Catecholamine metabolism in the brains of ageing male mice

doi:10.1016/0006-8993(73)90663-X

Brain Research

Volume 52, 30 March 1973, Pages 261-276

https://doi.org/10.1016/0006-8993(73)90663-X Get rights and content

Abstract

Several age-related changes of catecholamine metabolism in senescent C57B1/6J male mice were observed: (1) reduced levels of striatal dopamine, (2) reduced conversion of l-[³H]tyrosine and l-[³H]DOPA to catecholamines in 4 brain regions, and (3) slowed catabolism of total norepinephrine in the hypothalamus and of total dopamine in the striatum.

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This brings CA to the forefront of aging. The reasons to suspect that CA may play some special roles in aging piled up since early 1970-ies (Austin et al., 1978; Finch, 1973, 1978; Robinson et al., 1972; Simpkins et al., 1977). This issue was included into the list of the most important agendas of aging research (Strehler, 1977).
Macromolecules damaged by covalent modifications produced by chemically reactive metabolites accumulate in the slowly renewable components of living bodies and compromise their functions. Among such metabolites, catecholamines (CA) are unique, compared with the ubiquitous oxygen, ROS, glucose and methylglyoxal, in that their high chemical reactivity is confined to a limited set of cell types, including the dopaminergic and noradrenergic neurons and their direct targets, which suffer from CA propensities for autoxidation yielding toxic quinones, and for Pictet-Spengler reactions with carbonyl-containing compounds, which yield mitochondrial toxins. The functions progressively compromised because of that include motor performance, cognition, reward-driven behaviors, emotional tuning, and the neuroendocrine control of reproduction. The phenotypic manifestations of the resulting disorders culminate in such conditions as Parkinson’s and Alzheimer’s diseases, hypertension, sarcopenia, and menopause. The reasons to suspect that CA play some special role in aging accumulated since early 1970-ies. Published reviews address the role of CA hazardousness in the development of specific aging-associated diseases. The present integrative review explores how the bizarre discrepancy between CA hazardousness and biological importance could have emerged in evolution, how much does the chemical reactivity of CA contribute to the senescent phenotype in mammals, and what can be done with it.
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When sympathetic nerve activity is chronically high, catecholamine-releasing nerve fibers can self-destruct as a result of increased oxidative metabolites, such as hydroxylated (including 6-OHDA) or quinine derivatives. This phenomenon occurs in the age related loss of nigrostriatal dopaminergic and NA locus coeruleus neurons in the CNS (Felten et al., 1992; Finch, 1973; Haavik et al., 1997) and in diabetic neuropathy (Sullivan and Feldman, 2005). Increased oxidative stress resulting from elevated SNS activity and/or immune activation during the disease may over whelm the anti-oxidative stress systems.
Sympathetic nerves in the spleen undergo an injury and sprouting response with development of adjuvant-induced arthritis (AA), a model of rheumatoid arthritis (RA). The objective of the present study was to determine whether this injury and sprouting response is disease-specific or occurs in a non-specific manner similar to injury and sprouting responses following sympathectomy with specific neurotoxins. Changes in noradrenergic (NA) innervation in spleens from Lewis rats 28 days following adjuvant treatment to induce arthritis and/or local 6-hydroxydopamine (6-OHDA) treatment to destroy NA nerves were examined using immunocytochemistry for tyrosine hydroxylase (TH). We observed significant increases in sympathetic innervation of hilar regions, sites of nerve entry into the spleen, and a striking decline in innervation of splenic regions distant to the hilus in arthritic compared to non-arthritic rats. While increased hilar and decreased distal NA innervation in arthritic rats was strikingly similar to that of non-arthritic 6-OHDA-treated rats, there were differences in splenic compartments innervated by sympathetic nerves between these groups. In 6-OHDA-treated rats, NA nerves re-innervated splenic compartments normally innervated by sympathetic nerves. In arthritic rats, sympathetic nerves returned to normally innervated splenic compartments, but also abundantly innervated red pulp. These findings suggest that splenic sympathetic nerves undergo a disease-associated injury/sprouting response with disease development that alters the normal pattern and distribution of NA innervation. The altered sympathetic innervation pattern is likely to change NA signaling to immune cell targets, which could exert long-term regulatory influences on initiation, maintenance, and resolution of immune responses that impact disease pathology.
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Citation Excerpt :
Possible significance of α-synuclein phosphorylation to the etiology of α-synucleinopathy has been suggested by studies of effect of phosphorylation on the lipid binding property of α-synuclein [29] and increased tendency to fibril formation of phosphorylated α-synuclein [17]. A significant decrease of dopamine content in the St is the first neurochemically observable change in aging mouse brains [26]. Progressive decline of striatal dopamine content with age is also known in the humans [27].
α-Synuclein phosphorylated at Ser129 is the main component of Lewy bodies of Parkinson's and closely related diseases. We studied, by quantitative immunoblotting, changes in the phosphorylation level of α-synuclein in the mouse brains subjected to cold water stress. Relative basal level of α-synuclein phosphorylation at Ser129 was 40% higher in the striatum compared with the hippocampus. The phosphorylation level decreased to 57% in the striatum 20 min after 5 min of cold water stress, and also in the hippocampus and cortex to lesser degrees. Recovery to basal levels took place over several hours. The stress-induced temporary dephosphorylation was of smaller magnitude in the striatum of aged (18 months) mice. These results show that α-synuclein phosphorylation level at Ser129 in vivo responds to physiological stimuli. Relative prominence and age sensitivity of this phenomenon in the striatum may be relevant to the pathogenesis of Parkinson's disease.
Effects of Ca<sup>2+</sup> antagonists on motor activity and the dopaminergic system in aged mice
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We investigated the effects of the Ca²⁺ antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca²⁺ antagonist, amlodipine. Furthermore, we examined the close correlation between the dopaminergic system and motor activity during the aging process. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents were measured in 2-, 4-, 8-, 18- and 36-week-old mice. Behavioral tests (pole and catalepsy test) were performed with 4- and 36-week-old mice. Nilvadipine or amlodipine was administered intraperitoneally twice a day for 3 consecutive days to 30–36-week-old mice. The striatal dopamine, DOPAC and HVA contents were examined and behavioral tests were performed 1 h after the last injection of each Ca²⁺ antagonist. The dopamine, DOPAC and HVA contents in 2-week-old mice were significantly decreased in the striatum, as compared with 4-week-old animals. Thereafter, age-related increases in the dopamine, DOPAC and HVA contents were observed from 4 to 18 weeks old. However, in 36-week-old mice, the dopamine and DOPAC contents were reduced in the striatum, as compared with 18-week-old animals. Age-related decreases in motor function between 5- and 36-week-old mice were observed in both pole test and catalepsy tests. On the other hand, nilvalipine treatment produced a significant and dose-dependent increase in the striatal dopamine and DOPAC contents in 30–36-week-old mice. In contrast, no significant changes were observed in the striatal dopamine content in amlodipine-treated mice, although this drug showed a significant and dose-dependent increase in the striatal DOPAC and HVA content. In our behavioral study, nilvadipine also showed a significant and dose-dependent inhibition against motor deficits in 30–36-week-old mice. In contrast, amlodipine showed no significant effect on motor deficits in 30–36-week-old mice.
The present study demonstrated that nilvadipine has a protective effect against the deficits in both the striatal dopaminergic system and motor activity in aged mice. Our study also suggested that the beneficial effect of nilvadipine against motor abnormalities may be mediated by a protective effect against the reduced activity of the dopaminergic system in aged mice. These results suggested that nilvadipine may offer a new approach for the treatment of hypobulia in aged humans.
In vivo microdialysis studies of age-related alterations in potassium-evoked overflow of dopamine in the dorsal striatum of Fischer 344 rats
2000, International Journal of Developmental Neuroscience
Citation Excerpt :
Supporting this hypothesis have been numerous studies reporting modest alterations in DA neuronal structure and function in aged mammals. Reported alterations include decreased numbers of midbrain DA-containing cells, decreased numbers of DA receptors and transporters, and decreased DA synthesis, storage, release, and reuptake [2,5,7,8,10–13,15,20,22,26,28,31,32]. Because the degree of DA cell loss observed in non-pathological aging studies does not approach the robust decreases necessary to produce the motor deficits observed in PD or in animal models of PD [16,21,33,34], alterations in the functional properties of DA neurons potentially account for the majority of age-related motor deficits.
Intracerebral microdialysis was used to measure basal levels and potassium (K⁺)-stimulated overflow of dopamine (DA), homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), in the dorsal striatum of young (6 months) and aged (24 months) Fischer 344 (F344) rats. Basal levels of HVA were lower in aged rats whereas basal DA and DOPAC did not differ significantly between the two groups. The administration of three low to moderate doses of K⁺ (10, 25, and 50 mM) through the microdialysis probe for one collection period revealed differences between the two age groups of F344 rats. DA overflow increased in a dose-dependent manner in the young but not aged rats. Extracellular levels of DOPAC and HVA decreased during the K⁺ stimulation and there was a significant difference in the changes in HVA produced by K⁺ stimulation in the young vs aged animals. These data support the hypothesis that low to moderate doses of K⁺ may be necessary to demonstrate age-related differences in K⁺-evoked DA overflow, since previous microdialysis studies using higher doses have not reported age-related differences in DA overflow.

View all citing articles on Scopus

^*: Currently at the Andrus Gerontology Center of the University of Southern California, Los Angeles, Calif. 90007, U.S.A.

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Catecholamine metabolism in the brains of ageing male mice

Abstract

Life Sci.

J. Chron. Dis.

Lancet

Exp. Gerontol.

Advanc. Biol. Med. Phys.

J. biol. Chem.

Exp. Gerontol.

Life Sci.

Analyt. Biochem.

Analyt. Biochem.

An age dependent modification of enzyme regulation

J. biol. Chem.

A study of the factors affecting the aluminum-oxide trihydroxy-indole procedure for the analysis of catecholamines

J. Pharmacol. exp. Ther.

The distribution of dopamine and DOPA in various animals and a method for their determination in diverse biological material

J. Pharmacol. exp. Ther.

A survey of drug-induced extra-pyramidal reactions

J. Amer. med. Ass.

Age changes in conduction velocity, refractory period, number of fibres, connective tissue space, and blood vessels in sciatic nerve of rats

J. comp. Neurol.

Rigid and akinetic forms of Huntington's chorea

Arch. Neurol. (Chic.)

Structural changes in the ageing nervous system

Interdisciplinary Topics in Gerontology

A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid

Biochem. J.

Huntington's chorea in Michigan. III. Clinical observations

Neurology (Minneap.)

Effects of hypothalamic stimulation, hormones, and drugs on ovarian function in old female rats

Neuroendocrine status of old constant-estrous rats

Neuroendocrinology

Decrease in number of myelinated fibers in human spinal roots with age

Anat. Rec.

The in vivo life span of normal and preneoplastic mouse mammary glands: a serial transplantation study

Quantitative histochemical studies of formaldehyde-induced parenchymal fluorescence following l-DOPA administration

J. Neurochem.

Senile tremor versus Parkinson's disease

Postgrad. Med.

Normal and pathologic anatomy of the reticular tissues in laboratory mice with a classification and discussion of neoplasms

J. nat. Canc. Inst.

Effect of ageing on testicular metabolism in the rabbit

Amer. J. Physiol.

Effects of age on human sleep patterns

Comparative biology of senescence: some evolutionary and developmental considerations

Cellular pacemakers of ageing