A strategy for the generation, characterization and distribution of animal models by The Michael J. Fox Foundation for Parkinson's Research.

Progress in Parkinson's disease (PD) research and therapeutic development is hindered by many challenges, including a need for robust preclinical animal models. Limited availability of these tools is due to technical hurdles, patent issues, licensing restrictions and the high costs associated with generating and distributing these animal models. Furthermore, the lack of standardization of phenotypic characterization and use of varying methodologies has made it difficult to compare outcome measures across laboratories. In response, The Michael J. Fox Foundation for Parkinson's Research (MJFF) is directly sponsoring the generation, characterization and distribution of preclinical rodent models, enabling increased access to these crucial tools in order to accelerate PD research. To date, MJFF has initiated and funded the generation of 30 different models, which include transgenic or knockout models of PD-relevant genes such as Park1 (also known as Park4 and SNCA), Park8 (LRRK2), Park7 (DJ-1), Park6 (PINK1), Park2 (Parkin), VPS35, EiF4G1 and GBA. The phenotypic characterization of these animals is performed in a uniform and streamlined manner at independent contract research organizations. Finally, MJFF created a central repository at The Jackson Laboratory (JAX) that houses both non-MJFF and MJFF-generated preclinical animal models. Funding from MJFF, which subsidizes the costs involved in transfer, rederivation and colony expansion, has directly resulted in over 2500 rodents being distributed to the PD community for research use.

L-DOPA reverses motor deficits associated with normal aging in mice.

We wished to determine whether L-DOPA, a common treatment for the motor deficits in Parkinson's disease, could also reverse the motor deficits that occur during aging. We assessed motor performance in young (2-3 months) and old (20-21 months) male C57BL/6 mice using the challenge beam and cylinder tests. Prior to testing, mice were treated with L-DOPA or vehicle. Following testing, striatal tissue was analyzed for phenotypic markers of dopamine neurons: dopamine, dopamine transporter, and tyrosine hydroxylase. Although the dopaminergic markers were unchanged with age or L-DOPA treatment, L-DOPA reversed the motor deficits in the old animals such that their motor coordination was that of a young mice. These findings suggest that some of the locomotor deficits that accompany normal aging are responsive to L-DOPA treatment and may be due to subtle alterations in dopaminergic signaling.

Activation of the extracellular signal-regulated kinases 1 and 2 by glial cell line-derived neurotrophic factor and its relation to neuroprotection in a mouse model of Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to be neuroprotective in animal models of the dopamine deficiency in Parkinson's disease. To examine the role of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in this process, we infused a single dose of GDNF into the striatum of mice and analyzed the effect on ERK1/2 by immunohistochemistry and Western blot analysis. GDNF caused an increase in the phosphorylation of ERK1/2 both in the striatum and in tyrosine hydroxylase-positive neurons in the substantia nigra. In the striatum, the increase in ERK1/2 phosphorylation was evident by 3 hr and persisted for at least 7 days, whereas, in the substantia nigra, an increase in phosphorylated ERK1/2 was first evident at 24 hr and persisted for at least 7 days. The increase in phosphorylated ERK1/2 was maximal at 0.45 microg GDNF at the time points examined. GDNF also protected dopamine terminals against the loss of tyrosine hydroxylase immunoreactivity normally associated with the intrastriatal administration of 6-hydroxydopamine (0.5 microg/0.5 microl). However, this was observed only at a much higher dose of GDNF, 4.5 microg. Thus, our results suggest that the ability of GDNF to protect dopamine neurons cannot be explained solely in terms of its influence on ERK1/2 and that the role of other signaling pathways should be explored.

Voluntary exercise and tail shock have differential effects on amphetamine-induced dopaminergic toxicity in adult BALB/c mice.

Exercise exerts neuroprotective effects and facilitates neural recovery in animal models of Parkinson's disease. In the present studies, effects of exercise on amphetamine-induced dopaminergic toxicity were assessed in mice housed individually either with or without access to run wheels. Mice in run wheel cages ran approximately 20 000 revolutions/day (over 10 km/day). Some mice received amphetamine (18.5 mg/kg x 4 injections) whereas controls received saline. Amphetamine caused a 90% dopamine depletion in mice housed either with or without run wheels. A precipitous drop was seen in run wheel activity following amphetamine, lasting at least 7 days. A significant decrease in food intake, water intake and body weight also occurred. The opportunity to exercise did not facilitate behavioral or neurochemical recovery at 1, 2 or 3 days, or 2 weeks after injections. Therefore, shock stress, a component of some forced exercise studies, was evaluated to determine whether stress without exercise provided neuroprotection against amphetamine. Results indicate that shock stress exerted neuroprotective effects, reducing the amphetamine-induced dopamine depletion. It is concluded that voluntary running does not afford either behavioral or neuroprotection nor facilitate recovery from amphetamine-induced dopaminergic toxicity; rather, elevated glucocorticoid levels following shock stress were associated with a reduction in the dopamine depletion.

Shock stress protects mice against amphetamine-induced dopaminergic toxicity.

The effect of tail shock (ten, 2.0 mA/0.15 s shocks) on amphetamine-induced dopaminergic toxicity in adult, male BALB/c mice was assessed. Fifteen minutes following a single shock session, mice received amphetamine (50-mg/kg) or saline as follows: Shock/Saline; NoShock/Saline; Shock/Amphetamine; No Shock/Amphetamine. Amphetamine caused a 60% dopamine depletion in the No Shock/Amphetamine group. Tail shock provided neuroprotection against amphetamine-induced dopamine depletion, an effect likely related to the stress response.

Effects of phencyclidine on schedule-controlled responding following neurotoxic lesions of the striatum.

The effects of phencyclidine on an operant task were evaluated prior to and after neurotoxic lesions of the striatum in rats. Subjects were trained to respond on a fixed-interval 90-second schedule for water presentation. The degree to which phencyclidine disrupted responding was first evaluated (dose range 1.0-4.0 mg/kg). The subjects were then divided into three matched groups and received bilateral intraventricular injections of 6-hydroxydopamine (6-OHDA) (100 microg), kainic acid (0.25 microg), or vehicle delivered stereotaxically. 6-OHDA was used to destroy the presynaptic neurons of the nigro-striatal pathway and kainic acid was employed to destroy the postsynaptic neurons whose cell bodies are located in the striatum. Following recovery, the phencyclidine dose-response curve was repeated in the fixed-interval paradigm. It was observed that 6-OHDA-induced damage resulted in a rightward shift of the dose-response curve indicating tolerance to phencyclidine and caused a significant depletion of striatal dopamine and gamma-aminobutyric acid (GABA). Kainic acid-induced damage resulted in a leftward shift in the dose-response curve indicating sensitivity to the schedule-disruptive effects of phencyclidine and produced a significant GABA depletion. The vehicle-treated rats exhibited no shift in their sensitivity to phencyclidine. These observations indicate that the effects of phencyclidine are mediated, at least in part, by striatal dopaminergic neurons.

Effects of nicotine on target biting and resident-intruder attack.

The effects of acute administration of nicotine on target biting (defensive) and resident-intruder (offensive) attack of male mice were assessed. In the target biting procedure confined mice received tail shock on a fixed time, 2-min schedule. Under baseline conditions, biting attack directed toward an inanimate target occurred at three distinct rates. A high target biting rate (13.5 +/- 3.8 bites/15 sec) followed shock delivery, an intermediate biting rate (9.6 +/- 4.1 bites/15 sec) occurred during the inter-shock interval, and a low biting rate (1.0 +/- 0.5 bites/15 sec) occurred during a tone stimulus which signalled the impending shock. Nicotine (administered IP, 15 min presession) reduced post-shock and inter-shock interval target biting in a dose-dependent manner (ED50 values estimated at 0.13 and 0.14 mg/kg, respectively) but exerted more variable effects on target biting during the tone. In the resident-intruder paradigm the same mice were exposed to an intruder introduced into its home cage for a 10-min test session. Under baseline conditions, residents directed 20 +/- 3.2 biting attacks toward the intruder during the session with an average latency of 89 +/- 40 sec to the first attack. Nicotine caused a dose-dependent decrease in this attack behavior (ED50 values estimated to be 0.48 and 0.49 mg/kg, respectively). These observations are interpreted to indicate that nicotine has an increased potency at reducing "defensive" aggression.