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

Abstract

Propofol as an agonist of GABAA receptor has a rewarding and discriminative stimulus effect. However, which subtype of the GABAA 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 GABAA receptor on discriminative stimulus effects of propofol. Male Sprague-Dawley rats were trained to discriminate 10 mg/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 10 mg/kg, with response rate reduction only at a dose above those producing the complete substitution. CL218,872 (1–3 mg/kg, intraperitoneal), an α1 subunit-selective GABAA receptor agonist, and SL651,498 (0.3–3 mg/kg, intraperitoneal), an α2/3 GABAA receptor selective agonist, could partially substitute for the discriminative stimulus effects of propofol (40–80% propofol-appropriate responding). Meanwhile, L838,417 (0.2–0.6 mg/kg, intravenous), a α2/3/5 GABAA receptor selective agonist, could produce near 100% propofol-appropriate responding and completely substitute for propofol effects. Moreover, the administration of L655,708, the α5 GABAA receptor inverse agonist, could dose dependently attenuate the discriminative stimulus of propofol. In contrast, the α1 GABAA receptor antagonist β-CCt (1–3 mg/kg) combined with propofol (10 mg/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 α5 GABAA to produce the discriminative stimulus effect.

The Role of NMDA receptors in rat propofol self-administration

“…Our results clearly demonstrate that propofol is capable of mediating reinforcement in self-administration studies, consistent with previous studies [6][7][8]. We found that lower doses of MK-801 (0.1-0.2 mg/kg) were able to increase propofol self-administration infusion numbers in a dose-dependent fashion in rats without impacting general locomotor activity, in line with previous ndings.…”

“…Both conditioned place preference and self-administration studies in animals have further con rmed that propofol can provide reinforcement [3][4][5]. We have previously demonstrated a role for GABA receptors in the ventral tegmental area (VTA) as regulators of propofol self-administration behavior [6]. We further found that the D1R antagonist SCH23390 was able to mediate a simultaneous dose-dependent reduction in propofol selfadministration while also decreasing D1R-associated p-ERK/ERK levels in the nucleus accumbens (NAc) [7,8].…”

The Role of NMDA receptors in rat propofol self-administration

“…Our results clearly demonstrate that propofol is capable of mediating reinforcement in selfadministration studies, consistent with previous studies [6][7][8]. We found that lower doses of MK-801 (0.1-0.2 mg/kg) were able to increase propofol self-administration infusion numbers in a dosedependent fashion in rats without impacting general locomotor activity, in line with previous findings.…”

“…Similarly, MK-801 can mediate the partial inhibition of progressive ERK activation in the NAc and dorsal striatum of rats following acute Δ9tetrahydrocannabinol (THC) administration, while SCH23390 fully blocked this response [42]. We have previously found the D1 dopamine receptors to be linked with ERK activity in the NAc in the context of propofol self-administration [7,8] . This suggests that NMDAR activity is likely a mediator of propofol self-administration responses, with dopamine signaling being dominant and glutamate signaling playing a secondary role in this process.…”

“…We have previously demonstrated a role for GABA receptors in the ventral tegmental area (VTA) as regulators of propofol self-administration behavior [6]. We further found that the D1R antagonist SCH23390 was able to mediate a simultaneous dose-dependent reduction in propofol self-administration while also decreasing D1R-associated p-ERK/ERK levels in the nucleus accumbens (NAc) [7,8]. These previous results clearly indicate that propofol is susceptible to abuse, although the mechanistic basis for this susceptibility remains uncertain.…”