1 Extracellular single unit recording techniques were used to compare the e ects of (-)-3-amino-1-hydroxypyrrolidin-2-one ((7)-HA-966) and (+)-baclofen on the activity of dopamine-containing neurones in 300 mm slices of rat substantia nigra. Electrophysiological data were compared with the outcome of in vitro binding experiments designed to assess the a nity of (7)-HA-966 for g-aminobutyric acid (GABA B ) receptors. 2 Bath application of (7)-HA-966 produced a concentration-dependent inhibition of dopaminergic neuronal ®ring (EC 50 =444.0 mM; 95% con®dence interval: 277.6 mM ± 710.1 mM, n=27) which was fully reversible upon washout from the recording chamber. Although similar e ects were observed in response to (+)-baclofen, the direct-acting GABA B receptor agonist proved to be considerably more potent than (7)-HA-966 (EC 50 =0.54 mM; 95% con®dence interval: 0.44 mM ± 0.66 mM, n=29) in vitro. 3 Low concentrations of chloral hydrate (10 mM) were without e ect on the basal ®ring rate of nigral dopaminergic neurones but signi®cantly increased the inhibitory e ects produced by concomitant application of (7)-HA-966. 4 The inhibitory e ects of (7)-HA-966 were completely reversed in the presence of the GABA B receptor antagonists, CGP-35348 (100 mM) and 2-hydroxysaclofen (500 mM). Bath application of CGP-35348 alone increased basal ®ring rate. However, the magnitude of the excitation (9.2+0.3%) was not su cient to account for the ability of the antagonist to reverse fully the inhibitory e ects of (7)-HA-966. 5 (7)-HA-966 (0.1 ± 1.0 mM) produced a concentration-dependent displacement of [ 3 H]-GABA from synaptic membranes in the presence of isoguvacine (40 mM). However, the a nity of the drug for GABA B binding sites was signi®cantly less than that of GABA (0.0005 potency ratio) and showed no apparent stereoselectivity. 6 These results indicate that while (7)-HA-966 appears to act as a direct GABA B receptor agonist in vitro, its a nity for this receptor site is substantially less than that of GABA or baclofen and unlikely to account for the depressant actions of this drug which occur at levels approximately ten fold lower in vivo.
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