Abstract
The selective serotonin reuptake inhibitor fluoxetine and the 5-HT1A receptor agonist buspirone are used to treat depression and anxiety. Previously we demonstrated that chronic stress during pregnancy (prenatal stress) in rats, used as a model of maternal depression risk, increased inflammatory pain and depressive-like behavior in the offspring; buspirone injected to pregnant dams was protective. Clinically, the addition of buspirone to fluoxetine increases the latter’s efficacy in treating depression in patients. Here, we investigated the influence of repeated prenatal injections of fluoxetine, buspirone or their combination on pain- and depressive-like behaviors in prenatally stressed young male and female rats. Prenatal stress augmented depressive-like behavior and both thermal and inflammatory pain (formalin test), replicating our prior findings, and increased basal levels of corticosterone in the blood plasma. Both drugs and their combination reduced the effects of prenatal stress on thermal pain and depressive-like behavior independently of sex. The combination of fluoxetine and buspirone, compared with fluoxetine, was more antinociceptive in the hot plate test in both sexes, and when compared with buspirone, was more antinociceptive only in males. A detailed study of the time-course of formalin-induced pain showed a nuanced effect of these drugs that was sex-dependent. The combination of the two drugs was less effective in females than males during the initial acute phase of nociceptive behavior in flexing + shaking behaviors, whereas that combination was more effective than fluoxetine alone in the first acute phase of licking behavior in females. The antinociceptive effect of buspirone dominated that of the drug combination and of fluoxetine alone, especially during the interphase of the formalin test in both sexes for both flexing + shaking and licking, suggesting a more effective prenatal action of buspirone on the development of a descending serotonergic inhibitory system modulating pain in the spinal cord dorsal horn neurons. Our results indicate that inflammatory pain-like responses integrated at the spinal level in males were more vulnerable to prenatal stress than females. In licking, the antinociceptive effect of fluoxetine and drug combination in the interphase was more in males than females. The data underscore the importance of considering sexual dimorphism when using drug therapy.
Highlights
Clinical and experimental studies have found that strong and/or persistent stress during pregnancy is associated with lasting dysfunction in the central nervous system (CNS) that increases vulnerability towards affective disorders (Weinstock, 2010; Entringer et al, 2015; Kundakovic and Jaric, 2017; Scheinost et al, 2017; Hartman and Belsky, 2018; Huizink and de Rooij, 2018)
We found that in the second tonic phase of the formalin test, prenatal stress increased licking, organized at the supraspinal level, in the rats of both sexes, but flexing + shaking behavior, organized at the spinal level, differed significantly only in males
Thermal Test We found that prenatally stressed male and female rats treated with buspirone or combination of the drugs mitigated the effects of prenatal stress in the hot plate test
Summary
Clinical and experimental studies have found that strong and/or persistent stress during pregnancy (prenatal stress) is associated with lasting dysfunction in the central nervous system (CNS) that increases vulnerability towards affective disorders (Weinstock, 2010; Entringer et al, 2015; Kundakovic and Jaric, 2017; Scheinost et al, 2017; Hartman and Belsky, 2018; Huizink and de Rooij, 2018). In addition to increased risk of affective disorders, prenatal stress alters other neurobehavioral functions, including pain perception. Our knowledge of prenatal stress effects on reactivity of the pain, is limited (Sternberg and Ridgway, 2003; Sun et al, 2013; Knaepen et al, 2014). Prenatal stress alters serotonergic function (Van den Hove et al, 2006; Gemmel et al, 2018; Kiryanova et al, 2018; Soares-Cunha et al, 2018), the hypothalamopituitary-adrenal axis (Gemmel et al, 2017; Morsi et al, 2018), GABA-ergic (Nejatbakhsh et al, 2018), and glutamatergic systems (Cattane et al, 2018; Lin et al, 2018) and immune system function (Bittle and Stevens, 2018; Goldstein et al, 2019)
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