Selective inhibition of phosphodiesterase 7 enzymes reduces motivation for nicotine use through modulation of mesolimbic dopaminergic transmission

: About 5 million people die from diseases related to nicotine addiction and tobacco use each year. Nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. : We exami...

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Published in:	The Journal of neuroscience Vol. 41; no. 28; pp. 6128 - 6143
Main Authors:	Ciccocioppo, Roberto, Guglielmo, Giordano de, Li, Hongwu, Melis, Miriam, Caffino, Lucia, Shen, Quienwei, Domi, Ana, Fumagalli, Fabio, Demopulos, Gregory A, Gaitanaris, George A
Format:	Journal Article
Language:	English
Published:	United States Society for Neuroscience 14-07-2021
Subjects:	Adenosine monophosphate Circuits Cyclic AMP Cyclic AMP response element-binding protein Dopamine D1 receptors Drug abuse Drug addiction Drug self-administration Enzymes Inhibitors Intravenous administration Kinases Mesolimbic system Neurons Nicotine Nucleus accumbens Phosphodiesterase Place preference conditioning Potentiation Protein kinase A Proteins Receptor mechanisms Receptors Reinstatement Tobacco Ventral tegmentum Yohimbine γ-Aminobutyric acid
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Summary:	: About 5 million people die from diseases related to nicotine addiction and tobacco use each year. Nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. : We examined the notion of re-equilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. Using selective PDE7 inhibitors, we demonstrated in male rats that systemic PDE7 enzyme inhibition reduced nicotine self-administration and prevented reinstatement to nicotine seeking evoked by cues or by the pharmacological stressor yohimbine. The effect was also observed by direct application of the PDE7 inhibitors into the nucleus accumbens (NAc) shell but not into the core. Inhibition of PDE7 resulted in increased DA- and cAMP-regulated neuronal phosphoprotein (DARPP-32) and cAMP response element-binding protein (CREB) and their phosphorylated forms in the NAc. It also enhanced the DA D1 receptor agonism-mediated effects, indicating potentiation of protein kinase A (PKA)-dependent transmission downstream of D1 receptor activation. In electrophysiological recordings from DA neurons in the lateral posterior ventral tegmental area (VTA), the PDE7 inhibitors attenuated the spontaneous activity of DA neurons. This effect was exerted through the potentiation of D1 receptor signaling and the subsequent facilitation of γ-aminobutyric acid (GABA) transmission. The PDE7 inhibitors did not elicit conditioned place preference and did not induce intravenous self-administration, indicating lack of reinforcing properties. : PDE7 inhibitors have the potential to treat nicotine abuse. The World Health Organization (WHO) estimates that there are 1.25 billion smokers worldwide, representing one third of the global population over the age of 15. Nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are critical for maintaining drug-use habits. Here we demonstrate that nicotine consumption and relapse to nicotine seeking are attenuated by re-equilibrating DAergic transmission through inhibition of phosphodiesterase 7 (PDE7), an intracellular enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation. PDE7 inhibition may represent a novel treatment approach to aid smoking cessation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: R.C., G.A.D., and G.A.G. designed research; G.d.G., H.W.L., M.M., L.C., Q.S., and A.D. performed research; G.d.G., H.W.L., M.M., L.C., and F.F. analyzed data; R.C. and G.A.G. wrote the paper.
ISSN:	0270-6474 1529-2401
DOI:	10.1523/JNEUROSCI.3180-20.2021