Nitrogen at Raised Pressure Interacts with the GABAAReceptor to Produce Its Narcotic Pharmacological Effect in the Rat

Abstract

Background Strong evidence supports the concept that conventional anesthetics, including inhalational agents and inert gases, such as xenon and nitrous oxide, interact directly with ion channel neurotransmitter receptors. However, there is no evidence that nitrogen, which only exhibits narcotic potency at increased pressure, may act by a similar mechanism. Methods We compared the inhibitory and sedative effects of gamma-aminobutyric acid (GABA) and nitrogen pressure on locomotor activity and striatal dopamine release in freely moving rats and investigated the pharmacologic properties of the GABA-induced and nitrogen pressure-induced narcotic action using the highly selective competitive GABA(A) receptor antagonist bicuculine. Results Intracerebroventricular GABA infusion up to 60 micromol or exposure to nitrogen pressure up to 3 MPa decreased to a similar extent striatal dopamine release (r2= 0.899, df = 4, P < 0.01) and locomotor activity (r2 = 0.996, df = 28, P < 0.001). However, both agents only showed small effects on striatal dopamine release, reducing dopamine currents by only 12-13% at sedative concentrations. Pretreatment with bicuculline at 0.5, 1, and 2.5 pmol reduced the sedative action of GABA on locomotor activity by 10, 20, and 41%, respectively. Bicuculline in the nanomole range at 1, 2.5, and 5 nmol but not in the picomole range reduced the sedative action of nitrogen pressure by 5, 37, and 73%, respectively. Schild plot analysis is consistent with the fact that bicuculline is a competitive antagonist of both GABA and nitrogen at pressure. Conclusions These results suggest (1) that the presynaptic effects of both GABA and nitrogen pressure on striatal dopamine transmission are modest and not mainly involved in their sedative action and (2) that nitrogen at increased pressure may interact directly with the GABA(A) receptor. However, because the antagonistic effect of bicuculline on nitrogen sedation only occurred at much higher bicuculline concentrations than seen with GABA, it is suggested that nitrogen does not compete for the same site as GABA.