2012). latter Cariporide but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output ARHGEF2 pathways. = 400), the following all-or-none criteria were selected to assess drug-induced effects: (1) C induction of miosis: pupil diameter 11 units (4.3% false positive controls; 400); induction of mydriasis: pupil diameter 25 units (5.2% false positives); inhibition and blockade of tail-pinch response: latency 45 sec and 120 sec, respectively (5.2% and 0.2% false positives, respectively); (2) C reversal of the tail-pinch response blockade: latency 120 sec (4.1% false positives); reversal of miosis: pupil diameter 8 units (1.1% false positives); reversal of palpebral ptosis: score for palpebral opening 1 (3.2% false positives); and reversal of sedation: score 3 (1.1% false positives). Locomotor activity in mice The procedure room was only sparsely lit Cariporide (3C30 lx) to provide better contrast for the video tracking. Each locomotor activity arena (gray PVC cylinder; height: 40 cm; diameter: 22.5 cm) was placed on an infrared LED (8 8 LEDs) lit box (white PVC squared box; 40 40 cm2; height 12.5 cm). An infrared-sensitive tube camera and a white light source (in arena: 4C7 lx) were mounted to the ceiling above the arena to track the animal. Distance travelled was recorded and analyzed using the Noldus Ethovision XT Video Tracking System (Version 3.1; Noldus, Wageningen, the Netherlands). Locomotion was measured over a 30-min period by introducing the mouse into the motor activity arena 30 min after pretreatment with test Cariporide compound or solvent. The arena was cleaned after each trial. In order to stimulate or suppress locomotion, following treatments were used: d-amphetamine (5.0 mg/kg, s.c.; ?0.5 h), SCH-23390 (0.08 mg/kg, i.v.; 0 h), RO-4-1284 (0.63 mg/kg, s.c.; ?0.5 h), or haloperidol (0.31 mg/kg, i.v.; 0 h). General procedure and statistics General procedure All experiments were performed by unbiased trained technicians using coded solutions. Doses were selected from the geometrical series 0.01C0.02C0.0440.0C80.0C160 mg/kg. Each dose group consisted of at least five animals which were tested in separate daily experimental sessions in order to account for day-to-day variability and to minimize systematic errors. Control injections of solvent were included in each experimental session. In Figures ?Figures44C6, dose 0 mg/kg refers to results obtained in solvent-treated control animals that were tested concurrently with the test compounds. Open in a separate window Figure 4 Reversal of Ro-4-1284 (10 mg/kg, s.c.)-induced catalepsy in rats that were cotreated (at the same time) with the PDE10AIs JNJ-42314415, PQ-10, or MP-10 or the dopamine D1 agonist SKF-82958. Shown are individual and median catalepsy scores (symbols and stripes, respectively) per dose group measured 2, 3, and 4 h after dosing. The dotted horizontal lines represent the critical levels adopted for drug-induced reversal of catalepsy (score 2 at 2 h; score 5 at 3 and 4 h) that were used for the determination of the ED50 values listed in Tables ?Tables66C8, ?,10.10. The PDE10AIs dose dependently reduced catalepsy scores to below the critical level. The D1 Cariporide agonist was effective at the 2-h interval and, to a lesser extent, at the 3-h time interval. PDE10AI, phosphodiesterase 10A inhibitor. Open in a separate window Figure 6 Dose-dependent reversal of reserpine-induced sedation and replacement by excitation. Shown are individual and median scores (symbols and stripes, respectively) for sedation and excitation (measured 1 h post reserpine) in.