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. 2013 Apr:67:46-56.
doi: 10.1016/j.neuropharm.2012.10.016. Epub 2012 Nov 9.

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

Y A Blednov  1 , J M Benavidez, M Black, D Chandra, G E Homanics, U Rudolph, R A Harris
Affiliations

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

Y A Blednov et al. Neuropharmacology. 2013 Apr.

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 (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, they indicate that aversive property of ethanol is dependent on ethanol action on α2-containing GABA(A)-R. Deletion of the α2-subunit led to faster recovery whereas absence of the α3-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 α2 and α3 null mutants were found for flurazepam motor incoordination. However, no differences in recovery were found in motor-incoordinating effects of an α1-selective modulator (zolpidem) or an α4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABA(A)-R subunits: α2 and α3. For motor activity, α3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both α2 (-/-) and α3 (-/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 α2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the α2 subunit with human alcoholism.

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Figures

Figure 1
Figure 1. The development of ethanol induced conditioned taste aversion was decreased only in mice lacking of α2 subunit
Changes in saccharin consumption produced by injection of saline or ethanol expressed in percent from control trial (Trial 0). A – Development CTA in α1 (-/-) knockout mice (n = 9 for saline injection for both genotypes; n = 9-14 for groups with ethanol injection). B – Development CTA in α2 (-/-) knockout mice (n = 10 for saline injection for both genotypes; n = 11-14 for groups with ethanol injection). C – Development CTA in α3 (-/Y) knockout mice (n = 7-9 for saline injection for both genotypes; n = 16-19 for groups with ethanol injection). D - Development CTA in α4 (-/-) knockout mice (n = 6 for saline injection for both genotypes; n = 6-7 for groups with ethanol injection). E - Development CTA in α5 (-/-) knockout mice (n = 10 for saline injection for both genotypes; n = 10-12 for groups with ethanol injection). F - Development CTA in δ (-/-) knockout mice (n = 11 for saline injection for both genotypes; n = 12-13 for groups with ethanol injection). Values represent mean ± SEM.
Figure 2
Figure 2. Faster recovery from motor incoordinating effect of ethanol in α2 (-/-) knockout mice and slower recovery in α3 (-/Y) knockout mice
Time on the rotarod (sec) after injection of ethanol (2 g/kg). A – Rotarod recovery in α1 (-/-) knockout mice (n = 5-7 for each genotype). B – Rotarod recovery in α2 (-/-) knockout mice (n = 7 for each genotype). C – Rotarod recovery in α3 (-/Y) knockout mice (n = 5-7 for each genotype). D - Rotarod recovery in α4 (-/-) knockout mice (n = 5 for each genotype). E - Rotarod recovery in α5 (-/-) knockout mice (n = 5-6 for each genotype). F - Rotarod recovery in δ (-/-) knockout mice (n = 6 each genotype). Data are shown as means ± S.E.M. and analyzed by two-way ANOVA with Bonferroni post hoc test. ** P < 0.01, *** P < 0.01 vs wild type group for the time point.
Figure 3
Figure 3. Recovery from motor incoordinating effects of flurazepam, gaboxadol and zolpidem in α2 (-/-) and α3 (-/Y) knockout mice
Time on the rotarod (sec) after injection of flurazepam (35 g/kg), zolpidem (5 mg/kg) and gaboxadol (10 mg/kg). A, C, E – Rotarod recovery in α2 (-/-) knockout mice. B, D, F – Rotarod recovery in α3 (-/Y) knockout mice. A, B – Flurazepam, (n = 5-6 per genotype in α2 colony and n = 6-7 per genotype in α3 (-/Y) colony). C, D – Zolpidem, (n = 6-7 per genotype in α2 colony and n = 6 per genotype in α3 (-/Y) colony). E, F – Gaboxadol, (n = 7-6 per genotype in α2 colony and n = 5-6 per genotype in α3 (-/Y) colony). Data are shown as means ± S.E.M. and analyzed by two-way ANOVA with Bonferroni post hoc test. ** P < 0.01, *** P < 0.01 vs wild type group for the time point.
Figure 4
Figure 4. Effect of ethanol on the motor activity of α2 (-/-) and α3 (-/Y) knockout mice after pre-habituation
A – α2 (-/-) knockout mice (n = 20-21 per genotype). B – α3 (-/Y) knockout mice (n = 13-19 per genotype). Data are shown as means ± S.E.M. and analyzed by two-way ANOVA with repeated measures with Bonferroni post hoc test ($ P < 0.05, $$$ P < 0.001, vs another genotype for the same condition) and within each genotype by one-way ANOVA with repeated measures with Dunnett's test for Multiple comparisons (* P < 0.05, ** P < 0.01, *** P < 0.001 vs saline group).
Figure 5
Figure 5. Effect of ethanol on the grip strength and number of missteps in α2 (-/-) and α3 (-/Y) knockout mice
A, C – α2 (-/-) knockout mice. B, D – α3 (-/Y) knockout mice. A, B – grip strength (n = 8-10 per genotype in α2 colony and n = 15-19 per genotype in α3 colony). C, D – number of missteps (n = 8-10 per genotype in α2 colony and n = 15-19 per genotype in α3 colony). Data are shown as means ± S.E.M. and analyzed by two-way ANOVA with repeated measures.
Figure 6
Figure 6. Anxiolytic effect of ethanol in in α2 (-/-) and α3 (-/Y) knockout mice in elevated plus maze test
A, B, C, D - α2 (-/-) knockout mice. E, F, G, H - α3 (-/Y) knockout mice. A, E – percent of time in open arms (n = 7-13 per genotype in α2 colony and n = 15-13 per genotype in α3 (-/Y) colony). B, F – percent of enters into the open arms. C, G – number of enters into the closed arms. D, H – total number of entries. Data from females and males were combined as there were no sex differences. Data are shown as means ± S.E.M. and analyzed by two-way ANOVA
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