Circuit-Wide Gene Network Analysis Reveals Sex-Specific Roles for Phosphodiesterase 1b in Cocaine Addiction

• Published in: The Journal of neuroscience 2024-06, Vol.44 (23), p.e1327232024
• Main Authors: Teague, Collin D, Markovic, Tamara, Zhou, Xianxiao, Martinez-Rivera, Freddyson J, Minier-Toribio, Angelica, Zinsmaier, Alexander, Pulido, Nathalia V, Schmidt, Kyra H, Lucerne, Kelsey E, Godino, Arthur, van der Zee, Yentl Y, Ramakrishnan, Aarthi, Futamura, Rita, Browne, Caleb J, Holt, Leanne M, Yim, Yun Young, Azizian, Corrine H, Walker, Deena M, Shen, Li, Dong, Yan, Zhang, Bin, Nestler, Eric J
• Format: Article
• Language: English
• Subjects: Addictions; Animals; Brain; Ca2+/calmodulin-dependent phosphodiesterase; Calcium ions; Calmodulin; Circuits; Cocaine; Cocaine - pharmacology; Cocaine-Related Disorders - genetics; Cocaine-Related Disorders - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 1 - metabolism; Drug abuse; Drug self-administration; Drug therapy; Excitability; Female; Females; Gene Regulatory Networks - drug effects; Gene Regulatory Networks - genetics; Gene sequencing; Male; Males; Mice; Mice, Inbred C57BL; Modules; Molecular modelling; Narcotics; Network analysis; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Phosphodiesterase; Public health; Rats; Reward; Sex Characteristics; Sex differences; Spiny neurons
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.1327-23.2024

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b ( ), a Ca /calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of in regulating the molecular, cellular, and behavioral responses to cocaine.