Ifenprodil induced disruption in rat rotarod performance is potentiated by verapamil M. Maginn. Department of Safety Pharmacology, H. Lundbeck A/S., Copenhagen, Denmark, DK 2500.

Print abstract Search PubMed for: Maginn M

Ifenprodil (IFEN) is marketed as Vadilex®, for the treatment of transient ischaemic attack and generalised symptoms of mental deterioration related to cerebrovascular insufficiency (Boyce et al. 1999). It was further shown however that IFEN acts as an NMDA_2B, L-type Ca ²⁺ and œ₁ adrenoceptor antagonist (Boyce et al., 1999). Previous studies have examined the effects of IFEN and more selective NMDA_2B antagonists in rotarod performance in rats (Boyce et al., 1999). The results suggested that IFEN decreased rotarod performance, which is not noted with more selective NMDA2B antagonists. The aim of this study was to examine L-type Ca⁺ involvement in the IFEN effect on rotarod performance, by co-administering IFEN with verapamil (VER) in rats and testing rotarod performance.

To determine the effects of IFEN and verapamil on motor co-ordination, male Wistar rats (180-200 g; Møllegård & Bomholdtgård A/S., Denmark) were first trained on the rotarod on four separate occasions, 2 times per day starting two days before the test. The animals were trained to remain for 120 s on a Harvard Apparatus Coordin8® accelerating rotarod (increasing from 4 to 12 r.p.m.). Any animal that fell off the wheel within the first 30 s was replaced on the wheel and retested. On the day of testing the animals were then randomised into separate groups to receive either IFEN (2, 10 or 20 mg/kg) or saline vehicle (dose volume 5 ml/kg). IFEN was administered intraperitoneally 60 min prior to testing and VER 2.0 and 20 mg/kg or saline (dose volume 5 ml/kg) was administered intraperitoneally 30 min prior to testing. The animals were placed on the accelerating rotarod (increasing from 4 to 40 r.p.m. during a 5 min period) and the time for which the rats were able to remain on the rotarod was recorded. The results are expressed as time (sec) on the wheel.

Table 1: Effect of IFEN and verapamil on rotarod performance

*p<0.01 IFEN (20 mg/kg) vs vehicle, *p<0.05 IFEN (20 mg/kg) + VER (20 mg/kg) vs IFEN (20 mg/kg), #p<0.01 VER (20 mg/kg) + IFEN (20 mg/kg) vs IFEN 20 mg/kg + VER (2 mg/kg) (Repeated measures ANOVA followed by a Dunnett's Multiple Comparison test when p< 0.05).

IFEN behavioural effects are in contrast to the lack of effects of more selective NMDA_2B antagonists (Gill et al., 2002; Higgins et al., 2003). Although verapamil alone had no effect, in combination with IFEN it significantly reduced rotarod performance. Out data suggest that L-type Ca²⁺ channel blockade may be involved in the behavioural effects of IFEN.

Boyce S, et al., (1999) Neuropharmacology, 38, 611-623.
Higgins GA, et al., (2003) Neuropharmacology, 44, 324-341.
Gill R, et al., (2002) J. Pharm & Exp. Ther., 302, 940-948.