The 5HT(1B) receptor agonist, CP-93129, inhibits [(3)H]-GABA release from rat globus pallidus slices and reverses akinesia following intrapallidal injection in the reserpine-treated rat.
This study examined whether activation of 5HT(1B) receptors in the rodent globus pallidus (GP) could reduce GABA release in vitro and reverse reserpine-induced akinesia in vivo. Microdissected slices of GP from male Sprague Dawley rats (300-350 g) were preloaded with [(3)H]-GABA. During subsequent superfusion, 4 min fractions were collected for analysis of release. The effects of the 5HT(1B) receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3, 2-b]pyrid-5-one (CP-93129), on 25 mM KCl-evoked release were examined using a standard dual stimulation paradigm. Male Sprague Dawley rats (270 - 290 g), stereotaxically cannulated above the GP, were rendered akinetic by injection of reserpine (5 mg kg(-1) s.c.). Eighteen hours later, the rotational behaviour induced by unilateral injection of CP-93129 was examined. CP-93129 (0.6-16.2 microM) produced a concentration-dependent inhibition of 25 mM KCl-evoked [(3)H]-GABA release reaching a maximum inhibition of 52.5+/-4.5%. The effect of a submaximal concentration of CP-93129 (5.4 microM) was fully inhibited by the 5HT(1B) receptor antagonist, isamoltane (10 microM). Following intrapallidal injection, CP-93129 (30-330 nmol in 0.5 microl) produced a dose-dependent increase in net contraversive rotations reaching a maximum of 197+/-32 rotations in 240 min at 330 nmol. Pre-treatment with isamoltane (10 nmol in 1 microl) inhibited the effects of a submaximal dose of CP-93129 (220 nmol) by 84+/-6%. These data suggest that at least some 5HT(1B) receptor function as heteroreceptors in the GP, reducing the release of GABA. Moreover, CP-93129-mediated activation of these receptors in the GP provides relief of akinesia in the reserpine-treated rat model of PD.
Chadha
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Neurodegenerative Disease Research Group, Wolfson Centre for Age-Related Diseases, Hodgkin Building, GKT School of Biomedical Sciences, King's College London, London SE1 1UL.
Sur
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Atack
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Duty
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D005917:Globus Pallidus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control*; D011412:Propanolamines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D012110:Reserpine / Q000009:adverse effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism
D011412:Propanolamines; D011725:Pyridines; D011758:Pyrroles; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014316:Tritium; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D005680:gamma-Aminobutyric Acid; D012110:Reserpine; C058392:isamoltane