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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 (Pde1b), a Ca2+/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 Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b 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 genemodules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine. [ABSTRACT FROM AUTHOR]

The article explores how drugs of abuse disrupt the natural reward processing system by hijacking a common neural pathway, particularly focusing on the nucleus accumbens (NAc). Topics include identifying NAc as pivotal for drug-induced interference with natural rewards, tracking dopaminoceptive neuron activity, and revealing Rheb's role in diminishing natural reward consumption post chronic drug exposure through CRISPR perturbation and single-cell transcriptomics.

Rodent studies suggest that dopamine signaling at D2/3 receptors in the ventral striatum is critical for reward motivation. Whether this is also true in humans is unclear. Positron emission tomography studies in healthy humans have generally not observed a relationship between D2/3 receptor availability in the ventral striatum and motivation. We developed the "mounting-effort for reward task" to assess high motivational demand for (a) gaining money (CS+), (b) losing money or avoiding electric shock (CS-), and (c) non-reward (Neutral). Receipt was contingent on participants making sufficient button responses relative to a "reward-threshold" determined by prior motor performance. This reward-threshold was dynamically increased if surpassed, making the task increasingly more difficult on every trial. The mounting-effort for reward task was preliminarily validated in 29 healthy volunteers (mean age: 25.83±3.58; 15 female). In this sample, %CS+ and %CS- significantly correlated with different dimensions of self-reported apathy. In a sub-sample of eight healthy volunteers (mean age: 25.75±1.91; four female), the mounting-effort for reward task demonstrated good test-retest reliability (%variance: 0.20-2.61%). Seven healthy male volunteers (mean age: 31.14±5.43) completed the mounting-effort for reward task and provided both [11C]-raclopride and [11C]-(+)-PHNO PET scans to assess D2/3 receptor availability. %CS+ and %CS- were positively correlated with [11C]-raclopride binding in the dorsal striatum. %CS+, %Cs-, and %Neutral were positively correlated with [11C]-(+)-PHNO binding in the globus pallidus. Thus, increased expression of D2 receptors in the dorsal striatum, and D3 receptors in the globus pallidus, may be related to motivation for rewards. Larger positron emission tomography studies are required to formally validate the mounting-effort for reward task and replicate our pilot findings. [ABSTRACT FROM AUTHOR]

Depression and substance use disorders are often comorbid, but the reasons for this are unclear. In human studies, it is difficult to determine how one disorder may affect predisposition to the other and what the underlying mechanisms might be. Instead, animal studies allow experimental induction of behaviors relevant to depression and drug-taking, and permit direct interrogation of changes to neural circuits and molecular pathways. While this field is still new, here we review animal studies that investigate whether depression-like states increase vulnerability to drug-taking behaviors. Since chronic psychosocial stress can precipitate or predispose to depression in humans, we review studies that use psychosocial stressors to produce depression-like phenotypes in animals. Specifically, we describe how postweaning isolation stress, repeated social defeat stress, and chronic mild (or unpredictable) stress affect behaviors relevant to substance abuse, especially operant self-administration. Potential brain changes mediating these effects are also discussed where available, with an emphasis on mesocorticolimbic dopamine circuits. Postweaning isolation stress and repeated social defeat generally increase acquisition or maintenance of drug self-administration, and alter dopamine sensitivity in various brain regions. However, the effects of chronic mild stress on drug-taking have been much less studied. Future studies should consider standardizing stress-induction protocols, including female subjects, and using multi-hit models (e.g. genetic vulnerabilities and environmental stress). [ABSTRACT FROM PUBLISHER]

A hallmark of addiction is the ability of drugs of abuse to trigger relapse after periods of prolonged abstinence. Here, we describe an epigenetic mechanism whereby chronic cocaine exposure causes lasting chromatin and downstream transcriptional modifications in the nucleus accumbens (NAc), a critical brain region controlling motivation. We link prolonged withdrawal from cocaine to the depletion of the histone variant H2A.Z, coupled with increased genome accessibility and latent priming of gene transcription, in D1 dopamine receptor-expressing medium spiny neurons (D1 MSNs) that relate to aberrant gene expression upon drug relapse. The histone chaperone ANP32E removes H2A.Z from chromatin, and we demonstrate that D1 MSN-selective Anp32e knockdown prevents cocaine-induced H2A.Z depletion and blocks cocaine's rewarding actions. By contrast, very different effects of cocaine exposure, withdrawal, and relapse were found for D2 MSNs. These findings establish histone variant exchange as an important mechanism and clinical target engaged by drugs of abuse to corrupt brain function and behavior. [ABSTRACT FROM AUTHOR]

The development of drug addiction is characterized by molecular changes in brain reward regions that lead to the transition from recreational to compulsive drug use. These neurobiological processes in brain reward regions, such as the nucleus accumbens (NAc), are orchestrated in large part by transcriptional regulation. Our group recently identified the transcription factor E2F3a as a novel regulator of cocaine's rewarding effects and gene expression regulation in the NAc of male mice. Despite this progress, no information is available about the role of E2F3a in regulating cocaine reward at the sex- and cell-specific levels. Here, we used male and female mice expressing Cre-recombinase in either D1- or D2-type medium spiny neurons (MSNs) combined with viral-mediated gene transfer to bidirectionally control levels of E2F3a in a cell-type-specific manner in the NAc during conditioned place preference (CPP) to cocaine. Our findings show that selective overexpression of E2F3a in D1-MSNs increased cocaine CPP in both male and female mice, whereas opposite effects were observed under knockdown conditions. In contrast, equivalent E2F3a manipulations in D2-MSNs had no significant effects. To further explore the role of E2F3a in sophisticated operant and motivated behaviors, we performed viral manipulations of all NAc neurons in combination with cocaine self-administration and behavioral economics procedures in rats and demonstrated that E2F3a regulates sensitivity aspects of cocaine seeking and taking. These results confirm E2F3a as a central substrate of cocaine reward and demonstrate that this effect is mediated in D1-MSNs, thereby providing increased knowledge of cocaine action at the transcriptional level.