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1. Extracellular single unit recording techniques were used to compare the effects of (-)-3-amino-1-hydroxypyrrolidin-2-one ((-)-HA-966) and (+/-)-baclofen on the activity of dopamine-containing neurones in 300 microns slices of rat substantia nigra. Electrophysiological data were compared with the outcome of in vitro binding experiments designed to assess the affinity of (-)-HA-966 for gamma-aminobutyric acid (GABAB) receptors. 2. Bath application of (-)-HA-966 produced a concentration-dependent inhibition of dopaminergic neuronal firing (EC50 = 444.0 microM; 95% confidence interval: 277.6 microM - 710.1 microM, n = 27) which was fully reversible upon washout from the recording chamber. Although similar effects were observed in response to (+/-)-baclofen, the direct-acting GABAB receptor agonist proved to be considerably more potent than (-)-HA-966 (EC50 = 0.54 microM; 95% confidence interval: 0.44 microM - 0.66 microM, n = 29) in vitro. 3. Low concentrations of chloral hydrate (10 microM) were without effect on the basal firing rate of nigral dopaminergic neurones but significantly increased the inhibitory effects produced by concomitant application of (-)-HA-966. 4. The inhibitory effects of (-)-HA-966 were completely reversed in the presence of the GABAB receptor antagonists, CGP-35348 (100 microM) and 2-hydroxysaclofen (500 microM). Bath application of CGP-35348 alone increased basal firing rate. However, the magnitude of the excitation (9.2 +/- 0.3%) was not sufficient to account for the ability of the antagonist to reverse fully the inhibitory effects of (-)-HA-966. 5. (-)-HA-966 (0.1-1.0 mM) produced a concentration-dependent displacement of [3H]-GABA from synaptic membranes in the presence of isoguvacine (40 microM). However, the affinity of the drug for GABAB binding sites was significantly less than that of GABA (0.0005 potency ratio) and showed no apparent stereoselectivity. 6. These results indicate that while (-)-HA-966 appears to act as a direct GABAB receptor agonist in vitro, its affinity 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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H M daSilva, and
N G Bowery, and
S T Connelly, and
P D Shepard
June 1990,
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K C Grobaski, and
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