Bicuculline insensitive effects of baclofen

The action of bicuculline on the effect of baclofen and muscimol were investigated in behavioural, biochemical and binding studies in rats. Both (+/-)-baclofen (5 mg kg-1 i.p.) and muscimol (1.4 mg kg-1 i.p.) decreased motor activity and aggressiveness. In investigated doses the drugs mentioned raised DOPAC concentration in the rat striatum. (+)-Bicuculline (1.25 mg kg-1 s.c.) potentiated the behavioural effects of baclofen but failed to alter significantly those of muscimol. The DOPAC rise caused by baclofen and muscimol was not substantially affected by bicuculline. 3H-GABA binding to bicuculline insensitive GABA sites was determined in the rat striatal tissue. (+)-Bicuculline was used to suppress bicuculline sensitive GABA binding. Two GABA binding sites were revealed in the presence of calcium ions of which the low affinity site (KD = 447 nM, B max = 109 pmol g-1 protein) was affected by bicuculline whereas the high affinity site (KD = 8 nM, B max = 24 pmol g-1 protein) was not. Muscimol, GABA and (+/-)-baclofen bound in vitro to these GABA sites with IC50, 44, 49 and 431 nM respectively. The involvement of bicuculline insensitive GABA sites in the effects of (+/-)-baclofen on behaviour and dopamine metabolism is suggested.