(–)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor

Abstract

The existence of a receptor for γ-aminobutyric acid (GABA) on neurones of the mammalian central nervous system (CNS) is now firmly established^1–3. It is generally accepted that bicuculline (and its methohalide salts) is an antagonist of the actions of GABA^4,5, although resistance to bicuculline has been described^6,7. The view that bicuculline prevents GABA from interacting with a membrane recognition site is supported by results obtained in radiolabelled ligand binding studies^8,9. Bicuculline-sensitive GABA receptors are not confined to neurones in the CNS but are also present on neurones and axons of the peripheral nervous system^10,11. Their existence on neurones in sympathetic ganglia made us consider the possibility that they are also present on the terminals of such neurones. This has recently been tested^12,13 by assuming that if GABA depolarises the terminals in a manner similar to the cell bodies, evoked transmitter output might be decreased (see ref. 14). GABA (ED₅₀, 4µM) clearly decreased the evoked release of accumulated ³H-noradrenaline from rat atria in vitro and ³H-acetylcholine from preganglionic terminals in the rat superior cervical ganglion in vitro without affecting the basal release of tritium. In neither system was the effect of GABA antagonised by bicuculline methobromide, even though the ganglion terminal depolarisation was¹³. This suggested that the two phenomena, depolarisation and inhibition of transmitter release, were separate. The decrease in transmitter release not surprisingly leads to a decrease in the postsynaptic response¹⁵. Again, the decrease in response was not prevented by bicuculline or other GABA antagonists. We believe that these results indicate the presence of a novel GABA receptor on nerve terminals, a theory supported by results obtained with a variety of GABA analogues. For example, 3-aminopropane sulphonic acid (3-APS) which is at least as active as GABA at bicuculline sensitive sites^10,16,17 is inactive at the terminal receptor. By contrast, the analogue baclofen (β-chlorophenyl GABA) is inactive at bicuculline-sensitive sites^18,19 but is as active as GABA in reducing evoked transmitter output¹⁵. This effect of baclofen is stereospecific, the (−) isomer being > 100-fold more active than the (+) isomer¹⁵. We now report the presence of the novel GABA receptor within the mammalian CNS.