Contribution of the α5 GABAA receptor to the discriminative stimulus effects of propofol in rat

Propofol as an agonist of GABA(A) receptor has a rewarding and discriminative stimulus effect. However, which subtype of the GABA(A) receptor is involved in the discriminative stimulus effects of propofol is still not clear. We observed the effects of an agonist or an antagonist of the subtype-selective GABA(A) receptor on discriminative stimulus effects of propofol. Male Sprague-Dawley rats were trained to discriminate 10mg/kg (intraperitoneal) propofol from intralipid under a fixed-ratio 10 schedule of food reinforcement. We found that propofol produced dose-dependent substitution for propofol at 10mg/kg, with response rate reduction only at a dose above those producing the complete substitution. CL218,872 (1-3mg/kg, intraperitoneal), an 1 subunit-selective GABA(A) receptor agonist, and SL651,498 (0.3-3mg/kg, intraperitoneal), an 2/3 GABA(A) receptor selective agonist, could partially substitute for the discriminative stimulus effects of propofol (40-80% propofol-appropriate responding). Meanwhile, L838,417 (0.2-0.6mg/kg, intravenous), a 2/3/5 GABA(A) receptor selective agonist, could produce near 100% propofol-appropriate responding and completely substitute for propofol effects. Moreover, the administration of L655,708, the 5 GABA(A) receptor inverse agonist, could dose dependently attenuate the discriminative stimulus of propofol. In contrast, the 1 GABA(A) receptor antagonist -CCt (1-3mg/kg) combined with propofol (10mg/kg) failed to block the propofol effect. The data showed that propofol produces discriminative stimulus effects in a dose-dependent manner and acts mainly on the 5 GABA(A) to produce the discriminative stimulus effect.