Clinical efficacy of the new antidepressant bupropion (Wellbutrin) [proceedings].
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Biomedical subjects
Publications and source records attributed to A E Halaris.
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The subsynaptosomal distributions of dopamine (DA) in striatum and of norepinephrine (NE) in hypothalamus and cerebral cortex were examined. Isolated nerve-endings from each region were osmotically disrupted and subfractionated into a soluble cytoplasmic fraction (end supernatant, Se) and a synaptic vesicle fraction (P2V). DA and NE were measured in the crude homogenate and in subcellular fractions by a radioenzymatic assay. Levels of NE and DA were 3--5 times higher in the nerve-ending cytoplasm than in the synaptic vesicles, suggesting that catecholamines within the nerve-endings are predominantly in soluble form. Amphetamine increased DA levels in the tissue homogenate and in the nerve-ending cytoplasm but not in synaptic vesicles. Pargyline and gamma-butyrolactone (GBL) increased DA levels in all fractions with the greatest increase occurring in the cytoplasmic fraction. Both 6-hydroxydopamine (6-OHDA) and alpha-methyltyrosine (AMT) caused uniform DA decreases in all fractions. Hypothalamic levels of NE in the two nerve-ending compartments were also reduced to a similar extent after AMT. Reserpine produced uniform depletions of striatal DA in both nerve-ending fractions while the rate of DA repletion was more rapid in the vesicular compartment. Levels of hypothalamic NE were also uniformly depleted by reserpine at the times examined. The cytoplasmic storage compartment is discussed in terms of a possible anatomical correlate such as the smooth endoplasmic reticulum.
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Microinjections of the excitatory neurotoxin kainic acid into the lateral hypothalamus of rats produced a period aphagia and adipsia. Kainate-treated rats displayed transient motor effects during the first hours after the injection but did not show the persisting sensory-motor and arousal disturbances typically observed in animals with electrolytic lesions in this part of the hypothalamus. Histological examination revealed a significant reduction in the number of nerve cell bodies in the lateral hypothalamus. Silver-stained material indicated no evidence of damage to fiber systems passing through the affected region. Assays of dopamine in hypothalamus, striatum, and telencephalon did not indicate significant differences between experimental and control animals. These results are in agreement with recent reports of the anatomical and biochemical effects of intracerebral kainic acid injections and suggest that the observed effect on feeding behavior is related to the destruction of neurons in the lateral hypothalamus.
Improved methods are described for the fluorimetric determination of 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan (TRP) in plasma, platelet and RBC blood compartments. The methods for 5-HT and 5-HIAA utilize ion exchange chromatography and allow simultaneous determinations to be made on the same blood sample. The tryptophan assay is a modification of an existing extraction method. All of the 5-HT in whole blood was found to be associated with the platelet fraction (122.6 ng/ml), whereas all 5-HIAA was distributed between the plasma (78.3 ng/ml) and RBC (124.0 ng/ml) compartments. Tryptophan was found in all three compartments although the majority of this amino acid was in the plasma (4.3 microgram/ml) and RBC (1.7 microgram/ml) fractions.
The ascending projections of serotonin neurons of the midbrain raphe were analyzed in the rat using the autoradiographic tracing method. Axons of raphe serotonin neurons ascend in the ventral tegmental area and enter the medial forebrain bundle. A number of fibers leave the major group to ascend along the fasciculus retroflexus. Some fibers enter the habenula but the majority turn rostrally in the internal medullary lamina of the thalamus to innervate dorsal thalamus. Two additional large projections leave the medial forebrain bundle in the hypothalamus; the ansa peduncularis-ventral amygdaloid bundle system turns laterally through the internal capsule into the striatal complex, amygdala and the external capsule to reach lateral and posterior cortex, and another system of fibers turns medially to innervate medial hypothalamus and median eminence and form a contrelateral projection via the supraoptic commissures. Rostrally the major group in the medial forebrain bundle divides into several components: fibers entering the stria medullaris to terminate in thalamus; fibers entering the stria terminalis to terminate in the amygdala; fibers traversing the fornix to the hippocampus; fibers running through septum to enter the cingulum and terminate in dorsal and medial cortex and in hippocampus; fibers entering the external capsule to innervate rostral and lateral cortex; and fibers continuing forward in the medial olfactory stria to terminate in the anterior olfactory nucleus and olfactory bulb.
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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.
Axonal transport of protein and metabolites of L-[3H(G)]3, 4-dihydroxyphenylalanine ([3H]DOPA) was studied in the central noradrenaline neurons of the pontine nucleus locus coeruleus and was correlated with regional alterations of noradrenaline content following destruction of the nucleus. Unilateral lesions of the locus coeruleus produce a partial depletion of noradrenaline in the ipsilateral hypothalamus and telencephalon, indicating that these neurons project widely to the ipsilateral forebrain. Twenty-four to 48 h following local injections of 50 micronCi [3H]proline, locus coeruleus neurons take up labeled material and transport it, presumably as protein, to ipsilateral structures in the midbrain, diencephalon and telencephalon including the neocortex. Similarly 8 h after injection of 25 micronCi [3H]DOPA into the locus coeruleus, transport of material including catecholamines occurs to ipsilateral diencephalon and telencephalon. Axonal transport of proteins to telencephalic structures is greatly diminished by selective lesions of catecholamine terminals with 6-hydroxydopamine (6-OHDA) and following destruction of the medial forebrain bundle. These results provide further support for the view that noradrenaline neurons of the locus coeruleus nucleus project widely within the neuraxis to ipsilateral structures of the brain stem, diencephalon and telencephalon, including all cortical areas. In addition, evidence is presented for a contralateral projection with a similar distribution. The rate of axonal transport of labeled protein and metabolites of [3H]DOPA including [3H]catecholamines in central noradrenaline neurons is estimated to be 3-4 mm/h and is accordingly similar to that reported for noradrenaline neurons of the peripheral sympathetic nervous system.
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