Publications
Parsegian A, Garcia-Fuster MJ, Hebda-Bauer E, Watson SJ, Flagel SB, & Akil H. (2022). Adolescent cocaine differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes. Frontiers in Psychiatry, 13, 1024617. https://doi.org/10.3389/fpsyt.2022.1024617
Adolescent drug use reliably predicts increased addiction liability in adulthood, but not all individuals are equally impacted. To explore the biological bases of this differential reactivity to early life drug experience, we used a genetic rat model of temperament and evaluated the impact of adolescent cocaine exposure on adult psychomotor sensitization. Relative to adult bred low-responder (bLR) rats, bred high-responders (bHR) are more sensitive to the psychomotor-activating effects of cocaine and reinstate drug-seeking behavior more readily following prolonged cocaine exposure and/or abstinence. We found that a 7-day sensitizing cocaine regimen (15 mg/kg/day) during either adolescence or adulthood produced psychomotor sensitization in bHRs only, while a dual cocaine exposure prevented further sensitization, suggesting limits on neuroplasticity. By contrast, adolescent cocaine in bLRs shifted their resilient phenotype, rendering them more responsive to cocaine in adulthood following adolescent cocaine. To begin to explore the neural correlates of these behavioral phenotypes, we assessed two functionally opposite epigenetic chromatin modifications implicated in addiction liability, permissive acetylation (ac) and repressive tri-methylation (me3) on Histone 3 Lysine 9 (H3K9), in four striatal sub-regions. In bHRs, decreased H3K9me3 and increased acH3K9 in the nucleus accumbens (NAc) core associated with cocaine sensitization. In bLRs, the combination of cocaine exposure in adolescence and adulthood, which lead to an increased response to a cocaine challenge, also increased acH3K9 in the core. Thus, adolescent cocaine experience interacts with genetic background to elicit different behavioral profiles relevant to addiction in adulthood, with concurrent modifications in the epigenetic histone profiles in the NAc that associate with cocaine sensitization and with metaplasticity.
Chang SE, Krueger LD, & Flagel SB. (2022). Investigating individual differences in opioid-taking and opioid-seeking behavior in male rats. Psychopharmacology, 239(4), 1065-1080. https://doi.org/10.1007/s00213-021-06023-2
Understanding the behavioral and neurobiological factors that render some individuals more susceptible than others to opioid addiction will be critical in combatting the opioid crisis. The purpose of the current study was to determine if behavioral traits associated with an increased likelihood to take and seek cocaine are the same traits that render one more susceptible to opioid-taking and opioid-seeking behavior. Individual differences in the acquisition of remifentanil self-administration and subsequent cue-induced reinstatement of remifentanil-seeking behavior were investigated using two animal models: the high-responder (HR)/low-responder (LR) and sign-tracker (ST)/goal-tracker (GT) models. Relative to LR rats, HR rats show increased novelty-induced locomotion or “sensation-seeking” behavior, and are more likely to acquire cocaine-taking behavior and do so at a faster rate. Relative to GT rats, ST rats attribute greater incentive motivational value to reward cues and are more likely to exhibit reinstatement of cocaine-seeking behavior. In contrast to previous work using cocaine, we did not observe individual differences with respect to the acquisition of remifentanil self-administration- or cue-induced reinstatement of remifentanil-seeking behavior within the context of either the HR/LR or ST/GT model. Thus, neither the sensation-seeking trait nor the propensity to attribute incentive motivational value to reward cues predicts remifentanil-taking or remifentanil-seeking behavior. These findings suggest that different traits may confer the initiation of opioid- vs. cocaine-taking behavior, and the propensity to relapse to opioid- vs. cocaine-seeking. Additional studies are needed to identify which neurobehavioral constructs confer liability to opioid use and relapse.
Flagel SB. (2022). The paraventricular nucleus of the thalamus and its potential role in psychopathology. Neuropsychopharmacology, 47, 385-386. https://doi.org/10.1038/s41386-021-01112-4
The role of the thalamus extends beyond that of a relay station in the brain. The thalamus is comprised of groups of specialized nuclei each with distinct neuroanatomical connections supporting their roles in sensory processing, motor control, and emotional regulation. Given the structural and functional heterogeneity across thalamic nuclei, it is not surprising that, collectively, this brain structure has been implicated in psychiatric disorders, including addiction, depression, and schizophrenia. Although the neuroanatomical resolution of human imaging studies have, to-date, largely limited our ability to elucidate the involvement of specific thalamic nuclei in these disorders, studies emerging from the preclinical literature suggest that the paraventricular nucleus of the thalamus (PVT) is a critical component of the neural pathways underlying these disorders (see [1,2,3]).