NMDA receptor antagonists ameliorate the stepping deficits produced by unilateral medial forebrain bundle injections of 6-OHDA in rats

Abstract

These data indicate that deficits in contralateral stepping are a reliable and sensitive measure of akinesia in unilateral 6-OHDA-lesioned rats, and they support the hypothesis that excess glutamatergic transmission at NMDA receptors may play a role in the expression of PD symptomology.

The Nociceptin/Orphanin FQ Receptor Antagonist J-113397 and l-DOPA Additively Attenuate Experimental Parkinsonism through Overinhibition of the Nigrothalamic Pathway

“…The bar test essentially measures the time to initiate a movement (akinesia), whereas the drag test measures both the time to initiate and to execute it (bradykinesia). The degree of motor asymmetry in the drag test (ϳ65%) was consistent with that reported by Wessell et al (2004) (ϳ75%) and in line with that found with the stepping [ϳ90% (Olsson et al, 1995); 80 -90% (Winkler et al, 2002); ϳ70% (Tillerson et al, 2001); ϳ75% (Tseng et al, 2005); 50 -90% (Kelsey et al, 2004)] or the postural adjustment [ϳ75% (Lindner et al, 1996); Ͼ95% (Chang et al, 1999)] tests. Powerful, dose-dependent attenuation of parkinsonism was produced by increasing L-DOPA doses: reduction of akinesia at both the ipsilateral and the contralateral forepaw (0.1 mg/kg), improvement of exercise-induced motor performance (0.3 mg/kg), and reversal of motor asymmetry both under resting (bar test) and dynamic (drag test) conditions (6 mg/kg).…”

“…Powerful, dose-dependent attenuation of parkinsonism was produced by increasing L-DOPA doses: reduction of akinesia at both the ipsilateral and the contralateral forepaw (0.1 mg/kg), improvement of exercise-induced motor performance (0.3 mg/kg), and reversal of motor asymmetry both under resting (bar test) and dynamic (drag test) conditions (6 mg/kg). Similar findings were reported by using the stepping (Olsson et al, 1995;Chang et al, 1999;Winkler et al, 2002;Kelsey et al, 2004), postural adjustment (Lindner et al, 1996), and "wheelbarrow" [i.e., forward dragging (Schallert et al, 1979)] tests. It is noteworthy that L-DOPA exerted an antiparkinsonian action at doses (0.1-6 mg/kg) lower than those eliciting contralateral rotations (25 mg/ kg), strengthening the view that ethological tests may be more sensitive than analysis of pharmacologically induced (e.g., by dopamine agonists) turning behavior in screening for antiparkinsonian drugs.…”

The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat

“…As in prior studies from our laboratory and elsewhere (Chang et al 1999;Kelsey et al 2004;Olsson et al 1995), unilateral 6-OHDA lesions of the MFB produced profound deficits in contralateral forepaw stepping. Across all five batches of rats, the lesioned animals stepped 74-83% less with the contralateral right paw than with the left paw.…”

“…This preparation appears to provide an excellent model of the akinesic effects of PD as the impairment in contralateral stepping is correlated with the loss of DA in the dorsal striatum and is improved, but not normalized, by injections of L-DOPA (Chang et al 1999;Kelsey et al 2004;Olsson et al 1995). Moreover, this model appears to be more sensitive to therapeutic effects than other rodent models as improvement in stepping can be seen with doses of L-DOPA as low as 1 mg/kg (Kelsey et al 2004), whereas 25-50 mg/kg are typically used to produce contralateral turning (Engber et al 1994;Löschmann et al 1991) and 50-100 mg/kg are typically used to reduce catalepsy and rigidity (Shiozaki et al 1999;Wardas et al 2001).…”

“…The intent of this study was to examine the extent to which caffeine and more selective adenosine antagonists could provide monotherapeutic and adjunctive therapeutic effects on the impaired contralateral forepaw stepping produced by unilateral 6-OHDA lesions of the medial forebrain bundle (MFB) in rats (Chang et al 1999;Kelsey et al 2004;Olsson et al 1995). This preparation appears to provide an excellent model of the akinesic effects of PD as the impairment in contralateral stepping is correlated with the loss of DA in the dorsal striatum and is improved, but not normalized, by injections of L-DOPA (Chang et al 1999;Kelsey et al 2004;Olsson et al 1995).…”