The Phosphodiesterase‐4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol‐Preferring Fawn‐Hooded Rats

Abstract

Background Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Since the cyclic AMP (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase 4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents as a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse. Methods Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, s.c.); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of ethanol, sucrose, or water using the two-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity. Results Acute administration of rolipram dose-dependently reduced operant self-administration of 5% ethanol, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in ethanol consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent-access to ethanol at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% ethanol consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 min, respectively, which did not likely alter long-term ethanol drinking. Conclusions These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Rolipram is a selective PDE4 inhibitor thought to represent a novel treatment option for alcoholism due to its effects on the cAMP cascade. 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).…”

“…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).…”