Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in C57BL/6J mice - PubMed (original) (raw)

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

Yuri A Blednov et al. Front Neurosci. 2014.

Abstract

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.

Keywords: CDP840; PDE inhibitors; alcohol; mesopram; piclamilast; rolipram; two-bottle choice.

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Figures

Figure 1

Figure 1

PDE4 inhibitors reduce alcohol intake during the first 6 h of the 24-h two-bottle choice paradigm. Ethanol consumption is presented as g/kg/6 h: (A) Rolipram (D) Mesopram (G) CDP840 (J) Piclamilast. Preference for ethanol: (B) Rolipram (E) Mesopram (H) CDP840 (K) Piclamilast. Total fluid intake (g/kg/6 h): (C) Rolipram (F) Mesopram (I) CDP840 (L) Piclamilast. Data were analyzed by Two-Way ANOVA with repeated measures followed by Bonferroni's test for multiple comparisons. *p < 0.05; **p < 0.01; ***p < 0.001 compared to control (n = 6 per group; EtOH = ethanol).

Figure 2

Figure 2

Effects of PDE4 inhibitors on alcohol intake during the next 18 h of the 24-h two-bottle choice paradigm. Ethanol consumption is presented as g/kg/18 h: (A) Rolipram (D) Mesopram (G) CDP840 (J) Piclamilast. Preference for ethanol: (B) Rolipram (E) Mesopram (H) CDP840 (K) Piclamilast. Total fluid intake (g/kg/18 h): (C) Rolipram (F) Mesopram (I) CDP840 (L) Piclamilast. Data were analyzed by Two-Way ANOVA with repeated measures followed by Bonferroni's test for multiple comparisons. **p < 0.01; ***p < 0.001 compared to control (n = 6 per group; EtOH = ethanol).

Figure 3

Figure 3

PDE3 and PDE5 inhibitors do not alter alcohol intake during the first 6 h of the 24-h two-bottle choice paradigm. Ethanol consumption is presented as g/kg/6 h: (A) Milrinone (D) Olprinone (G) Zaprinast. Preference for ethanol: (B) Milrinone (E) Olprinone (H) Zaprinast. Total fluid intake (g/kg/6 h): (C) Milrinone (F) Olprinone (I) Zaprinast. Data were analyzed by Two-Way ANOVA with repeated measures followed by Bonferroni's test for multiple comparisons (n = 6 per group; EtOH = ethanol).

Figure 4

Figure 4

PDE1 inhibitor vinpocetine and nonspecific inhibitor propentofylline do not alter alcohol intake during the first 6 h of the 24-h two-bottle choice paradigm. Ethanol consumption is presented as g/kg/6 h: (A) Propentofylline (D) Vinpocetine. Preference for ethanol: (B) Propentofylline (E) Vinpocetine. Total fluid intake (g/kg/6 h): (C) Propentofylline (F) Vinpocetine. Data were analyzed by Two-Way ANOVA with repeated measures followed by Bonferroni's test for multiple comparisons (n = 6 per group; EtOH = ethanol).

Figure 5

Figure 5

PDE1,3,5 and nonspecific inhibitors do not alter alcohol intake during the last 18 h of the 24-h two-bottle choice paradigm. Ethanol consumption is presented as g/kg/18 h: (A) Milrinone (D) Olprinone (G) Zaprinast (J) Propentofylline (M) Vinpocetine. Preference for ethanol: (B) Milrinone (E) Olprinone (H) Zaprinast (K) Propentofylline (N) Vinpocetine. Total fluid intake (g/kg/18 h): (C) Milrinone (F) Olprinone (I) Zaprinast (L) Propentofylline (O) Vinpocetine. Data were analyzed by Two-Way ANOVA with repeated measures followed by Bonferroni's test for multiple comparisons (n = 6 per group; EtOH = ethanol).

Figure 6

Figure 6

Effects of PDE4 inhibitors on alcohol intake during a limited access (3-h) two-bottle choice Drinking in the Dark test. Ethanol consumption is presented as g/kg/3 h: (A) Rolipram (D) Mesopram (G) CDP840 (J) Piclamilast. Preference for ethanol: (B) Rolipram (E) Mesopram (H) CDP840 (K) Piclamilast. Total fluid intake (g/kg/3 h): (C) Rolipram (F) Mesopram (I) CDP840 (L) Piclamilast. Data were analyzed by Two-Way ANOVA with repeated measures followed by Bonferroni's test for multiple comparisons. *p < 0.05; **p < 0.01; ***p < 0.001 compared to control (n = 6 per group; EtOH = ethanol).

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