Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity

Kim, Kyoung Shim; Kim, Hannah; Lee, Ko Woon; Han, Pyung Lim

doi:10.1007/s00213-010-2143-x

Cited by 26 publications

(18 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, inhibition of PKA prior to ethanol administration decreased loss of righting reflex duration (Lai et al, 2007) and withdrawal-induced anxiety . Studies utilizing mutant mouse lines with reduced PKA activity mimic results found with pharmacological inhibition of PKA (Thiele et al, 2000;Naassila et al, 2002;Kim et al, 2011). The precise role of PKA in mediating these behaviors is complex, however, as some studies have found increased ethanol sensitivity in animals with diminished PKA activity (Wand et al, 2001;Yang et al, 2003;Maas et al, 2005).…”

Section: Discussionmentioning

confidence: 78%

Ethanol Activation of Protein Kinase A Regulates GABAA α1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Carlson

Kumar

Werner

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Ethanol exposure produces alterations in GABAergic signaling that are associated with dependence and withdrawal. Previously, we demonstrated that ethanol-induced protein kinase C (PKC) g signaling selectively contributes to changes in GABA A a1 synaptic receptor activity and surface expression. Here, we demonstrate that protein kinase A (PKA) exerts opposing effects on GABA A receptor adaptations during brief ethanol exposure. Cerebral cortical neurons from day 0-1 rat pups were tested after 18 days in culture. Receptor trafficking was assessed by Western blot analysis, and functional changes were measured using whole-cell patch-clamp recordings of evoked and miniature inhibitory postsynaptic current (mIPSC) responses. Onehour ethanol exposure increased membrane-associated PKC and PKA, but steady-state GABA A a1 subunit levels were maintained.Activation of PKA by Sp-adenosine 39,59-cyclic monophosphothioate triethylamine alone increased GABA A a1 subunit surface expression and zolpidem potentiation of GABA responses, whereas coexposure of ethanol with the PKA inhibitor Rp-adenosine 39,59-cyclic monophosphothioate triethylamine decreased a1 subunit expression and zolpidem responses. Exposure to the PKC inhibitor calphostin-C with ethanol mimicked the effect of direct PKA activation. The effects of PKA modulation on mIPSC decay t were consistent with its effects on GABA currents evoked in the presence of zolpidem. Overall, the results suggest that PKA acts in opposition to PKC on a1-containing GABA A receptors, mediating the GABAergic effects of ethanol exposure, and may provide an important target for the treatment of alcohol dependence/withdrawal.

show abstract

Section: Discussionmentioning

confidence: 78%

Ethanol Activation of Protein Kinase A Regulates GABAA α1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Carlson

Kumar

Werner

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

show abstract

“…This is a very important finding in view of the fact that LND also comprises extrapyramidal motor problems (Nyhan 1997;Jinnah and Friedmann 2000;Torres et al 2012). Moreover, AC5 is involved in alcohol drinking behavior and stress responses (Kim and Han 2009;Kim et al 2011), pointing to a central role of this AC isoform in CNS function.…”

Section: Discussionmentioning

confidence: 90%

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Kinast

Ohe

Burhenne

et al. 2012

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

Hypoxanthine phosphoribosyl transferase (HPRT) deficiency results in Lesch-Nyhan disease (LND). The link between the HPRT defect and the self-injurious behavior in LND is still unknown. HPRT-deficient rat B103 neuroblastoma cells serve as a model system for LND. In B103 cell membranes, HPRT deficiency is associated with a decrease of basal and guanosine triphosphate-stimulated adenylyl cyclase (AC) activity (Pinto and Seifert, J Neurochem 96:454-459, 2006). Since recombinant AC2 possesses a high basal activity, we tested the hypothesis that AC2 function and expression is impaired in HPRT deficiency. We examined AC regulation in B103 cell membranes, cAMP accumulation in intact B103 cells, AC isoform expression, and performed morphological studies. As most important pharmacological tool, we used 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene forskolin (BODIPY-FS) that inhibits recombinant AC2 but activates ACs 1 and 5 (Erdorf et al., Biochem Pharmacol 82:1673-1681, 2011). In B103 control membranes, BODIPY-FS reduced catalysis, but in HPRT(-) membranes, BODIPY-FS was rather stimulatory. 2'(3')-O-(N-methylanthraniloyl) (MANT)-nucleoside 5'-[γ-thio]triphosphates inhibit recombinant ACs 1 and 5 more potently than AC2. In B103 control membranes, MANT-guanosine 5'-[γ-thio]triphosphate inhibited catalysis in control membranes less potently than in HPRT(-) membranes. Quantitative real-time PCR revealed that in HPRT deficiency, AC2 was virtually absent. In contrast, AC5 was up-regulated. Forskolin (FS) and BODIPY-FS induced cell clustering and rounding and neurite extension in B103 cells. The effects of FS and BODIPY-FS were much more prominent in control than in HPRT(-) cells, indicative for a differentiation defect in HPRT deficiency. Neither FS nor BODIPY-FS significantly changed cAMP concentrations in intact B103 cells. Collectively, our data show that HPRT deficiency in B103 cells is associated with impaired AC2 function and expression and reduced sensitivity to differentiation induced by FS and BODIPY-FS. We discuss the pathophysiological implications of our data for LND.

show abstract

“…Also, mice with genetic deletion of both adenylyl cyclase 1 (AC1) and AC8 exhibited decreased ethanol consumption and enhanced sensitivity to ethanol sedation (Maas et al, 2005). In contrast, mice lacking AC5 showed increased ethanol consumption and preference and reduced sensitivity to ethanol sedation (Kim et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice

et al. 2014

View full text Add to dashboard Cite

Some anti-inflammatory medications reduce alcohol consumption in rodent models. Inhibition of phosphodiesterases (PDE) increases cAMP and reduces inflammatory signaling. Rolipram, an inhibitor of PDE4, markedly reduced ethanol intake and preference in mice and reduced ethanol seeking and consumption in alcohol-preferring fawn-hooded rats (Hu et al., 2011; Wen et al., 2012). To determine if these effects were specific for PDE4, we compared nine PDE inhibitors with different subtype selectivity: propentofylline (nonspecific), vinpocetine (PDE1), olprinone, milrinone (PDE3), zaprinast (PDE5), rolipram, mesopram, piclamilast, and CDP840 (PDE4). Alcohol intake was measured in C57BL/6J male mice using 24-h two-bottle choice and two-bottle choice with limited (3-h) access to alcohol. Only the selective PDE4 inhibitors reduced ethanol intake and preference in the 24-h two-bottle choice test. For rolipram, piclamilast, and CDP840, this effect was observed after the first 6 h but not after the next 18 h. Mesopram, however, produced a long-lasting reduction of ethanol intake and preference. In the limited access test, rolipram, piclamilast, and mesopram reduced ethanol consumption and total fluid intake and did not change preference for ethanol, whereas CDP840 reduced both consumption and preference without altering total fluid intake. Our results provide novel evidence for a selective role of PDE4 in regulating ethanol drinking in mice. We suggest that inhibition of PDE4 may be an unexplored target for medication development to reduce excessive alcohol consumption.

show abstract

Mice lacking adenylyl cyclase type 5 (AC5) show increased ethanol consumption and reduced ethanol sensitivity

Abstract: These results suggest that AC5 is an important signaling molecule regulating alcohol sensitivity and preference in animals. These data provide critical information for AC5 activation as a candidate target for the treatment of alcoholism.

Cited by 26 publications

References 38 publications

Ethanol Activation of Protein Kinase A Regulates GABAA α1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Ethanol Activation of Protein Kinase A Regulates GABAA α1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch–Nyhan disease: BODIPY–forskolin as pharmacological tool

Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice

Contact Info

Product

Resources

About