GABA(B) receptor agonists reverse akinesia following intranigral or intracerebroventricular injection in the reserpine-treated rat.

Abstract

1. This study examined whether GABA(B) receptor agonists injected directly into the substantia nigra pars reticulata (SNr) and globus pallidus (GP), or given intracerebroventricularly, could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, stereotaxically cannulated above the SNr, GP or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg(-1) s.c.). After 18 h, the locomotor effects of the GABA(B) receptor agonists, baclofen or SKF 97541 were examined. 3. Unilateral injection of baclofen (1-5 micro g in 0.5 micro l) into the GP failed to evoke any locomotor response (n=6). In contrast, unilateral intranigral injection of baclofen (0.08-1.6 micro g in 0.5 micro l) produced a dose-dependent increase in net contraversive rotations reaching a maximum of 162+/-24 turns 90 min(-1) (n=6-8). Pretreatment with the selective GABA(B) receptor antagonist, CGP 46381 (2.4 micro g in 0.5 micro l), inhibited the effects of baclofen (0.8 micro g) by 68+/-9% (n=6). 4. Following intracerebroventricular injection, baclofen (0.8-4 micro g in 2 micro l) produced a dose-dependent increase in net arbitrary locomotor units (ALUs), reaching a maximum of 447+/-154 ALUs in 35 min (n=6-7). SKF 97541 (4-32 micro g in 2 micro l) similarly reversed akinesia, reaching 129+/-69 ALUs in 15 min (n=6). 5. These data show that activation of GABA(B) receptors within the SNr, but not the GP, reverses reserpine-induced akinesia. The success of intracerebroventricular injection of baclofen suggests a potential for systemically active GABA(B) receptor agonists in the treatment of akinesia in Parkinson's disease.