In the present study, we describe a new role of the neuronal nitric oxide synthase (nNOS) gene in the regulation of alcohol drinking behavior. Mice deficient in the nNOS gene (nNOS Ϫ/Ϫ) and wild-type control mice were submitted to a two-bottle free-choice procedure with either water or increasing concentrations of alcohol (2-16%) for 6 weeks. nNOS Ϫ/Ϫ mice did not differ in consumption and preference for low alcohol concentrations from wild-type animals; however, nNOS Ϫ/Ϫ mice consumed sixfold more alcohol from highly concentrated alcohol solutions than wild-type mice. Taste studies with either sucrose or quinine solutions revealed that alcohol intake in nNOS Ϫ/Ϫ and wild-type mice is associated, at least in part, with sweet solution intake but not with the taste of bitterness. When compared with wild-type mice, the nNOS Ϫ/Ϫ mice were found to be less sensitive to the sedative effects of ethanol as measured by shorter recovery time from ethanol-induced sleep and did not develop rapid tolerance to ethanol-induced hypothermia, although plasma ethanol concentrations were not significantly different from those of controls. Our findings contrast with previous reports that showed that nonselective NOS inhibitors decrease alcohol consumption. However, because alcohol consumption was suppressed in wild-type as well as nNOS Ϫ/Ϫ mice by the NOS inhibitor N G -nitro-L-arginine methyl ester, we conclude that the effect of nonselective NOS inhibitors on alcohol drinking is not mediated by nNOS. Other NOS isoforms, most likely in the periphery or other splice variants of the NOS gene, might contribute to the effect of nonselective NOS inhibitors on alcohol drinking. In summary, the nNOS gene is critically involved in the regulation of neurobehavioral effects of alcohol.

Previously, only in vitro studies have shown that chronic administration of morphine provokes long-lasting enhanced activity of accumbal cholinergic neurons, which may contribute to the behavioural sensitization, positive reinforcement and aversive effects associated with enhanced drug-seeking. The present study was aimed at clarifying whether these adaptive changes would also be supported by in vivo microdialysis measurements in freely moving rats, distinguishing between the accumbal substructures shell and core, and observing behavioural changes simultaneously. Acute administration of morphine dose-dependently decreased acetylcholine (ACh) release in the nucleus accumbens (NAc), with 10 mg/kg s.c. being most effective, 5 mg/kg ineffective. On day 5 of spontaneous abstinence from chronic morphine treatment (10-40 mg/kg morphine dose once daily for 5 days), when withdrawal symptoms were still present, even a lower morphine dose (5 mg/kg) was effective in decreasing ACh release in the NAc. During the later phase of abstinence, when no withdrawal symptoms were detectable, the opposite effect, i.e. an increase of ACh release was found. This later effect may represent a long-lasting neuroadaptive effect of morphine. These adaptive effects seemed to be more prominent in the NAc shell. Concurrent with these changes in ACh release, morphine challenges produced marked behavioural stereotypes, possibly indicating behavioural sensitization.

Iosimenol is the only CM which, although isotonic, affords, unlike current nonionic dimers, at the same iodine concentration the low viscosity of monomeric, nonionic agents, which are all hypertonic. Iosimenol's pharmacologic characteristics closely resemble those of iotrolan and iodixanol.

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