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Incubation of craving is a well-documented phenomenon referring to the intensification of drug craving over extended abstinence. The neural adaptations that occur during forced abstinence following chronic drug taking have been a topic of intense study. However, little is known about the transcriptomic changes occurring throughout this window of time. To define gene expression changes associated with morphine consumption and extended abstinence, male and female rats underwent 10 days of morphine self-administration. Separate drug-naive rats self-administered sucrose in order to compare opioid-induced changes from those associated with natural, non-drug rewards. After one or 30 days of forced abstinence, rats were tested for craving, or nucleus accumbens shell tissue was dissected for RNA sequencing. Morphine consumption was predictive of drug seeking after extended (30 days) but not brief (1 day) abstinence in both sexes. Extended abstinence was also associated with robust sex- and reinforcer-specific changes in gene expression, suggesting sex differences underlying incubation of morphine and sucrose seeking respectively. Importantly, these changes in gene expression occurred without re-exposure to drug-paired cues, indicating that chronic morphine causes long-lasting changes in gene expression that prime the system for increased craving. These findings lay the groundwork for identifying specific therapeutic targets for curbing opioid craving without impacting the natural reward system in males and females., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Early life adversity can alter reproductive development in humans, changing the timing of pubertal onset and sexual activity. One common form of early adversity is limited access to resources. This adversity can be modeled in rats using the limited bedding/nesting model (LBN), in which dams and pups are placed in a low resource environment from pups' postnatal days 2-9. Our laboratory previously found that adult male rats raised in LBN conditions have elevated levels of plasma estradiol compared to control males. In females, LBN had no effect on plasma hormone levels, pubertal timing, or estrous cycle duration. Estradiol mediates male reproductive behaviors. Thus, here we compared reproductive behaviors in adult males exposed to LBN vs. control housing. LBN males acquired the suite of reproductive behaviors (mounts, intromissions, and ejaculations) more quickly than their control counterparts over 3 weeks of testing. However, there was no effect of LBN in males on puberty onset or masculinization of certain brain regions, suggesting LBN effects on estradiol and reproductive behaviors manifest after puberty. In male and female rats, we next used RNA sequencing to characterize LBN-induced transcriptional changes in the medial preoptic area (mPOA), which underlies male reproductive behaviors. LBN produced sex-specific alterations in gene expression, with many transcripts showing changes in opposite directions. Numerous transcripts altered by LBN in males are regulated by estradiol, linking hormonal changes to molecular changes in the mPOA. Pathway analysis revealed that LBN induced changes in neurosignaling and immune signaling in males and females, respectively. Collectively, these studies reveal novel neurobiological mechanisms by which early life adversity can alter reproductive strategies., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Cocaine-associated contextual cues can trigger relapse behavior by recruiting the hippocampus. Extinction of cocaine-associated contextual memories can reduce cocaine-seeking behavior, however the molecular mechanisms within the hippocampus that underlie contextual extinction behavior and subsequent reinstatement remain poorly understood. Here, we extend our previous findings for a role of Ca v 1.2 L-type Ca 2+ channels in dopamine 1 receptor (D1R)-expressing cells in extinction of cocaine conditioned place preference (CPP) in adult male mice. We report that attenuated cocaine CPP extinction in mice lacking Ca v 1.2 channels in D1R-expressing cells (D1 cre , Ca v 1.2 fl/fl ) can be rescued through chemogenetic activation of D1R-expressing cells within the dorsal dentate gyrus (dDG), but not the dorsal CA1 (dCA1). This is supported by the finding that Ca v 1.2 channels are required in excitatory cells of the dDG, but not in the dCA1, for cocaine CPP extinction. Examination of the role of S1928 phosphorylation of Ca v 1.2, a protein kinase A (PKA) site using S1928A Ca v 1.2 phosphomutant mice revealed no extinction deficit, likely due to homeostatic scaling up of extinction-dependent S845 GluA1 phosphorylation in the dDG. However, phosphomutant mice failed to show cocaine-primed reinstatement which can be reversed by chemogenetic manipulation of excitatory cells in the dDG during extinction training. These findings outline an essential role for the interaction between D1R, Ca v 1.2, and GluA1 signaling in the dDG for extinction of cocaine-associated contextual memories.

Treating cocaine addiction is a major challenge and currently no FDA approved pharmacotherapies exist. One complicating factor is a high rate of comorbidity between cocaine and neuropsychiatric conditions such as anxiety. The relationship between anxiety symptoms and cocaine addiction is complicated; anxiety can be both a predisposing factor and a consequence of cocaine use as anxiety symptoms often emerge during drug use and withdrawal. Identifying and understanding the shared biological mechanisms that lead to comorbid anxiety and cocaine addiction, irrespective of which comes first, is critical for the identification of new treatments.