CSF and endocrine studies of premenstrual syndrome.

Eight women with prospectively documented premenstrual syndrome (PMS) underwent multiple samplings for estradiol, progesterone, prolactin, cortisol, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) during an asymptomatic midcycle (late follicular) and a symptomatic premenstrual (late luteal) phase of the menstrual cycle. Cerebrospinal fluid (CSF) was collected for analysis of MHPG, norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), gamma-aminobutyric acid (GABA), homovanillic acid (HVA), tyrosine, tryptophan, beta-endorphin, prostaglandins, adrenocorticotropic hormone (ACTH), and arginine vasopressin (AVP). In subsequent months, a dexamethasone suppression test (DST) and a thyrotropin-releasing hormone (TRH) stimulation test were performed during midcycle and premenstrual phases. Significant results included increased CSF concentrations of MHPG in the premenstrual, as compared with the midcycle, phase of the cycle, and increased plasma cortisol concentrations during the midcycle phase. The DST showed a 62% overall rate of nonsuppression, irrespective of menstrual cycle phase. Though there were no abnormalities of thyrotropin-stimulating hormone (TSH) after TRH stimulation, the mean delta maximum prolactin values after TRH stimulation were higher than reported normal values both at midcycle and premenstrually. These pilot data suggest hormonal axes that might be worthy of further systematic investigation in future studies of PMS.

Interactions between neuropeptide Y and alpha 2-adrenoceptors in selective rat brain regions.

Neuropeptide Y significantly reduced the potassium-stimulated release of [3H]norepinephrine [( 3H]NE) from slices of rat hippocampus, hypothalamus and frontal cortex but not from slices of parieto-occipital cortex. The NPY-induced inhibition of [3H]NE release from frontal cortical slices was concentration dependent, reaching statistical significance at 10 nM. The alpha 2-adrenoceptor partial agonist, clonidine, also reduced the potassium-stimulated release of [3H]NE. The combination of NPY and clonidine in hippocampal slices produced a greater reduction of stimulated [3H]NE release than either of the two compounds alone, suggesting a potentiation of their activity, whereas in frontal cortical slices, the effect was additive. When NPY and clonidine were added to frontal cortical slices, they independently produced a significant concentration-dependent reduction in forskolin-stimulated cAMP accumulation. However, NPY and clonidine combined did not produce a further reduction in forskolin-induced cAMP accumulation than either compound when used alone. These results suggest that the ability of NPY to potentiate alpha 2-adrenoceptor-induced inhibition of [3H]NE release in discrete brain regions does not depend on the reductions in cAMP.

Chronic desipramine treatment reduces regional neuropeptide Y binding to Y2-type receptors in rat brain.

Chronic treatment of rats with desipramine and imipramine (5 mg/kg/twice daily/i.p.) for 14 days caused a significant reduction in the binding of [3H]propionyl NPY to membranes prepared from frontal cortex, nucleus accumbens, hypothalamus and hippocampus. There was no change in binding of [3H]propionyl NPY in the parieto-occipital cortex, striatum or amygdala. Scatchard analysis of binding data from frontal cortical and hippocampal membranes showed that [3H]propionyl NPY bound to a single site with a Kd of approximately 0.3 nM. The loss of [3H]propionyl NPY binding in hippocampal and frontal cortical membranes revealed that chronic tricyclic antidepressant treatment produced a reduction in the number of binding sites with no change in the affinity for the ligand. Chronic desipramine treatment did not alter the ability of NPY (0.01-25 microM) to stimulate inositol phosphate accumulation in rat frontal cortical slices as compared to saline-treated animals. The lack of change of NPY-induced inositol phosphate accumulation following chronic desipramine treatment showed that there was no change to Y1 NPY-type receptors which are linked to the hydrolysis of inositol phospholipids. However, the ability of NPY (0.05-0.5 microM) to inhibit forskolin (1 microM) stimulated adenylate cyclase via Y2 NPY-type receptors in rat frontal cortical slices was significantly reduced following chronic desipramine treatment. This finding suggests that the reduction of [3H]proprionyl NPY binding in selective brain regions may be the result of an antidepressant-induced loss of Y2-type NPY receptors which are negatively linked to adenylate cyclase.

A comparison of the binding of [3H]proprionyl-neuropeptide Y to rat and human frontal cortical membranes.

The binding characteristics of [3H]proprionyl-neuropeptide Y ([3H]proprionyl-NPY) were studied in frontal cortical membranes prepared from rat and human postmortem tissue. The specific binding of NPY decreased as the magnesium concentration increased from 1.05 to 10 mM. The binding was also influenced by the concentration of GTP in the buffer medium, with a resulting 45% decrease in NPY binding in the presence of 10(-6) M GTP. Using equilibrium binding studies, [3H]proprionyl-NPY was found to bind in both tissues with high affinity to a single class of receptors with a similar KD (0.035 nM). However, kinetic experiments in both tissues provided evidence for two components of [3H]proprionyl-NPY binding which may be related to receptor states. Competition binding experiments showed that peptide YY (PYY) was equal to NPY in its ability to displace [3H]proprionyl-NPY, whereas rat and human pancreatic polypeptide were without effect up to a concentration of 10(-6) M. This suggests that, whereas PYY and NPY may compete for the same receptor(s), the pancreatic polypeptides probably act on a separate population of receptors.

Effects of neuropeptide Y on alpha 1-and beta-adrenoceptor-stimulated second messenger systems in rat frontal cortex.

Neuropeptide Y (NPY) (1 microM) significantly reduced the basal cAMP concentration in slices of rat frontal cortex. However, NPY (10(-9)-10(-6)M) did not alter the isoproterenol-stimulated (10(-9)-10(-5) M) accumulation of cAMP in the frontal cortical slices, showing that Y2 NPY receptors do not modulate the beta-adrenoceptor-stimulated adenylase cyclase activity. NPY (10(-8)-2.5 x 10(-5) M) was also demonstrated to stimulate inositol phosphate accumulation in rat frontal cortex slices in a dose-dependent manner. However, NPY (1 microM) did not potentiate the ability of phenylephrine (5 X 10(-8)-10(-4) M), an alpha 1-adrenoceptor agonist, to stimulate inositol phosphate hydrolysis. The combined effects of phenylephrine and NPY (1 microM) on inositol phosphate hydrolysis were additive, suggesting that the alpha 1-adrenoceptor and NPY Y1 receptor sites are located on different postsynaptic sites in rat frontal cortex. This study demonstrates the existence of both Y2 and Y1 NPY receptors in the rat frontal cortex based on second messenger systems, but there does not appear to be an interaction of NPY with either alpha 1- or beta-adrenoceptors.

Evaluation of the safety and efficacy of bupropion in depression.

A placebo-controlled double-blind study was conducted to test the antidepressant effects of bupropion at dosage levels of 300 or 450 mg/day. Subjects were 30 hospitalized primary major depressives who were treated for 4 weeks. Physical and behavioral measures were obtained at baseline and at the end of each experimental week. The combined results of the two bupropion groups were significantly better than placebo. Preliminary results showed a significant antidepressant effect of the 300 mg/day dose, but not the 450 mg/day dose, compared to placebo. Anxiety symptoms were also somewhat reduced by the 300 mg/day dose. The results are compared with those of a previous study, which utilized higher dosages.

Bupropion in depression: a tri-center placebo-controlled study.

In a double-blind, placebo-controlled, variable-dose study of 59 hospitalized nonpsychotic depressed patients, bupropion was significantly (p less than .05 to less than .001) more effective than placebo on measures of depression, anxiety, and global improvement. Statistically significant drug-placebo differences appeared as early as day 5 of treatment and increased on subsequent assessments. In an evaluation of Baseline X Treatment interactions, bupropion was particularly more effective than placebo in those patients with more severe depression. Placebo and bupropion groups had similar frequencies and severity of side effects. Laboratory data showed minimal differences between the two treatments. The most common adverse experience was mild dry mouth (20% of patients). Compared to placebo, bupropion was found to be effective in the treatment of depression and to have a favorable safety profile.

Determination of plasma 3-methoxy-4-hydroxyphenyl-glycol by pulsed electron capture gas chromatography.

An improved method is described for determining picogram quantities of 3-methoxy-4-hydroxyphenylglycol (MHPG) in plasma of humans and of other species. The method makes use of gas-liquid chromatography and electron capture detection. Low level nonlinearity of detector response was corrected by operating the detector in the pulsed rather then the customary steady state mode. Detector overloading was prevented by heat coagulation of plasma proteins and subsequent ultrafiltration. Sensitivity was significantly enhanced by utilizing a derivatizing agent carrying a higher number of electrophores. Baseline conditions are described and control values for plasma MHPG of human volunteers, Rhesus monkeys and rats are presented.

A correlational analysis of the effects of surgical transections of three components of the MFB on ingestive behavior and hypothalamic, striatal, and telencephalic amine concentrations.

A retractable wire knife was used to transect medial or lateral components of the MFB or its lateral projections to the striatum and amygdaloid complex. All cuts produced significant depletions of NE, DA, and 5-HT from telencephalon and striatum but little or no effect on hypothalamic NE or 5-HT. Two of our cuts resulted in aphagia and adipsia, the third in hyperphagia and obesity. A detailed correlational analysis of the magnitude and direction of the behavioral and biochemical consequences of our cuts indicated that the ingestive behavior of all of our experimental animals (including animals which had been aphagic and adipsic after surgery as well as animals which were hyperphagic and obese) was positively correlated with the concentration of DA in striatum and telencephalon and negatively correlated with telencephalic 5-HT. Less consistent evidence for facilitatory noradrenergic influences on food intake was also obtained. Our results suggest that the regulation of food intake may be the result of an interaction between telencephalic serotonergic mechanisms and dopaminergic pathways which exert opposite effects on ingestive behavior.