GABA(B) receptor agonists reverse akinesia following intranigral or intracerebroventricular injection in the reserpine-treated rat.
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.
Johnston
Tom
T
Neurodegenerative Disease Research Group, Wolfson Centre for Age-Related Diseases, Hodgkin Building, GKT School of Biomedical Sciences, King's College London, London SE1 1UL.
Duty
Susan
S
D000818:Animals; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D058786:GABA-B Receptor Agonists; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D018476:Hypokinesia / Q000139:chemically induced / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology; D010721:Phosphinic Acids / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D018755:GABA Agonists; D018756:GABA Antagonists; D058786:GABA-B Receptor Agonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; C086109:3-aminopropyl-cyclohexylmethylphosphinic acid; C068457:3-aminopropyl(methyl)phosphinic acid; D012110:Reserpine; D001418:Baclofen