Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal.

Marian L Logrip,Eric P Zorrilla

doi:10.3389/fnint.2014.00030

Abstract

Alcohol use disorders are persistent problems with high recidivism rates despite repeated efforts to quit drinking. Neuroadaptations that result from alcohol exposure and that persist during periods of abstinence represent putative molecular determinants of the propensity to relapse. Previously we demonstrated a positive association between phosphodiesterase 10A (PDE10A) gene expression and elevations in relapse-like alcohol self-administration in rats with a history of stress exposure. Because alcohol withdrawal is characterized by heightened anxiety-like behavior, activation of stress-responsive brain regions and an elevated propensity to self-administer alcohol, we hypothesized that Pde10a expression also would be upregulated in reward- and stress-responsive brain regions during periods of acute (8–10 h) and protracted (6 weeks) alcohol withdrawal. During acute withdrawal, elevated Pde10a mRNA expression was found in the medial and basolateral amygdala (BLA), as well as the infralimbic and anterior cingulate subdivisions of the medial prefrontal cortex, relative to alcohol-naïve controls. The BLA was the only region with elevated Pde10a mRNA expression during both acute and protracted withdrawal. In contrast to the elevations, Pde10a mRNA levels tended to be reduced during protracted withdrawal in the dorsal striatum, prelimbic prefrontal cortex, and medial amygdala. Together these results implicate heightened PDE10A expression in the BLA as a lasting neuroadaptation associated with alcohol dependence.

Highlights

Phosphodiesterase 10A (PDE10A) is a dual-specificity phosphodiesterase, a family of enzymes that regulates cyclic nucleotide activity to modulate intracellular signaling pathways (Francis et al, 2011)
Pde10a mRNA levels were significantly elevated in the infralimbic and anterior cingulate (ACC; F1,20 = 6.89, p < 0.05) subdivisions of the medial prefrontal cortex (mPFC) during acute alcohol withdrawal. These alterations in Pde10a mRNA levels did not persist into protracted withdrawal (Figure 1B), as neither ilPFC (F1,16 = 0.05, p = 0.82) nor ACC (F1,18 = 0.52, p = 0.48) Pde10a expression levels differed from alcohol-naïve controls at the later withdrawal time point
No significant alteration in Pde10a levels was seen in the prelimbic prefrontal cortices (plPFCs) during acute withdrawal (Figure 1A; F1,21 = 0.84, p = 0.37), whereas a trend toward reduced expression in the plPFC was found during protracted withdrawal (Figure 1B; F1,19 = 3.41, p = 0.08)

Summary

Introduction

Phosphodiesterase 10A (PDE10A) is a dual-specificity phosphodiesterase, a family of enzymes that regulates cyclic nucleotide activity to modulate intracellular signaling pathways (Francis et al, 2011). Like other PDEs, PDE10A may play an important role in neuronal plasticity by modulating the levels of active cAMP and cGMP available to participate in intracellular signaling cascades (Kroker et al, 2012; Wiescholleck and Manahan-Vaughan, 2012; Zhong et al, 2012; Uthayathas et al, 2013). PDE10A has been implicated in both appetitive and aversive conditioning (Piccart et al, 2011, 2013), as well as in regulating striatal dopaminergic responses to amphetamine (Sotty et al, 2009). Taken together, these data suggest key roles for PDE10A in reward-related learning and neural responses to reinforcers, including drugs of abuse

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