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Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.

ABSTRACT: GABA type A receptors (GABA(A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABA(A)-R subunits (?1, ?2, ?3, ?4, ?5 and ?). Only mice lacking the ?2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the ?2-subunit (Blednov et al., 2011). All together, they indicate that aversive property of ethanol is dependent on ethanol action on ?2-containing GABA(A)-R. Deletion of the ?2-subunit led to faster recovery whereas absence of the ?3-subunit slowed recovery from ethanol-induced incoordination (rotarod). Deletion of the other four subunits did not affect this behavior. Similar changes in this behavior for the ?2 and ?3 null mutants were found for flurazepam motor incoordination. However, no differences in recovery were found in motor-incoordinating effects of an ?1-selective modulator (zolpidem) or an ?4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABA(A)-R subunits: ?2 and ?3. For motor activity, ?3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both ?2 (-/-) and ?3 (-/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg). These studies demonstrate that the effects of ethanol at GABAergic synapses containing ?2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the ?2 subunit with human alcoholism.

SUBMITTER: Blednov YA

PROVIDER: S-EPMC3562427 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.

Blednov Y A YA Benavidez J M JM Black M M Chandra D D Homanics G E GE Rudolph U U Harris R A RA

Neuropharmacology 20121109

GABA type A receptors (GABA(A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABA(A)-R subunits (α1, α2, α3, α4, α5 and δ). Only mice lacking the α2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the α2-subunit (Blednov et al., 2011). All together ...[more]

PMID: 23147414

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Project description:BackgroundNegative outcomes of alcoholism are progressively more severe as the duration of problem of alcohol use increases. Additionally, alcoholics demonstrate tendencies to neglect negative consequences associated with drinking and/or to choose to drink in the immediate presence of warning factors against drinking. The recently derived crossed high-alcohol-preferring (cHAP) mice, which volitionally drink to heavier intoxication (as assessed by blood ethanol [EtOH] concentration) than other alcohol-preferring populations, as well as spontaneously escalating their intake, may be a candidate to explore mechanisms underlying long-term excessive drinking. Here, we hypothesized that an extended drinking history would reduce the ability of 2 manipulations (forced abstinence [FA] and conditioned taste aversion [CTA]) to attenuate drinking.MethodsExperiment 1 examined differences between groups drinking for either 14 or 35 days, half of each subjected to 7 days of FA and half not, to characterize the potential changes in postabstinence drinking resulting from an extended drinking history. Experiment 2 used a CTA procedure to assess stimulus specificity of the ability of an aversive flavorant to decrease alcohol consumption. Experiment 3 used this taste aversion procedure to assess differences among groups drinking for 1, 14, or 35 days in their propensity to overcome this aversion when the flavorant was mixed with either EtOH or water.ResultsExperiment 1 demonstrated that although FA decreased alcohol consumption in mice with a 14-day drinking history, it failed to do so in mice drinking alcohol for 35 days. Experiment 2 showed that the addition of a flavorant only suppressed alcohol drinking if an aversion to the flavorant was previously established. Experiment 3 demonstrated that an extended drinking history expedited extinction of suppressed alcohol intake caused by a conditioned aversive flavor.ConclusionsThese data show that a history of long-term drinking in cHAP mice attenuates the efficacy of interventions that normally reduce drinking. Analogous to alcoholics who may encounter difficulties in limiting their intake, cHAP mice with long drinking histories are relatively insensitive to both abstinence and signals of harmful consequences. We propose that the cHAP line may be a valid model for adaptations that occur following the extended heavy alcohol drinking.

Dataset Information

Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.

Publications

Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication.

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