Affective disorders: The catecholamine hypothesis revisited (original) (raw)

Characterization, localization and regulation of dopamine-β-hydroxylase and of other catecholamine synthesizing enzymes

Life Sciences, 1973

This presentation describes the localization, characterization and regulation of dopamine-/3-hydroxylase and of other catecholamine synthesizing enzymes. Three enzymes involved in catecholamine biosynthesis, namely dopamine-/3-hydroxylase (D/3H) aromatic L~amino acid decarboxylase (AADC) and phenylethanolamine N-methyl transferase (PNMT) were purified from bovine adrenal glands . D~iH was also purified from human serum, adrenal glands and pheochromocytoma tumor tissues. The purified enzymes were used to induce the production of immunologically pure antienzymes in rabbits . The latter were utilized for immunochemical studies as well as for localization of catecholamine synthesizing enzymes in peripheral tissue and brain by an indirect immunofluorescence method .

Compartmentation of catecholamines in rat brain: Effects of agonists and antagonists

Brain Research, 1980

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 7-butyrolactone (GBL) increased DA levels in all fractions with the greatest increase occurring in the cytoplasmic fraction. Both 6hydroxydopamine (6-OHDA) and a-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

d-Amphetamine-Induced Increase in Catecholamine Synthesis in the Corpus Striatum of the Rat: Persistence of the Effect After Tolerance 1

J Neural Transm, 1979

The effect of d-amphetamine on in vivo catecholamine synthesis in four regions of rat brain was determined by measuring the accumulation of dopa a~er inhibition of dopa decarboxylase. In doses up to 2.5 mg/kg, d-amphetamine caused dose-dependent increases in striatal dopa accumulation to a maximum of 280 ~ of control; further increases in dose resulted in smaller effects until 10 mg/kg d-amphetamine was not significantly different from control, d-Amphetamine did not alter dopa accumulation in telencephalon, in diencephalon-mesencephalon, or in pons-medulla oblongata, d-Amphetamine did not affect either dopamine levels in striatum or NE levels in pons-medulla oblongata; at high doses, d-amphetamine did reduce norepinephrine levels in telencephalon and in diencephalon-mesencephalon. Daily administration of pre-session but not of post-session d-amphetamine produced tolerance to the effects of d-amphetamine on milk consumption in rats. The ability of d-amphetamine to increase striatal catecholamine synthesis was not altered by the development of tolerance to d-amphetamine. These results suggest that tolerance to d-amphetamine is not related to its effect on catecholamine synthesis but instead occurs via

Time course study of changes in the activity of the catecholamine synthesizing enzymes in the rat medulla oblongata after intraventricular injection of 6-hydroxydopamine

Brain Research, 1983

adrenaline-containing neurons-dopamine-fl-hydroxylase-medulla oblongata-noradrenaline-containing neurons-phenylethanolamine-N-methyltransferase-tractus intermediolateralistyrosine hydroxylase-6-hydroxydopamine Recent data have shown that 5 days after intraventricular injection of 6-hydroxydopamine (6-OHDA), the tyrosine hydroxylase activity (TH) was increased within the locus coeruleus (LC). We sought to determine if such an alteration occurs within the AI and A2 noradrenergic (NA) and CI and C2 adrenergic (A) neurons of the rat medulla oblongata. The TH activity within the cell bodies was significantly increased 2 days after 6-OHDA injection with a maximum at 5 days (LC, + 109%, P < 0.001; A I-CI, +40%, P < 0.01; A2-C2; + 24%, P < 0.01) while a significant decrease was present 21 days after 6-OHDA. Conversely, dopamine-fl-hydroxylase (DBH) activity exhibited a decrease which was maximal at 21 days (LC,-41%; A 1-C 1,-33%; A2-C2,-35%, P < 0.001). Both the TH (-47% at 5 days) and the DBH (-82% at 12 days) activities were decreased within the terminals of the tractus intermediolateralis (TIML). The phenylethanolamine-N-methyltransferase (PNMT) activity was never altered in the cell bodies nor in the terminals analyzed. These data demonstrate that the NA neurons of the rat medulla oblongata and of the LC exhibit a similar pattern of response to the neurotoxin 6-OHDA. Conversely, the lack of change in the PNMT activity confirms the hypothesis of a resistance of the A neurons to 6-OHDA or questions the validity of the PNMT as an A marker.

Catecholamines: Knowledge and understanding in the 1960s, now, and in the future

Brain and Neuroscience Advances, 2019

The late 1960s was a heyday for catecholamine research. Technological developments made it feasible to study the regulation of sympathetic neuronal transmission and to map the distribution of noradrenaline and dopamine in the brain. At last, it was possible to explain the mechanism of action of some important drugs that had been used in the clinic for more than a decade (e.g. the first generation of antidepressants) and to contemplate the rational development of new treatments (e.g. l-dihydroxyphenylalanine therapy, to compensate for the dopaminergic neuropathy in Parkinson’s disease, and β1-adrenoceptor antagonists as antihypertensives). The fact that drug targeting noradrenergic and/or dopaminergic transmission are still the first-line treatments for many psychiatric disorders (e.g. depression, schizophrenia, and attention deficit hyperactivity disorder) is a testament to the importance of these neurotransmitters and the research that has helped us to understand the regulation of ...

Short-Term Regulation of Catecholamine Biosynthesis in a Nerve Growth Factor Responsive Clonal Line of Rat Pheochromocytoma Cells

Journal of Neurochemistry, 1978

A clonal cell line (designated PC12) has been previously established from a transplantable rat adrenal medullary pheochromocytoma. Tissue cultures of PC12 cells synthesize, store, release and take up catecholamines. PC12 cells also respond to nerve growth factor (NGF) protein by cessation of mitosis and extension of neurites. The present studies concern the comparison of several aspects of catecholamine metabolism in PC12 cultures with that in normal noradrenergic tissues. One question was why the ratio of dopamine to norepinephrine in PC12 cultures (in contrast to that in normal noradrenergic tissue) is considerably more than one. The presence of exogenous reduced ascorbate (a cofactor for dopamine-b-monooxygenase) enhanced by 5-10-fold the rate at which PC12 cultures converted C3H]tyrosine to [-'H]norepinephrine. Under such conditions, the rate of synthesis of C3H]dopamine was unchanged. It was also found that the ratio of norepinephrine to dopamine increased by 10-fold when the cells were grown in uiuo as tumors. Since tissue culture medium is essentially free of reduced ascorbate. it is likely that the absence of this cofactor is responsible for the low norepinephrine to dopamine ratio in PC12 cultures. Experiments were also carried out on short-term regulation of catecholamine synthesis in PC12 cultures. These studies revealed the following: (1) The rate of conversion of ['Hltyrosine to [3H]catechols was increased 2-3-fold (as compared with controls) in the presence of depolarizing levels of K' (51.5 mM), and by 2-fold in the presence of 0.5-2 mM-dibutyryl cyclic adenosine 3', 5' monophosphoric acid (db-CAMP). (2) Similar increases occurred in cultures which had been treated with (and had responded to) nerve growth factor. (3) The stimulatory effects of 51.5 mM-K+ rapidly returned toward control levels when the cultures were returned to control medium and (4) required the presence of Ca2+ in the extracellular medium. (5) Stimulation of catechol synthesis by 51.5 rnM-K+ and db-CAMP also occurred in the presence of an inhibitor of DOPA decarboxylase. Thus, the ultimate effects of these agents were probably at the level of conversion of tyrosine to dopa by tyrosine 3-monooxygenase. (6) Simultaneous exposure of cultures to 51.5 mM-K+ and mM-db-CAMP gave additive levels of stimulation. Such findings demonstrate that catecholamine synthesis in cultures of PC12 cells undergoes short-term regulation which is similar to that previously demonstrated in normal monoaminergic tissues. As a homogeneous tissue culture line, the PC12 bears certain advantages for studying the primary mechanisms of such effects. A CLONAL cell line (designated PC12) has recently been established (GREENE & TISCHLER, 1976) from a transplantable rat adrenal medullary pheochromocytoma (WARREN & CHUTE, 1972). Within a few days after PC12 cells in tissue culture are exposed t o 0.1 n M levels of nerve growth factor (NGF) protein (LEVI-MONTALCINI & ANGELETTI, 1968), they cease mitosis, extend long, branching neurites (GREENE & TISCHLER, 1976) and become electrically excitable (DICKTER et al., 1977). PC12 cells (both NGF-treated and-untreated) also express a number of neurotransmitter properties of noradrenergic tissues. F o r example, PC12 cells synthesize a n d store substantial levels of dopamine (DA) a n d norepinephrine (NE)