After the intraventricular injection of 6-hydroxydopamine (6-OHDA), there was a long lasting reduction in the brain concentrations of noradrenaline (NA) and dopamine (DA). The brain concentration of NA was affected by lower doses of 6-OHDA than were required to deplete DA. A high dose of 6-OHDA which depleted the brain of NA and DA by 81 per cent and 66 per cent respectively, had no significant effect on brain concentrations of 5-hydroxytryptamine (5-HT) or γ-aminobutyric acid (GABA). The fall in catecholamines was accompanied by a long lasting reduction in the activities of tyrosine hydroxylase and DOPA decarboxylase in the hypothalamus and striatum, areas in the brain which are rich in catecholamine containing nerve endings. There was, however, no consistent effect on catechol-O-methyl transferase or monamine oxidase activity in these brain regions. The initial accumulation of [3H]NA into slices of the hypothalamus and striatum was markedly reduced 22–30 days after 6-OHDA treatment. These results are consistent with the evidence in the peripheral sympathetic nervous system that 6-OHDA causes a selective destruction of adrenergic nerve endings and suggest that this compound may have a similar destructive effect on catecholamine neurones in the CNS.

Effects of 6-hydroxydopamine on catecholamine containing neurones in the rat brain.

After the intracisternal administration of 6-hydroxydopamine, brain levels of norepinephrine were reduced significantly with or without pargyline pretreatment. Depletion of dopamine in the central nervous system was found to be enhanced markedly by pargyline administration at higher dose levels of 6-hydroxydopamine. Brain serotonin concentrations were not altered. The effects of 6-hydroxydopamine were long-lasting with the depletion of brain amines persisting at 78 days. After norepinephrine-H3 intracisternally to animals treated with 6-hydroxydopamine, labeled norepinephrine uptake was diminished with a corresponding reduction of deaminated catechols and a marked increased in methylated amines. Tyrosine hydroxylase activity was found to be reduced in brainstem, caudate nucleus and whole brain in 6-hydroxydopamine-treated animals. Conversion of tyrosine-H3 to labeled norepinephrine and dopamine was also markedly diminished. The results support the view that 6-hydroxydopamine produces a “central sympathectomy” when introduced into cerebrospinal fluid.

https://cdr.lib.unc.edu/downloads/5h73pz00k

Effect of 6-hydroxydopamine on brain norepinephrine and dopamine: evidence for selective degeneration of catecholamine neurons

Molecular Neurobiology of the Mammalian Brain

Basal forebrain dopamine (DA) and 5-HT neurotransmission has been implicated in the mediation of the acute reinforcing actions of ethanol. Neuroadaptation theories predict that compensatory changes in neurochemical systems that are activated by alcohol acutely may underlie symptoms of withdrawal after chronic administration. To test this hypothesis, the release of DA and 5-HT was monitored by microdialysis in the nucleus accumbens of dependent male Wistar rats at the end of a 3-5 week ethanol (8.7% w/v) liquid diet regimen, during 8 hr of withdrawal, and during renewed availability of ethanol involving (1) the opportunity to operantly self-administer ethanol (10% w/v) for 60 min, followed by (2) unlimited access to the ethanol-liquid diet. Results were compared to control groups pair-fed with ethanol-free liquid diet and trained to self-administer either ethanol or water. In nondependent rats, operant ethanol self-administration increased both DA and 5-HT release in the NAC. Withdrawal from the chronic ethanol diet produced a progressive suppression in the release of these transmitters over the 8 hr withdrawal period. Self-administration of ethanol reinstated and maintained DA release at prewithdrawal levels but failed to completely restore 5-HT efflux. 5-HT levels recovered rapidly, however, within 1 hr of reexposure to ethanol liquid diet. These findings suggest that deficits in accumbal monoamine release may contribute to the negative affective consequences ethanol withdrawal and, thereby, motivate ethanol-seeking behavior in dependent subjects.

https://www.jneurosci.org/content/jneuro/16/10/3474.full.pdf

Ethanol Self-Administration Restores Withdrawal-Associated Deficiencies in Accumbal Dopamine and 5-Hydroxytryptamine Release in Dependent Rats

Catecholamine systems as the neural substrate for intracranial self-stimulation: a hypothesis.

There is general agreement as to the properties of tyrosine hydroxylase from the adrenal medulla, but the properties of brain tyrosine hydroxylase are more controversial. This is perhaps not so surprising when one considers that the adrenal medullary cells are secretory cells which do not possess the long axons and multiplicity of nerve endings characteristic of central catecholaminergic neurons. The relatively complex structure of the neuron has complicated the problem of defining the properties of brain tyrosine hydroxylase and will probably prove important to an understanding of the factors which control or modify enzyme activity in vivo.

Some characteristics of brain tyrosine hydroxylase

The distribution of tyrosine hydroxylase activity in various areas of brain was studied in mature rats, rabbits, cats, and in kittens of various ages. Distribution was closely similar in all species. Areas known to have high concentrations of catecholinergic nerve endings, such as the caudate, septal area and pineal, showed very high adult levels and sharp increases during the neonatal period. Areas such as the pons–medulla and midbrain, known to contain predominantly catecholinergic cell bodies, showed, on the other hand, relatively low adult levels and little or no change in the neonatal period. Developmental data correlate with known neonatal changes in endogenous catecholamine levels and adult distributions correlate with known turnover rates. The results are in conformity with previous findings that tyrosine hydroxylase is concentrated largely in nerve endings and suggest that measurement of this enzymic activity may provide a more convenient and more sensitive index of catecholinergic nerve activity...

Distribution of tyrosine hydroxylase activity in adult and developing brain.

Effect of selective inhibitors of tyrosine and tryptophan hydroxylases on self-stimulation in the rat

IT IS well established that animals exposed to cold show increased excretion of catecholamines (LEDUC, 1961). Norepinephrine is thought to be particularly important in adaptation to cold, with increased secretion of epinephrine acting as a secondary defence mechanism (LEDUC, 1961; CARLSON, 1966). The content of catecholamines in adrenal glands of animals in the cold is greatly increased (LEDUC, 1961; MOORE, CALVERT and BRODY, 1961), but conflicting results have been reported for liver (LEDUC, 1961; CHAN and JOHNSON, 1968), heart (OLIVERIO and STJARNE, 1965; GORDON, SPECTOR, SJOERDSMA and UDENFRIEND, 1966; CORRODI, FUXE and HOKFELT, 1967; DUCE, CRABAI, VARGIU, PIRAS, ADAMO and GESSA 1967 and CHAN and JOHNSON, 1968) and brain. The level of norepinephrine in brain or in hypothalamus has been reported to be unchanged on short exposure to cold (MOORE et al., 1961 ; GORDON et al., 1966; Cox and POTKONJAK, 1967) and increased (INGENITO and BONNYCASTLE, 1967; INGENITO, 1968) or decreased (LEBLANC, 1967) after long exposure. The turnover rate of catecholamines in brain, as measured by the rate of depletion after treatment with a hydroxylase inhibitor, has also been variously reported as normal in cold-exposed animals (CORRODI et al., 1967), slightly decreased (WELSCH and WELSCH, 1967), or somewhat increased (GORDON et al., 1966; DUCE et al., 1967). Further study is desirable in view of the possible role of central catecholamines in regulation of temperature (FELDBERG and MYERS, 1964) and in behavioural responses (MILLER, 1965). A sensitive assay is now available for tyrosine hydroxylase, the enzyme catalysing the rate-limiting step in the synthesis of catecholamines, and this paper reports measurements of the activity of tyrosine hydroxylase and of the turnover of catecholamines in rats exposed to cold. Wistar rats (150-200 g) were placed in individual metabolic cages at 3\" or 27\". Food and water were allowed ad lib. Both sets of rats were exposed to a cycle of 12 hr of light and 12 hr of darkness. Analysis of 24-hr urine samples for catecholamines showed the expected 2to 3-fold increase in excretion of norepinephrine during the first 24 hr in the cold and persistence of the same elevated levels for up to 3 weeks. The animals were killed at intervals during this period for determination of the levels of catecholamines in brain, heart, adrenals and spleen and of the activities of tyrosine hydroxylase in brain and adrenals by methods previously reported (WADA and MCGEER, 1966; MCGEER, GIBSON and MCGEER, 1967). The concentrations of catecholamines and the activities of tyrosine hydroxylase in the various tissues appeared to be independent of the duration of exposure to cold within the experimental period used. Hence the results are grouped (Table 1). The levels of catecholamines and the activity of tyrosine hydroxylase in brain, as well as the levels of dopamine in the adrenals, were normal in rats exposed to cold, but, in the adrenals, there was a significant increase (40 per cent) in levels of norepinephrine + epinephrine and a parallel but less significant increase in activity of tyrosine hydroxylase when expressed per g of tissue. Since the size of the adrenals also increased in rats exposed to cold, the activity of tyrosine hydroxylase also increased significantly (70 per cent) when expressed per adrenal gland (Table 1). The changes in levels of norepinephrine + epinephrine in heart and spleen (Table 1) were not significant (P > 0.5) and concentrations of dopamine in spleen and heart are not shown in Table 1 because they were so very variable. As another possible measure of the effects of exposure to cold on the metabolism of catecholamines, the rate of depletion of norepinephrine + epinephrine was measured at 2 , 4 and 6 hr after i.p. injection of an inhibitor of tyrosine hydroxylase, L-cc-methyl-rnor L-a-methyl-p-tyrosine; the latter was kindly supplied to us by Merck, Sharp & Dohme of Canada. At a dose of 100 mg of inhibitor per kg body wt., levels of dopamine in all tissues studied were not significantly affected. In brain, heart and spleen the plots of levels of catecholamines as a function of time after administration of either inhibitor are the same or closely parallel for cold-exposed and for normal rats

S. Gibson

Papers

Some characteristics of brain tyrosine hydroxylase

Distribution of tyrosine hydroxylase activity in adult and developing brain.

Effect of selective inhibitors of tyrosine and tryptophan hydroxylases on self-stimulation in the rat

Metabolism of catecholamines in cold-exposed rats.