TY - JOUR

T1 - Electrophysiological studies of the GABAA receptor ligand, 4‐PIOL, on cultured hippocampal neurones

AU - Kristiansen, U.

AU - Lambert, J. D.C.

AU - Falch, E.

AU - Krogsgaard‐Larsen, P.

PY - 1991/9

Y1 - 1991/9

N2 - Whole‐cell, patch‐clamp recordings from cultured hippocampal neurones have been used to characterize the action of the GABAA ligand, 5‐(4‐piperidyl)isoxazol‐3‐ol (4‐PIOL). The action of 4‐PIOL was compared with that of the established GABAA agonist, isoguvacine. With a symmetrical Cl−gradient across the membrane and a holding potential of −60 mV, both isoguvacine and 4‐PIOL evoked an inward current. The reversal potentials of the responses to both agents were identical (+8.8 mV, n = 4) and the current/voltage relationships showed outward‐going rectification. The response to 300 μm 4‐PIOL was completely blocked by the GABAA antagonist, bicuculline methobromide (BMB, 10 μm). The pA2 of BMB was >6.46. With 2 mm 4‐PIOL about 15% of the response remained in the presence of 100 μm BMB. This may represent a non‐specific component of the response to large concentrations of 4‐PIOL. 4‐PIOL was about 200 times less potent as an agonist than isoguvacine. Because of the rapid fade (desensitization) of isoguvacine‐induced currents, the maximum response to this agonist was not determined. However, the response to 2 mm 4‐PIOL was only a small fraction of that evoked by submaximal concentrations of isoguvacine. Setting the response to 1 mm 4‐PIOL as maximum, the EC50 for 4‐PIOL was 91 μm (95% confidence limits: 73–114 μm). 4‐PIOL antagonized the response to isoguvacine with a parallel shift to the right of the dose‐response curve. The antagonist action of 4‐PIOL was about 30 times weaker than that of BMB. When allowance was made for the intrinsic agonist action of 4‐PIOL, the Ki was 116 μm (95% confidence limits: 102–130 μm). This was not significantly different from EC50 (P = 0.86; non‐parametric Mann‐Whitney test). It is concluded that 4‐PIOL is a partial agonist at the GABAA receptor on cultured hippocampal neurones. 1991 British Pharmacological Society

AB - Whole‐cell, patch‐clamp recordings from cultured hippocampal neurones have been used to characterize the action of the GABAA ligand, 5‐(4‐piperidyl)isoxazol‐3‐ol (4‐PIOL). The action of 4‐PIOL was compared with that of the established GABAA agonist, isoguvacine. With a symmetrical Cl−gradient across the membrane and a holding potential of −60 mV, both isoguvacine and 4‐PIOL evoked an inward current. The reversal potentials of the responses to both agents were identical (+8.8 mV, n = 4) and the current/voltage relationships showed outward‐going rectification. The response to 300 μm 4‐PIOL was completely blocked by the GABAA antagonist, bicuculline methobromide (BMB, 10 μm). The pA2 of BMB was >6.46. With 2 mm 4‐PIOL about 15% of the response remained in the presence of 100 μm BMB. This may represent a non‐specific component of the response to large concentrations of 4‐PIOL. 4‐PIOL was about 200 times less potent as an agonist than isoguvacine. Because of the rapid fade (desensitization) of isoguvacine‐induced currents, the maximum response to this agonist was not determined. However, the response to 2 mm 4‐PIOL was only a small fraction of that evoked by submaximal concentrations of isoguvacine. Setting the response to 1 mm 4‐PIOL as maximum, the EC50 for 4‐PIOL was 91 μm (95% confidence limits: 73–114 μm). 4‐PIOL antagonized the response to isoguvacine with a parallel shift to the right of the dose‐response curve. The antagonist action of 4‐PIOL was about 30 times weaker than that of BMB. When allowance was made for the intrinsic agonist action of 4‐PIOL, the Ki was 116 μm (95% confidence limits: 102–130 μm). This was not significantly different from EC50 (P = 0.86; non‐parametric Mann‐Whitney test). It is concluded that 4‐PIOL is a partial agonist at the GABAA receptor on cultured hippocampal neurones. 1991 British Pharmacological Society

KW - 4‐PIOL (5‐(4‐piperidyl)isoxazol‐3‐ol)

KW - bicuculline methobromide

KW - cultured hippocampal neurones

KW - GABA partial agonist/antagonist

KW - isoguvacine

KW - THIP analogue

KW - whole‐cell patch‐clamp

UR - http://www.scopus.com/inward/record.url?scp=0025918363&partnerID=8YFLogxK

U2 - 10.1111/j.1476-5381.1991.tb12389.x

DO - 10.1111/j.1476-5381.1991.tb12389.x

M3 - Journal article

C2 - 1664767

AN - SCOPUS:0025918363

VL - 104

SP - 85

EP - 90

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 1

ER -