This article represents the proceedings of a symposium at the 2002 ISBRA/RSA meeting in San Francisco. The organizers were Kalervo Kiianmaa and Andrey E. Ryabinin. The chairs were Kalervo Kiianmaa and Jörgen A. Engel. The presentations were (1) The role of opioidergic and dopaminergic networks in ethanol-seeking behavior, by Kalervo Kiianmaa and Petri Hyytiä; (2) Interaction between the dopamine systems in the prefrontal cortex and nucleus accumbens during ethanol self-administration, by Herman H. Samson; (3) Neurochemical and behavioral studies on ethanol and nicotine interactions, by Jörgen A. Engel, Lennart Svensson, Bo Söderpalm, and Anna Larsson; (4) Involvement of the GABA receptor in alcohol reinforcement in sP rats, by Giancarlo Colombo and Giovanni Vacca; (5) Neuroactive steroids and ethanol reinforcement, by Deborah A. Finn, and (6) Potential contribution of the urocortin system to regulation of alcohol self-administration, by Andrey E. Ryabinin and Ryan K. Bachtell.(B)

G protein-coupled inwardly rectifying potassium channels (GIRKs) provide a common link between numerous neurotransmitter receptors and the regulation of synaptic transmission. We asked whether GIRKs specify a single behavioral action that is produced by drugs acting on the diverse receptors coupled with GIRKs. By using GIRK2-null mutant mice, we found marked reduction or complete elimination of the antinociceptive (hot plate test) effects of ethanol, oxotremorine, nicotine, baclofen, clonidine, and the cannabinoid receptor agonist WIN 55,212. However, ketamine analgesia remained intact. For most drugs, there was a sex difference in antinociceptive action, and the impact of deletion of the GIRK2 channel was less in female mice. The deletion of the GIRK2 channel blocks the opioid-dependent component of stress-induced analgesia (SIA), whereas nonopioid SIA was not changed. We propose that opioid, alpha adrenergic, muscarinic cholinergic, gamma-aminobutyric acid-B, and cannabinoid receptors are coupled with postsynaptic GIRK2 channels in vivo. Furthermore, this pathway accounts for essentially all of the antinociceptive effects in males, although females appear to recruit additional signal transduction mechanisms for some analgesic drugs.

RATIONALE: Previous studies have shown that GIRK2 channel function is enhanced by ethanol and that GIRK2 null mutant mice are less sensitive to some of ethanol's effects, including anxiolysis, habituated locomotor stimulation, and acute handling-induced convulsions than wild types. Under some conditions, GIRK2 knockout mice consume more ethanol than wild types, but it is unclear whether they do so because they are more sensitive to ethanol's rewarding effects or less sensitive to its aversive effects. OBJECTIVE: To further assess the role of GIRK2 in ethanol action, GIRK2 null mutant and wild type mice were tested in conditioning models that measure the motivational effects of ethanol. METHOD: In a conditioned taste aversion (CTA) procedure, knockout and wild type mice were given ethanol (0.0, 2.0, 2.5, or 3.5 g/kg, IP) following 1-h access to saccharin every 48 h over a 10 day period. In a conditioned place preference (CPP) procedure, knockout and wild type mice were given ethanol (2.0 or 3.0 g/kg, IP) paired with one stimulus (grid or hole floor) and saline paired with the other. After four 5-min trials with each stimulus, a 60-min choice test was done. RESULTS: The results demonstrated a genotypic difference in both paradigms. In CTA, there was no difference between genotypes at 0.0 or 3.5 g/kg ethanol, but at the 2.0 and 2.5 g/kg doses, wild types developed a stronger aversion to saccharin than knockouts. In CPP, wild types developed place preference, but knockouts did not. CONCLUSIONS: These studies show that GIRK2 deletion reduced ethanol's impact in tasks that are commonly used to index the drug's rewarding and aversive effects. These findings could reflect either a learning/memory deficit or decreased sensitivity to ethanol's motivational effects in null mutant mice. The latter interpretation is more consistent with previous data showing that knockout mice consume higher doses of ethanol than wild type mice.

Acute functional tolerance to ethanol develops during a single exposure to ethanol; it has been suggested to be a predisposing factor for the development of ethanol dependence. Genetic determinants of acute functional tolerance, as well as of ethanol dependence, have been clearly demonstrated. We describe a novel approach that uses a combination of selective breeding (to segregate genes contributing to the phenotype of interest, i.e., acute functional tolerance to the incoordinating effect of ethanol), quantitative trait locus analysis (to define chromosomal regions associated with acute functional tolerance), and DNA microarray technology (to identify differentially expressed genes in the brains of the selected lines of mice) to identify candidate genes for the complex phenotype of ethanol tolerance. The results indicate the importance of a signal transduction cascade that involves the glutamate receptor delta2 protein, the Ephrin B3 ligand, and the NMDA receptor, as well as a transcriptional regulatory protein that may be induced by activation of the NMDA receptor (zinc finger protein 179) and a protein that can modulate downstream responses to NMDA receptor activation (peroxiredoxin), in mediating acute tolerance to the incoordinating effect of ethanol.