General anesthetics are among the most widely used and important therapeutic agents. The molecular targets mediating different endpoints of the anesthetic state in vivo are currently largely unknown. The analysis of mice carrying point mutations in neurotransmitter receptor subunits is a powerful tool to assess the contribution of the respective receptor subtype to the pharmacological actions of clinically used general anesthetics. We examined the involvement of beta3-containing GABA(A) receptors in the respiratory, cardiovascular, hypothermic, and sedative actions of etomidate and propofol using beta3(N265M) knock-in mice carrying etomidate- and propofol-insensitive beta3-containing GABA(A) receptors. Although the respiratory depressant action of etomidate and propofol, as determined by blood gas analysis, was almost absent in beta3(N265M) mice, the cardiac depressant and hypothermic effects, as determined by radiotelemetry, and the sedative effect, as determined by decrease of motor activity, were still present. Taken together with previous findings, our results show that both immobilization and respiratory depression are mediated by beta3-containing GABA(A) receptors, hypnosis by both beta3- and beta2-containing GABA(A) receptors, while the hypothermic, cardiac depressant, and sedative actions are largely independent of beta3-containing GABA(A) receptors.

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Nitric oxide (NO) and the C-type natriuretic peptide (CNP) exert their action on brain via the cGMP signaling pathway. NO, by activating soluble guanylyl cyclase, and CNP, by stimulating membrane-bound guanylyl cyclase, cause intracellular increases of cGMP, activating cGMP-dependent protein kinases (PKGs). We show here that injection of CNP into the rat ventral tegmental area strongly reduced cocaine-induced egr-1 expression in the nucleus accumbens in a dose-dependent manner. The effect of CNP was reversed by the previous injection of a selective PKG inhibitor, KT5823. Activation of PKG by 8-bromo-cGMP reduced, like CNP, cocaine-induced gene transcription in dopaminergic structures. To confirm the involvement of PKG, this was overexpressed in either the mesencephalon or the caudateputamen. Using the polyethyleneimine delivery system, an active protein was expressed by injecting a plasmid vector containing the human PKG-I␣ cDNA. PKG was overexpressed in dopaminergic and GABAergic neurons when the plasmid was injected in the ventral tegmental area, whereas overexpression was observed in medium spiny GABAergic neurons and in both cholinergic and GABAergic interneurons when the PKG vector was injected into the caudate-putamen. Activation of the overexpressed PKG reduced cocaineinduced egr-1 expression in dopaminergic structures and affected behavior (i.e., locomotor activity). These effects were again reversed by previous injection of the selective PKG inhibitor. The current data suggest that NO and the neuropeptide CNP are potential regulators of cocaine-related effects on behavior.

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