Inhibition of phosphodiesterase-4 decreases ethanol intake in mice

Abstract

Rationale Cyclic AMP (cAMP)-protein kinase A (PKA) signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown. Objective To examine whether PDE4 was involved in regulating ethanol intake. Methods The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram. Results Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking. Conclusions These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…A recent preclinical study found that rolipram acutely reduced ethanol self-administration in a dose-dependent fashion and also, after chronic dosing, reduced ethanol preference and consumption (Wen et al, 2012). This is consistent with a previous study showing that acute rolipram administration substantially reduced ethanol consumption and preference in mice (Hu et al, 2011). Together, these findings suggest that rolipram as well as other PDE4 inhibitors, may have potential for the treatment of alcoholism and perhaps other substance use disorders.…”

“…It has been hypothesized that GDNF functions to reduce these alcohol-related behaviors in animal models by reversing an alcohol-induced allostatic DA deficiency in the mesolimbic system caused by prolonged excessive alcohol consumption and repeated withdrawal (Barak, Ahmadiantehrani, et al, 2011;Barak, Carnicella, et al, 2011). Furthermore, there is evidence that pharmacological inhibition of phosphodiesterase-4 (PDE4), an enzyme that hydrolyses cyclic adenosine monophosphate (cAMP), decreases alcohol intake in mice (Hu et al, 2011) and rat (Wen et al, 2012) models of alcoholism, as well as reduces neuroinflammation and neuronal death in rats . In addition, a recent study found that another phosphodiesterase, PDE10A, mRNA levels correlated with greater alcohol self-administration during a relapse model and with ethanol preference after acquisition (Logrip & Zorrilla, 2012), suggesting that inhibition of PDE10A may have behavioral effects on alcohol ingestion.…”

Ethanol Regulation of Synaptic GABAA 4 Receptors Is Prevented by Protein Kinase A Activation

“…Recent studies in rodent models have demonstrated decreased drinking behavior in animals given phosphodiesterase inhibitors (Hu et al, 2011;Wen et al, 2012;Blednov et al, 2014;Franklin et al, 2015). Together, these studies suggest that phosphodiesterase inhibition provides a promising target for the treatment of alcohol use disorders.…”

Regulation of Extrasynaptic GABAA 4 Receptors by Ethanol-Induced Protein Kinase A, but Not Protein Kinase C Activation in Cultured Rat Cerebral Cortical Neurons

“…Indeed, the loss of PKA activation at 4 hours may suggest that restoration of PKA activation could reverse the effect of ethanol at this time point. Recent studies finding a reduction in drinking of rodents coexposed to the phosphodiesterase inhibitor rolipram further underscore the potential therapeutic relevance of manipulating PKA signaling in the treatment of alcohol use disorders (Hu et al, 2011;Wen et al, 2012).…”