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. 2010 Jun 21:1339:11-7.
doi: 10.1016/j.brainres.2010.03.060. Epub 2010 Apr 7.

A potential role for adiponectin receptor 2 (AdipoR2) in the regulation of alcohol intake

Vez Repunte-Canonigo  1 , Fulvia Berton, Pietro Cottone, Anne Reifel-Miller, Amanda J Roberts, Marisela Morales, Walter Francesconi, Pietro Paolo Sanna
Affiliations

A potential role for adiponectin receptor 2 (AdipoR2) in the regulation of alcohol intake

Vez Repunte-Canonigo et al. Brain Res. .

Abstract

The anterior cingulate cortex (ACC) has been implicated in alcohol and drug addiction. We recently identified the small G protein K-ras as an alcohol-regulated gene in the ACC by gene expression analysis. We show here that the adiponectin receptor 2 (AdipoR2) was differentially regulated by alcohol in the ACC in a K-ras-dependent manner. Additionally, withdrawal-associated increased drinking was attenuated in AdipoR2 null mice. Intracellular recordings revealed that adiponectin increased the excitability of ACC neurons and that this effect was more pronounced during alcohol withdrawal, suggesting that AdipoR2 signaling may contribute to increased ACC activity. Altogether, the data implicate K-ras-regulated pathways involving AdipoR2 in the cellular and behavioral actions of alcohol that may contribute to overactivity of the ACC during withdrawal and excessive alcohol drinking.

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Figures

Fig. 1
Fig. 1. Alcohol induces AdipoR2 expression in the ACC in a K-ras-dependent manner
A) Significant increase of AdipoR2 gene expression was seen in the rat ACC by RT-PCR 12 hours after either acute or repeated administration of an intoxicating dose of alcohol (1-way ANOVA: F(2,12)= 15.67, p=0.0008, **p<0.01, ***p<0.001 from control). B) RT-PCR analysis of the ACC of K-ras+/− and Nf1+/− mice showed a significantly greater induction of AdipoR2 mRNA in the ACC of alcohol-treated Nf1+/− mice than in K-ras+/− mice after repeated administration of an intoxicating dose of alcohol (*p<0.05, **p<0.01 from respective controls or as indicated by the bracket. Pairwise Bonferroni-corrected comparisons). AdipoR2 was significantly increased in the ACC of both mouse lines (F(1,14)=19.47, P<0.001).
Fig. 2
Fig. 2. Alcohol vapor exposure significantly increased alcohol consumption in wild-type (WT), but not in AdipoR2−/− mice
A) Exposure to chronic intermittent alcohol vapor did not increase alcohol consumption over air-exposed in AdipoR2−/− mice, but did so in their wild-type littermate controls. Following the second vapor exposure there was a significant effect of condition in WT mice (F(1,11) = 6.6, p < 0.05), but not in AdipoR2 −/− mice (F(1,11) = 0.73, n.s.). B) Average consumptions across the final 5 days of the two bottle choice paradigm are shown. Alcohol vapor exposure significantly increased alcohol consumption in wild-type mice, but not in AdipoR2−/− mice (*p<0.05, by Bonferroni-corrected t-test).
Fig. 3
Fig. 3. Adiponectin increases intrinsic excitability in layer V/VI ACC neurons
A) Intracellular recordings from ACC layer V/VI neurons with sharp electrodes in current clamp mode in saline-injected control rats and in rats chronically treated with an intoxicating dose of alcohol. Depolarizing current pulses were injected to elicit a single action potential. Following application of adiponectin to the bath (10 nM for 15 min), a protracted decrease of the action potential latency was observable even after washout and for the whole duration of the recording session. The latency, i.e. the time from the onset of the stimulus to the time of occurrence of the first action potential is shaded in the four traces shown and indicated by the horizontal line marked ‘Lat.” in the control trace before addition of adiponectin. B) Quatification of the effect of adiponectin on the latency of layer V/VI ACC neurons. Adiponectin decreased action potential latency, as demonstrated by a main effect [F(1,17)= 37.88, p<0.0001]. Pairwise Bonferroni-corrected comparisons showed that adiponectin decreased latency both in ACC neurons from saline-injected controls and from alcohol-treated rats. Moreover, ACC neurons from adiponectin-treated slices from the alcohol-injected group also showed significantly briefer latencies than those from the adiponectin-treated slices from saline-injected controls. The resting membrane potential of the sample neurons shown was −67.8 mV for the control neurons and −63.67 mV for the neurons from the alcohol-treated rat. Data represent the Mean ± SEM. Because of unequal variance and non-Gaussian distribution of values, latency data are indicated as back-transformed Means ± SEM after logarithmic transformation. *p<0.05, ***p<0.001 from corresponding basal value or as indicated by the bracket, Bonferroni-corrected t-test).
Fig. 4
Fig. 4. Adiponectin receptors are widely expressed in the CNS
A, B) Hybridization signal at the level of the rostral forebrain showing moderate to strong adiponectin receptor expression in the cortex and low to moderate expression in the striatum, nucleus accumbens and septum. C, D) Prominent adiponectin receptor expression was observed in the hypothalamus in the medial preoptic area, ventromedial hypothalamus and arcuate nucleus and in the thalamus. Moderate signal was seen over the BNST and amygdala; Moderate to strong expression was also observed over the hypothalamus and thalamus, with the medial preoptic area, ventromedial hypothalamic and arcuate nuclei, paraventricular thalamic nucleus, anterodorsal, and habenula showing more robust signal. Strong signal was seen over the CA3 and dentate gyrus of the hippocampus, while the CA1 field displayed signal at a moderate level (D). E) Moderate to strong expression was seen in the mesencephalon with moderate signal over the substantia nigra and the ventral tegmental area and moderate to strong signal over the periacqueductal grey and pontine nuclei. F) Adiponectin receptor expression was also seen over the periacqueductal grey, superior colliculi and pontine nuclei. Intensity: red>yellow>green>blue
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