Mechanism of action of the hypnotic zolpidem in vivo

Abstract

Zolpidem is a widely used hypnotic agent acting at the GABA(A) receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high affinity to alpha 1-GABA(A) receptors, an intermediate affinity to alpha(2)- and alpha(3)-GABA(A) receptors and fails to bind to alpha(5)-GABA(A) receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying alpha1(H101R) mice, which possess zolpidem-insensitive alpha(1)-GABA(A) receptors, we show that the sedative action of zolpidem is exclusively mediated by alpha(1)-GABA(A) receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by alpha(1)-GABA(A) receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on alpha(1)-GABA(A) receptors and not on alpha(2)- or alpha(3)-GABA(A) receptors.

Figure 1

Effect of (A) diazepam (3–30 mg kg⁻¹) and (B) zolpidem (10–60 mg kg⁻¹) on motor activity in wild type and α₁(H101R) mice. Motor activity was recorded for 1 h after drug administration. Results are expressed as mean counts ×10³±s.e.mean. n=16 mice per group. V, vehicle; ^**P<0.01, Fisher's tests.

Figure 2

Effect of (A) diazepam (3–30 mg kg⁻¹) and (B) zolpidem (3–30 mg kg⁻¹) against the lethal tonic convulsion induced by pentylenetetrazole (120 mg kg⁻¹) in wild type and α₁(H101R) mice. Results are expressed as percentage of mice developing the tonic convulsion. n=10–11 per group. V, vehicle. ^*P<0.05, ^**P<0.01 and ^***P<0.001, Fisher's exact tests.

Figure 3

Effect of (A) diazepam (3–30 mg kg⁻¹) and (B) zolpidem (3–30 mg kg⁻¹) against the myoclonic jerks induced by pentylenetetrazole (120 mg kg⁻¹) in wild type and α₁(H101R) mice. Results are expressed as percentage of mice developing myoclonic jerks. n=10–11 per group. V, vehicle. ^*P<0.05, ^**P<0.01 and ^***P<0.001, Fisher's exact tests.