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Distribution of dopamine transporters in basal ganglia of cerebellar ataxic mice by [I-125]RTI-121 quantitative autoradiography

Département de Physiologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
Neurochemistry International (Impact Factor: 2.65). 02/1998; 32(1):61-8. DOI: 10.1016/S0197-0186(97)00042-9
Source: PubMed

ABSTRACT Dopamine (DA) uptake sites, or transporters, were examined with [125I]RTI-121 in mutant mice that exhibit motor control deficits, namely weaver, lurcher and dystonia musculorum. In lurcher mice, the distribution of [125I]RTI-121 binding was similar to controls, except for a decrease in the subthalamic nucleus. For dystonia musculorum mice, the labelling presented no differences between controls and mutants, except for decreases in the dorsal half of caudal neostriatum and in the ventral tegmental area. Moreover, in this mutant the left rostral neostriatum DA transporters were reduced, when compared to the right counterpart. In weaver heterozygote (wv/+) mice, the distribution and density gradients of [125I]RTI-121 labelling were similar as in their controls, except in caudal neostriatum, where binding was slightly higher. In contrast, the weaver homozygote (wv/wv) showed important decreases in labelling of the dorsal quadrant of rostral neostriatum as well as of the dorsal half of caudal neostriatum, where the reductions of binding densities were of 65% to 70%, respectively. There were also slight decreases in [125I]RTI-121 binding in olfactory tubercles as well as in subthalamic nucleus, but only in wv/wv mice. In substantia nigra pars compacta and ventral tegmental area of wv/wv mice the labelling was lower; however, while the 60% decrease in labelling in substantia nigra was highly significant, the 30% reduction in ventral tegmental area did not attain statistical significance. In summary, in the ataxic neurological mutant mice studied, important reductions of DA transporters were documented only for the weaver mice, the cerebellar mutant presenting, besides its cerebellar pathology, a known degeneration of mesencephalic dopaminergic neurons. The results rule out major alterations of the central DA systems in lurcher and dystonia musculorum, and are compatible with the hypothesis that the dopaminergic abnormalities of weaver mutants are not secondary to cerebellar atrophy, but may be a direct consequence of the abnormal weaver gene expressed by DA neurons leading to their apoptotic death.

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    • "The autoradiography procedure was conducted according to Strazielle et al. (1998). After preincubation in 0.05 M NaPB pH 7.4, brain sections were incubated with 20 pM [ 125 I]RTI121 in NaPB pH 7.4 with increasing concentrations of mephedrone or cocaine (0 -30 µM) for 60 minutes at room temperature. "
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    • "-RTI-121 autoradiography was performed to measure DAT levels as previously described (Strazielle et al. 1998). Briefly, slides were pre-washed for 30 min and incubated in 50 mM Tris–HCl (pH 7.4) with 26 pM [ 125 I]-RTI-121 (2200 Ci/ mmol, Perkin-Elmer) for 60 min at 25 °C. "
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    • "Although the cerebellar cortex has completely degenerated in the mutants, one cannot completely exclude that there were resting cannabinoid receptors in this structure responsible for these motor alterations. On the other hand, given the functional integrity of the striato-pallidal system in the Lurcher mice [40] [46], it is also possible that the alteration observed in the latter were the result of the local modulatory action of the delta 9 THC on neurotransmitters processes within basal ganglia [41], i.e. via the modulation of GABAergic and dopaminergic neurotransmission in these structures [8] [18] [42]. This hypothesis is consistent with that we previously proposed: basal ganglia would play a particularly important role in the motor processes in the Lurcher mice and their functional modulation could result in specific motor effects in these mutants [36]. "
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