Effect of aging on dopaminergic receptors and uptake sites in the rat brain studied by receptor autoradiography

Araki, Tsutomu; Kato, Harubumi; Shuto, Katsuro; Fujiwara, Takehiko; Itoyama, Yasuto

doi:10.1016/s0022-510x(96)05343-9

Cited by 39 publications

(18 citation statements)

References 49 publications

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“…; Spear, 2000), stress-induced gonadarche (Spear, 2000), and/or antioxidant systems (Kim et al, 2002). Changes in dopaminergic systems have also been reported (Araki et al, 1997;Cappon et al, 1997;Kokoshka et al, 2000), although this study is the first to evaluate the impact of methamphetamine on VMAT-2 function during this developmental period.…”

Section: Discussionmentioning

confidence: 81%

Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

Truong

Wilkins²,

Baudys

et al. 2005

J Pharmacol Exp Ther

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Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.According to the Substance Abuse and Mental Health Services Administration for 2003 (2004), 1.3% of adolescents aged 12 to 17 and 5.2% of young adults aged 18 to 25 have used illicit methamphetamine (METH) at least once in their lifetime. This is of concern because it is well established that high-dose methamphetamine administrations lead to persistent dopaminergic deficits in rodents, nonhuman primates, and humans, as determined by measuring striatal dopamine levels, tyrosine hydroxylase activity, and dopamine transporter function days to months after treatment (Koda and Gibb, 1973;Wagner et al., 1980;Bennett et al., 1998;Schmidt et al., 1985;Seiden, 1985;Wilson et al., 1996).Most studies of methamphetamine and its actions have involved adult animal models. However, given the prevalence of methamphetamine use among young people, increasing attention has focused on effects of the stimulant in adolescent animal models. For example, Cappon et al. (1997) demonstrated that multiple high-dose administrations of methamphetamine reduce striatal dopamine levels in postnatal day 60, but not postnatal day 20, rats. Similarly, this highdose methamphetamine regimen lead...

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Section: Discussionmentioning

confidence: 81%

Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

Truong

Wilkins²,

Baudys

et al. 2005

J Pharmacol Exp Ther

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“…These results are in accordance with the work of Cunha et al (1995), which showed an age-related decrease in the quantity of A1 adenosine receptors. The decreases observed in the A1 receptor density seem to be a part of a general ageing process affecting many neurotransmitter systems and their receptors, since the density of the receptors of cholinergic (Nabeshima et al, 1994; but also see Araki et al, 1996), dopaminergic (Morelli et al, 1990;Giorgi et al, 1992;Nabeshima et al, 1994;Araki et al, 1997), glutamatergic (Magnusson and Cotman. 1993;Nabeshima et al, 1994;Magnusson, 1995;Wardas et al, 1997) and GABAergic (Matsokis and Valkana, 1983;Nabeshima et al, 1994;Araki et al, 1996;Dalezios and Matsokis, 1998) systems decreases substantially in the aged rat and mouse brain (for review see also Gianquinto, 1988;Cotman and Peterson, 1989).…”

Section: A1 Receptor Quantitative Autoradiographymentioning

confidence: 99%

“…Since no neuronal cell loss in aged rodent neostriatum could be detected by McNeill and Koek (1990) and Zoli et al (1993) and the levels of extracellular adenosine remain unaffected in this area during ageing (Pazzagli et al, 1995), the lower density of A1 receptors seen here could indicate a specific reduction, as a result of the ageing process. Interestingly, several investigators have detected decreased density of D1 and D2 dopamine receptors, as well as dopamine uptake sites in the aged striatum (Morelli et al, 1990;Giorgi et al, 1992;Nabeshima et al, 1994;Araki et al, 1997). As the adenosinergic system interacts with the dopaminergic system in an A1/D1 and A2a/D2 receptor-receptor interaction in the basal ganglia Popoli et al, 1998), the diminuation of A1 adenosine receptors in this brain area could probably reflect a compensatory mechanism in order to re-establish the balance between the adenosinergic and the dopaminergic system during ageing.…”

Section: A1 Receptor Quantitative Autoradiographymentioning

confidence: 99%

“…In order to obtain a better understanding of the ageing process in the nervous system, many researchers have investigated the involvement of certain neurotransmitter systems such as those of acetylcholine (Nabeshima et al, 1994;Araki et al, 1996), dopamine (Morelli et al, 1990;Giorgi et al, 1992;Nabeshima et al, 1994;Araki et al, 1997), glutamate (Magnusson and Cotman. 1993;Nabeshima et al, 1994;Magnusson, 1995;Wardas et al, 1997), and GABA (Matsokis and Valkana, 1983;Nabeshima et al, 1994;Araki et al, 1996;Dalezios and Matsokis, 1998) in the ageing brain.…”

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confidence: 99%

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Age-dependent changes in adenosine A1 receptor and uptake site binding in the mouse brain: An autoradiographic study

2000

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Ageing is a multifactorial, inevitable event of life span, which affects neurotransmission in the CNS. Since adenosine is a major neuromodulator of the synaptic activity, it was of interest to investigate the possible modification of the adenosinergic system in the brain during ageing. Using "in vitro" quantitative autoradiography and the radioactive ligands [(3)H]Cyclohexyladenosine and [(3)H]Nitrobenzylthioinosine, we have studied the distribution of A1 adenosine receptors and adenosine uptake sites in the aged mice (26 months) compared to the young ones (3 months). Our results showed a widespread reduction in A1 receptor binding in the aged animals, which was brain area-specific, occurring in areas where adenosine plays a significant neuromodulatory role such as the hippocampus, cortex, basal ganglia, and thalamus. Interestingly, the significant reduction in NBI-sensitive adenosine uptake sites was restricted to few areas of the aged brain, mainly in thalamic nuclei. Since the alterations in the density of A1 receptors and adenosine uptake sites showed no regional correlation and since no significant changes in either neuronal or glial cell number are observed, at least in hippocampus and cortex in this mouse strain during ageing, our findings could be explained by a selective age-dependent reduction of these adenosinergic components rather than by a general neuronal cell degeneration. As adenosine depresses electrical activity in hippocampus, a downregulation of adenosinergic function could probably be related to enhanced excitability seen in hippocampal neurons of the CA1 subregion and dentate gyrus of aged animals.

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“…D 2 receptor binding was assayed in rat brain sections using [ 3 H]spiperone autoradiography (Palacios et al, 1981;Araki et al, 1997). Sections of rat brain at the level of the caudate/putamen from saline-and WF-23-treated animals were prepared as described above.…”

Section: Methodsmentioning

confidence: 99%

Time-Dependent Changes in Receptor/G-Protein Coupling in Rat Brain following Chronic Monoamine Transporter Blockade

O'Connor

Porrino²,

Davies³

et al. 2005

J Pharmacol Exp Ther

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The potent tropane analog, WF-23 [2␤-propanoyl-3␤-(2-naphthyl) tropane], blocks dopamine, serotonin, and norepinephrine transporters with high affinity in vitro and blocks transporters for at least 2 days following a single in vivo administration. Previous studies demonstrated desensitization of monoamine receptor-coupled G-proteins in brain following chronic treatment of rats with WF-23. The current study sought to determine the time course of this desensitization and the behavioral effects of receptor desensitization. Rats were treated with 1 mg/kg WF-23 and injected i.

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Effect of aging on dopaminergic receptors and uptake sites in the rat brain studied by receptor autoradiography

Cited by 39 publications

References 49 publications

Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

Age-Dependent Methamphetamine-Induced Alterations in Vesicular Monoamine Transporter-2 Function: Implications for Neurotoxicity

Age-dependent changes in adenosine A1 receptor and uptake site binding in the mouse brain: An autoradiographic study

Time-Dependent Changes in Receptor/G-Protein Coupling in Rat Brain following Chronic Monoamine Transporter Blockade

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