JPET150425 Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signalling Daniella Rylander, Alessandra Recchia, Flora Mela, Andrzej Dekundy, Wojciech Danysz, and Angela M Cenci
Supplemental material
Selection of drugs and doses
MTEP is a highly selective mGluR5 antagonist with much fewer off-target effects than any related mGluR5 antagonist compound (Cosford et al, 2003). In the acute study, MTEP was given at the doses of 1.25 and 6.25 mg/kg, which produce approximately 70% and 95% in vivo occupancy of mGluR5 in the brain 1 hour after administration (Busse et al, 2004). In the chronic study, the substance was given at 5 mg/kg, which is an effective antidyskinetic dose (Dekundy et al, 2006; Mela et al, 2007) and the most frequently used dose of the compound in behavioural studies. Some studies in cell cultures have indicated that the neuroprotective effects of mGluR5 antagonists may reflect their ability to inhibit NMDA receptor activity (O'Leary et al, 2000; Homayoun et al, 2004). However this occurs at concentrations that are at least 5- to 50-fold higher than the brain MTEP levels produced by a dose of 5 mg/kg i.p. (Loscher et al, 2006).
EMQMCM is a member of a novel class of quinoline derivatives, which acts as selective and highly potent noncompetitive antagonists at mGluR1 (Lavreysen et al, 2002; Mabire et al, 2005). EMQMCM was tested at doses of 1.25 and 5 mg/kg, which have shown to inhibit haloperidol-induced catalepsy and to attenuate freezing response in a fear conditioning test in the rat (Pietraszek et al, 2005; Dekundy et al, 2006). In the chronic experiment, the dose of 5 mg/kg EMQMCM was used, which has been reported as effective in several behavioural paradigms (Gravius et al, 2005; Dekundy et al, 2006).
LY 379268 is a potent, receptor selective, and systemically active mGluR2/3 agonist (Monn et al, 1999). The doses of the mGluR2/3 agonist in the acute study (1 and 10 mg/kg) were based on reports showing significant behavioural and/or neuroprotective effects in rodents (Bond et al, 2000; Kim & Vezina, 2002). In the chronic study, a dose of 3 mg/kg/day LY379268 was chosen based on preliminary behavioural tests, indicating that higher doses had motor depressant effects on the rotarod (data not shown).
Two selective NR2B antagonists were used in the acute and chronic experiment (Ro631908 and Ro256980, respectively) (Zhou et al, 1999; Nikam & Meltzer, 2002). The compounds had equal selectivity and potency (Mutel et al, 1998; Zhou et al, 1999) but were dissolved in different vehicles (saline and sterile water, respectively), based on the recommendations provided by the manufacturers. The two doses of Ro631908 in the acute study had been reported to produce dose-dependent effects in several behavioural tests in intact rats (Higgins et al, 2003). Since there was no dose-dependent effect of the compound on the expression of phospho-ERK1/2/phospho-MSK-1, the lower dose (3 mg/kg) was used when testing the analogous substance Ro256981 in the chronic experiment. This dose of Ro256981 has shown behavioral effects in several studies (Loschmann et al, 2004; Fantin et al, 2008).
Isradipine is a dihydropyridine antagonist of CaV1.2-1.3 L-type calcium channels (Hof et al, 1984). Drugs of the dihydropyridine family exert a voltage-dependent and frequency-dependent block on L-type calcium channels (Bean, 1984), display high affinity and selectivity for cerebral binding sites (Supavilai & Karobath, 1984) and high bioavailability in the brain following peripheral administration (Kupsch et al, 1996). In the acute study, isradipine was given i.p, 30 min before L-DOPA (Mills et al, 1998), at two doses, the clinically relevant dose of 0.5 mg/kg (see below) and a higher dose (5 mg/kg) that has been found to inhibit cocaine-induced locomotor activity and to affect central DA turnover (Gaggi et al, 1995; Mills et al, 1998). In the chronic study, isradipine was given with subcutaneous timed-release pellets delivering a dose of 0.2 mg/kg/day. At this dose and administration regimen, isradipine has been shown to prevent denervation-induced spine pruning in striatopallidal neurons (Schuster et al, 2008). The daily release from these pellets corresponds to the maximum daily human oral dosage recommended for treating hypertension (Surmeier, 2007). The continuous–release pellets were implanted 1 day before starting treatment with L-DOPA as in Schuster et al. (2008). Inert control pellets were implanted s.c. in animals treated with L-DOPA-only.
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