sensitivity, accuracy, and precision, the histamine and N tau-methylhistamine contents of single nuclei of the rat hypothalamus can be routinely quantified.

The hypothermic effect of 4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl (CGP 6085 A) in Wistar Kyoto rats.

CGP 6085 A [4-(5,6-dimethyl-2-benzofuranyl) piperidine HCl], a reported serotonin uptake and MAO (16) inhibitor, is a potent hypothermic agent. The hypothermic action of CGP 6085 A is dose dependent with a maximal reduction in rectal core temperature of greater than 1 degree C within one hour after drug administration. Fluoxetine and citalopram elicit a similar response at equal doses. These results suggest that inhibition of serotonin uptake may produce the hypothermic effect. To assess the in vivo action of CGP 6085 A in inhibiting hypothalamic serotonin uptake, CGP 6085 A (10 mg/kg) was injected one hour prior to injection of 3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine (H75/12), a serotonin depletor. The ability of CGP 6085 A to block the uptake of H75/12 by the 5HT uptake system was indicative of its ability to block serotonin uptake. Pretreatment with p-chlorophenylalanine (pCPA), an inhibitor of serotonin synthesis, resulted in the loss of the hypothermic response to CGP 6085 A. Thus, these data are consistent with the idea that CGP 6085 A may produce its hypothermic response by inhibiting serotonin uptake.

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments.

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serotonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after alpha-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man.(ABSTRACT TRUNCATED AT 250 WORDS)

Induced ovulation in aged female rats by L-dopa implants into the medial preoptic area.

Direct placement of L-dopa into the medial preoptic area (MPOA) of aged pseudopregnant or constant vaginal estrous female rats resulted in a reinitiation of vaginal cycles and ovulation. Similar treatment with L-dopa in the dorsomedial septum or cortex was ineffective. Direct placement of leucine into any of the three brain regions did not have an effect on ovarian function. Intermittent treatment with L-dopa to MPOA was found to reinstate and maintain vaginal cycles in constant estrous females only when administered on the day of vaginal estrus of successive cycles. These findings support the hypothesis that age-dependent disturbances in ovarian function may be initiated by changes in neurotransmitter metabolism within the central nervous system.

Effect of cold-exposure on serum thyrotrophin levels in man.

Serum TSH levels were measured after exposing male volunteers to cold, or successively to warmth and to cold, causing clear changes in body temperature. Very moderately heated Finnish sauna bath increased body temperature to about an average of 39 degrees C, and cooling in a relatively warm swimming pool (+25 to +28 degrees C, 30 min) decreased body temperature to below 35 degrees C after sauna, and to about 33 degrees C without sauna. In both cases a slight but significant initial increase of serum TSH was demonstrated. No changes in serum T3 or ETR were seen. The results suggest that a similar mechanism of initial TSH response may exist in humans as has previously been demonstrated in rats.