In vivo assessment of brain cyclic adenosine monophosphate cascade following chronic alcohol exposure in rats: a PET imaging study

Introduction: The cyclic adenosine monophosphate (cAMP) cascade plays important roles in regulating alcohol-dependent behaviors and in protecting the brain from alcohol-induced damage. Stimulation of the cAMP pathway is shown to be effective in reducing alcohol consumption. Cyclic nucleotide phosphodiesterase 4 (PDE4) is the enzyme that regulates the level of cAMP and is highly expressed in the brain. Long forms of PDE4 are activated downstream of cAMP and can serve as a biomarker of cAMP activity. PDE4B is the major subtype of the PDE4 family for mood regulation and neuroinflammation. In addition, PDE4B single nucleotide polymorphism is associated with substance use disorders including alcohol use disorders (AUD). Therefore, PDE4B is likely to be critical in mediating the pathophysiology of AUD and might be a target with therapeutic potential. The objective of this study is to estimate the brain level of PDE4B in a rat model of chronic alcohol exposure using PET imaging.

Methods: PET imaging using a PDE4B radioligand (¹⁸F-PF974) was performed to estimate the PDE4B level in vivo. Eight non-dependent rats (NON-DEP) and 10 dependent rats (DEP) were scanned at the acute withdrawal phase following chronic alcohol exposure (4.5-5 hours post-exposure when the blood alcohol level is close to zero). Regional brain uptake of ¹⁸F-PF974 was quantified as standardized uptake value (SUV) after controlling for the amount of injected radioligand and body weight. Two-sample t-test was performed to assess between group differences. In two separate pairs of NON-DEP and DEP rats, the radiometabolite-corrected arterial input function and ex vivo brain radioactivity were measured.

Results: A widespread reduction of ¹⁸F-PF974 brain uptake was detected with PET in DEP rats compared to NON-DEP rats (Figure 1A, 1B). The whole brain and regional uptake were significantly lower in DEP rats (26-28% reduction, p < 0.01). Ex vivo measurements showed that arterial input functions were similar between NON-DEP and DEP rats (Figure 1C), and that brain radioactivity matched PET imaging findings i.e., a reduction of ¹⁸F-PF974 uptake (16%) in DEP brains compared to NON-DEP brains.

Conclusions: The brain level of PDE4B is reduced by chronic alcohol exposure, suggesting a down-regulation of the cAMP cascade. However, other confounding factors, such as alcohol-induced upregulation of efflux transporters, need to be assessed. More studies will be performed to confirm this observation before extending the PDE4B imaging into patients with AUD.

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