The GABAB antagonist, CGP 35348, antagonizes the effects of baclofen, gamma-butyrolactone and HA 966 on rat striatal dopamine synthesis.
The effects of the new GABAB antagonist, CGP 35348 (3-aminopropane-diethoxymethylphosphinic acid), on rat striatal dopamine synthesis and the increases thereof, caused by (-)-baclofen, gamma-butyrolactone (GBL), and HA 966 (3-amino-1-hydroxypyrrolid-2-one), were investigated. CGP 35348 did not alter dopamine synthesis on its own up to the highest dose tested (500 mg/kg i.p.). However, it antagonized the increase elicited by 50 mg/kg s.c. (-)-baclofen at doses above 100 mg/kg i.p.; at 500 mg/kg i.p. this antagonism disappeared within about 6 h of interval between the administration of the compound and (-)-baclofen. CGP 35348 also clearly and significantly attenuated the effects of graded doses of GBL and HA 966 at 500 mg/kg i.p., but was unable to alter the responses elicited by 0.3 mg/kg i.p. haloperidol or 10 mg/kg i.p. tetrabenazine. This indicates that the compound did not generally attenuate increases of dopamine synthesis. It is likely that its GABAB antagonistic properties are responsible for the attenuation of the effect of (-)-baclofen, and our results suggest that this compound is useful for the characterization of the role of GABAB receptors in vivo, e.g. in behaviour. On the other hand, they also suggest the possibility that GBL and HA 966 elicit their effects on dopamine synthesis by means of an interaction with GABAB receptors; a weak in vitro interaction with the latter in radioligand binding experiments has been found for GBL, but not for HA 966.
Waldmeier
P C
PC
Research Department, Pharmaceuticals Division, Ciba-Geigy Ltd., Basel, Switzerland.
D015107:4-Butyrolactone / Q000037:antagonists & inhibitors*; D000818:Animals; D001418:Baclofen / Q000037:antagonists & inhibitors*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D058787:GABA-A Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000037:antagonists & inhibitors*; D051381:Rats; D013747:Tetrabenazine / Q000494:pharmacology
D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D011760:Pyrrolidinones; D004295:Dihydroxyphenylalanine; C066430:CGP 35348; C001369:1-hydroxy-3-amino-2-pyrrolidone; D001418:Baclofen; D006220:Haloperidol; D015107:4-Butyrolactone; D004298:Dopamine; D013747:Tetrabenazine