Strain-dependent recovery of open-field behavior and striatal dopamine deficiency in the mouse MPTP model of Parkinson’s disease

Abstract

The neurotoxin MPTP can damage dopamine systems in the brains of rodents, cats, or monkeys, and is therefore widely used to model degenerative processes that underlie human Parkinson's disease. Here, we investigated the relationships between behavioral and neurochemical effects of systemic MPTP treatment in C57Bl/6 and Balb/c mice. Initially, different doses of MPTP were used to determine which of them might be useful to establish severe striatal dopamine depletions. These data showed that four injections of 20mg/kg at two hour intervals, were more efficient than 10 or 15mg/kg per injection. However, this dose was not usable due to its severe lethality in females. In contrast, 4x 15mg/kg had a low risk of lethality and led to substantial dopamine depletions, which were more severe in the neostriatum than the ventral striatum, and more severe in C57 than in Balb mice. In the first open field test, which was performed two hours after the last injection, this treatment led to severe behavioral inactivation in all parameters taken (distance and speed of locomotion, peripheral activity, frequency and duration of rearing). This effect was seen in both strains and gender. Thereafter, recovery differed between strains, since Balb mice, which had sustained the smaller lesions, had completely recovered on the subsequent day, whereas similar recovery took longer in C57 mice. On the fourth day, all groups appeared largely normal; however, the measure of rearing behavior still showed a deficit in C57 mice. This deficit on day 4 was correlated with neostriatal dopamine depletion; that is, the larger the lesion, the less the number and duration of rearings. Interestingly, these relationships were also observed with respect to ventral striatal dopamine damage, which was correlated with the rearing deficit not only on day 4, but also on day 1. These data will be discussed with respect to mechanisms of toxicity, functional recovery, and the function of striatal dopamine systems.

Differential degradation of motor deficits during gradual dopamine depletion with 6-hydroxydopamine in mice

“…In contrast, vertical movement, assessed with rearing tasks, has been suggested to correlate strongly with dorsolateral striatal function (Jicha and Salamone 1991, Drago, Gerfen et al 1994, Schwarting, Sedelis et al 1999). To assess how rearing behavior changed over the course of our gradual dopamine depletion, mice were placed in a 1000 mL beaker for 10 minutes, and the number of rears were counted over this period (Fig.…”

“…However, models using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) require increased safety precautions when handling mice which has proven to be a deterrent for widespread application of these models. Furthermore MPTP has had questionable toxicity in various mouse strains and does not always result in persistent and progressive motor symptoms (Bezard, Dovero et al 1997, Schwarting, Sedelis et al 1999, Przedborski, Jackson-Lewis et al 2001, Betarbet, Sherer et al 2002, Meredith, Totterdell et al 2002, McNaught, Perl et al 2004, Schober 2004, Blume, Cass et al 2009, Blesa, Juri et al 2010). Other adapted models utilize 6-hydroxydopamine (6-OHDA), the neurotoxin used in the first animal model of PD associated with SNc dopaminergic neurodegeneration (Ungerstedt 1968).…”

Temporal mRNA profiles of inflammatory mediators in the murine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine model of Parkinson’s disease

“…A number of inbred strains of mice with differential sensitivity to MPTP have been identified and can be used to identify genetic factors (Hamre et al, 1999,Schwarting et al, 1999,Smeyne et al, 2001,Cook et al, 2003,Liu et al, 2003a,McLaughlin et al, 2006. As inflammatory responses have been associated with PD, genetically determined differences in these responses could contribute to the risk for developing this disease.…”

“…A more telling experiment will be to assess whether loss of Mcp-1/Ccl2 causes the normally resistant SWR strain to become sensitive. Finally, though the acute model of MPTP (4 X 20 mg/kg) is widely used (Jackson-Lewis et al, 1995,Hamre et al, 1999,Kaku et al, 1999,Schwarting et al, 1999,Araki et al, 2001,Bolin et al, 2002,Rousselet et al, 2002,Cook et al, 2003,Ferger et al, 2004,Faherty et al, 2005, inflammation could potentially have a different role when animals are chronically treated with this neurotoxicant. Indeed, MPTP dosage and its injection schedule are important determinants of the mode of neurodegeneration in the SNpc (Sonsalla and Heikkila, 1986,Jackson-Lewis et al, 1995,Eberhardt and Schulz, 2003,Youdim and Arraf, 2004,Novikova et al, 2006.…”

Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment

“…Here, only males were studied as Parkinson's disease is more common in men [21]. C57BL/6 mice were used because this strain has been shown to be the most sensitive to MPTP treatment [22][23][24][25]. The behavioral assessments were selected based on previous descriptions of their sensitivity to MPTP treatment or other models of neurodegenerative disease (e.g., assessments of activity, cognition, grip strength, motor coordination, and olfaction) [26,27] and the focus was on short-and long-term alterations.…”