CRF modulation of central monoaminergic function: Implications for sex differences in alcohol drinking and anxiety

Abstract

Decades of research have described the importance of corticotropin-releasing factor (CRF) signaling in alcohol addiction, as well as in commonly co-expressed neuropsychiatric diseases, including anxiety and mood disorders. However, CRF signaling can also acutely regulate binge alcohol consumption, anxiety, and affect in non-dependent animals, possibly via modulation of central monoaminergic signaling. We hypothesize that basal CRF tone is particularly high in animals and humans with an inherent propensity for high anxiety and alcohol consumption, and thus these individuals are at increased risk for the development of alcohol use disorder and comorbid neuropsychiatric diseases. The current review focuses on extrahypothalamic CRF circuits, particularly those stemming from the bed nucleus of the stria terminalis (BNST), found to play a role in basal phenotypes, and examines whether the intrinsic hyperactivity of these circuits is sufficient to escalate the expression of these behaviors and steepen the trajectory of development of disease states. We focus our efforts on describing CRF modulation of biogenic amine neuron populations that have widespread projections to the forebrain to modulate behaviors, including alcohol and drug intake, stress reactivity, and anxiety. Further, we review the known sex differences and estradiol modulation of these neuron populations and CRF signaling at their synapses to address the question of whether females are more susceptible to the development of comorbid addiction and stress-related neuropsychiatric diseases because of hyperactive extrahypothalamic CRF circuits compared to males.

Chemogenetic manipulation of the bed nucleus of the stria terminalis counteracts social behavioral deficits induced by early life stress in C57BL/6J mice

“…Sex differences in ELS effects on anxiety-like behaviors and adulthood neural transmission have been reported in humans (Brydges, Best, & Thomas, 2019;Kendler et al, 2002) and rodents (Bondar, Lepeshko, & Reshetnikov, 2018;Couto-Pereira et al, 2016;Wei et al, 2018), likely attributable to the fact that the BNST is sexually dimorphic (Allen & Gorski, 1990;Avery et al, 2014;Chung, De Vries, & Swaab, 2002;Smithers, Terry, Brown, & Randall, 2018;Uchida et al, 2019) and early neural developmental trajectories differ between sexes (Becker et al, 2007). Many studies have reported sex differences in BNST-mediated social behavior (Greenberg et al, 2014;Paul et al, 2014;Perkins et al, 2017) as well as stressor anxiety-related behaviors (Goodwill et al, 2019;Gracia-Rubio et al, 2016;Luster et al, 2019;Manzano-Nieves, Gaillard, Gallo, & Bath, 2018;Mavrikaki et al, 2019;Pleil & Skelly, 2018). Our findings provide some support for this.…”

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

“…Sex differences in analgesic responses to opioids have been observed in both humans and mice, wherein females are less sensitive to the pain‐relieving properties of these drugs (Kest, Sarton, & Dahan, ). However, females also show equal or enhanced responses to the rewarding properties of opioids (Le Merrer et al, ; Neelakantan et al, ; Pleil & Skelly, ), suggesting a dissociation between these two interoceptive states in response to opioids. Because of the association between locomotor sensitization and compulsive drug seeking and taking (Robinson & Berridge, ; Vezina, ), the lasting effects we observe here in protracted withdrawal may be highly significant for potential propensity to relapse.…”

Health anxiety in medical employees: A multicentre study

“…Another potential explanation is the consistent evidence in the literature that females are twice as likely to have an anxiety disorder than males. 20 The greater susceptibility of females to stress-related neuropsychiatric diseases because of hyperactive extrahypothalamic corticotropin-releasing factor circuits 21 may explain this sex difference in HA.…”