Limits...
Voluntary Ethanol Consumption Induced by Social Isolation Reverses the Increase of α(4)/δ GABA(A) Receptor Gene Expression and Function in the Hippocampus of C57BL/6J Mice.

Sanna E, Talani G, Obili N, Mascia MP, Mostallino MC, Secci PP, Pisu MG, Biggio F, Utzeri C, Olla P, Biggio G, Follesa P - Front Neurosci (2011)

Bottom Line: SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA(A)R.Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI.We conclude that self-administration of EtOH selectively abolishes the increase of α(4) subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

View Article: PubMed Central - PubMed

Affiliation: Section of Neuroscience, Department of Experimental Biology, Center of Excellence for the Neurobiology of Dependence, University of Cagliari Monserrato, Cagliari, Italy.

ABSTRACT
Post-weaning social isolation (SI) is a model of prolonged mild stress characterized by behavioral and neurochemical alterations. We used SI in C57BL/6J mice to investigate the effects of ethanol (EtOH) in the free-choice drinking paradigm on gene expression and function of γ-aminobutyric acid type A receptors (GABA(A)Rs) and the role of neuroactive steroids in the actions of EtOH in the hippocampus. SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA(A)R. The gene expression of the α(4) and δ subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the γ(2) subunit was decreased whereas that of the α(1) did not change. Patch-clamp recordings in dentate gyrus (DG) granule cells obtained from SI C57BL/6J mice revealed a greater enhancement of tonic currents induced by α-(4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) compared to that in control C57BL/6J mice. These neurochemical, molecular and functional changes observed in SI C57BL/6J mice were associated with an increased EtOH intake and EtOH preference. Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the α(4) subunit but not those of the δ and γ(2) subunits induced by SI. In addition, EtOH self-administration did not block the SI-induced changes in GABA(A)R-mediated tonic inhibition in hippocampal granule cells but increased the frequency of basal GABAergic sIPSCs in DG granule cells. We conclude that self-administration of EtOH selectively abolishes the increase of α(4) subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

No MeSH data available.


Related in: MedlinePlus

Effect of voluntary EtOH consumption on GABAergic tonic current in granule cells of the DG from GH and SI C57BL/6J mice. (A) Representative traces of GABAergic currents recorded in the whole-cell mode (holding potential, −65 mV) from granule cells of the DG are shown (left panel) for hippocampal slices obtained from group-housed (GH) or isolated (SI) mice exposed to water only, and GH and SI animals exposed to EtOH. All recordings were performed in the presence of kynurenic acid (3 mM) to block glutamatergic currents. After a baseline of 3 min, application of THIP (3 μM) induced an increase in noise variance and a negative shift in the holding current. All GABAergic currents were blocked by the application of bicuculline (Bic) at 20 μM. Calibration, 100 pA, 20 s. (B,C), bar graphs summarizing the changes in noise variance (B) and holding current (C) induced by the bath perfusion of THIP in experiments similar to those shown in (A). Data are mean ± SEM (n = 19–25 neurons). *p < 0.05 vs. GH mice exposed to water only (ANOVA followed by Scheffe's test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3039156&req=5

Figure 9: Effect of voluntary EtOH consumption on GABAergic tonic current in granule cells of the DG from GH and SI C57BL/6J mice. (A) Representative traces of GABAergic currents recorded in the whole-cell mode (holding potential, −65 mV) from granule cells of the DG are shown (left panel) for hippocampal slices obtained from group-housed (GH) or isolated (SI) mice exposed to water only, and GH and SI animals exposed to EtOH. All recordings were performed in the presence of kynurenic acid (3 mM) to block glutamatergic currents. After a baseline of 3 min, application of THIP (3 μM) induced an increase in noise variance and a negative shift in the holding current. All GABAergic currents were blocked by the application of bicuculline (Bic) at 20 μM. Calibration, 100 pA, 20 s. (B,C), bar graphs summarizing the changes in noise variance (B) and holding current (C) induced by the bath perfusion of THIP in experiments similar to those shown in (A). Data are mean ± SEM (n = 19–25 neurons). *p < 0.05 vs. GH mice exposed to water only (ANOVA followed by Scheffe's test).

Mentions: After a baseline period of ~3 min, slice were exposed to THIP (3 μM) for 6 min to activate preferentially high-affinity extrasynaptic GABAARs (Brown et al., 2002; Drasbek and Jensen, 2006). Exposure of granule cells from GH mice to THIP increased current noise variance and shifted the holding current in the negative direction with respect to baseline (Figure 9). The subsequent bath application of bicuculline (20 μM) blocked all GABAergic currents and reduced both noise variance and the holding current compared to baseline (Figure 9). In SI mice, the bath application of THIP resulted in a significant increase in noise variance and a larger holding current negative shift, compared to GH animals (Figure 9; p < 0.05). Tonic current parameters were also significantly increased in GH animals that consumed EtOH. In SI mice that consumed EtOH the effect of THIP on both noise variance and holding current shift, although still increased, was not statistically different compared to GH drinking water.


Voluntary Ethanol Consumption Induced by Social Isolation Reverses the Increase of α(4)/δ GABA(A) Receptor Gene Expression and Function in the Hippocampus of C57BL/6J Mice.

Sanna E, Talani G, Obili N, Mascia MP, Mostallino MC, Secci PP, Pisu MG, Biggio F, Utzeri C, Olla P, Biggio G, Follesa P - Front Neurosci (2011)

Effect of voluntary EtOH consumption on GABAergic tonic current in granule cells of the DG from GH and SI C57BL/6J mice. (A) Representative traces of GABAergic currents recorded in the whole-cell mode (holding potential, −65 mV) from granule cells of the DG are shown (left panel) for hippocampal slices obtained from group-housed (GH) or isolated (SI) mice exposed to water only, and GH and SI animals exposed to EtOH. All recordings were performed in the presence of kynurenic acid (3 mM) to block glutamatergic currents. After a baseline of 3 min, application of THIP (3 μM) induced an increase in noise variance and a negative shift in the holding current. All GABAergic currents were blocked by the application of bicuculline (Bic) at 20 μM. Calibration, 100 pA, 20 s. (B,C), bar graphs summarizing the changes in noise variance (B) and holding current (C) induced by the bath perfusion of THIP in experiments similar to those shown in (A). Data are mean ± SEM (n = 19–25 neurons). *p < 0.05 vs. GH mice exposed to water only (ANOVA followed by Scheffe's test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3039156&req=5

Figure 9: Effect of voluntary EtOH consumption on GABAergic tonic current in granule cells of the DG from GH and SI C57BL/6J mice. (A) Representative traces of GABAergic currents recorded in the whole-cell mode (holding potential, −65 mV) from granule cells of the DG are shown (left panel) for hippocampal slices obtained from group-housed (GH) or isolated (SI) mice exposed to water only, and GH and SI animals exposed to EtOH. All recordings were performed in the presence of kynurenic acid (3 mM) to block glutamatergic currents. After a baseline of 3 min, application of THIP (3 μM) induced an increase in noise variance and a negative shift in the holding current. All GABAergic currents were blocked by the application of bicuculline (Bic) at 20 μM. Calibration, 100 pA, 20 s. (B,C), bar graphs summarizing the changes in noise variance (B) and holding current (C) induced by the bath perfusion of THIP in experiments similar to those shown in (A). Data are mean ± SEM (n = 19–25 neurons). *p < 0.05 vs. GH mice exposed to water only (ANOVA followed by Scheffe's test).
Mentions: After a baseline period of ~3 min, slice were exposed to THIP (3 μM) for 6 min to activate preferentially high-affinity extrasynaptic GABAARs (Brown et al., 2002; Drasbek and Jensen, 2006). Exposure of granule cells from GH mice to THIP increased current noise variance and shifted the holding current in the negative direction with respect to baseline (Figure 9). The subsequent bath application of bicuculline (20 μM) blocked all GABAergic currents and reduced both noise variance and the holding current compared to baseline (Figure 9). In SI mice, the bath application of THIP resulted in a significant increase in noise variance and a larger holding current negative shift, compared to GH animals (Figure 9; p < 0.05). Tonic current parameters were also significantly increased in GH animals that consumed EtOH. In SI mice that consumed EtOH the effect of THIP on both noise variance and holding current shift, although still increased, was not statistically different compared to GH drinking water.

Bottom Line: SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA(A)R.Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI.We conclude that self-administration of EtOH selectively abolishes the increase of α(4) subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

View Article: PubMed Central - PubMed

Affiliation: Section of Neuroscience, Department of Experimental Biology, Center of Excellence for the Neurobiology of Dependence, University of Cagliari Monserrato, Cagliari, Italy.

ABSTRACT
Post-weaning social isolation (SI) is a model of prolonged mild stress characterized by behavioral and neurochemical alterations. We used SI in C57BL/6J mice to investigate the effects of ethanol (EtOH) in the free-choice drinking paradigm on gene expression and function of γ-aminobutyric acid type A receptors (GABA(A)Rs) and the role of neuroactive steroids in the actions of EtOH in the hippocampus. SI stress induced a marked reduction in hippocampal 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA(A)R. The gene expression of the α(4) and δ subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the γ(2) subunit was decreased whereas that of the α(1) did not change. Patch-clamp recordings in dentate gyrus (DG) granule cells obtained from SI C57BL/6J mice revealed a greater enhancement of tonic currents induced by α-(4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) compared to that in control C57BL/6J mice. These neurochemical, molecular and functional changes observed in SI C57BL/6J mice were associated with an increased EtOH intake and EtOH preference. Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3α,5α-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the α(4) subunit but not those of the δ and γ(2) subunits induced by SI. In addition, EtOH self-administration did not block the SI-induced changes in GABA(A)R-mediated tonic inhibition in hippocampal granule cells but increased the frequency of basal GABAergic sIPSCs in DG granule cells. We conclude that self-administration of EtOH selectively abolishes the increase of α(4) subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.

No MeSH data available.


Related in: MedlinePlus