Exposure to antidepressants during the first few weeks of pregnancy has long term implications for sensory processing in the offspring

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Exposure to antidepressants during pregnancy and the first weeks of life can alter sensory processing well into adulthood, according to research in mice recently published in eNeuro.

Physicians are increasingly prescribing a common antidepressant to their pregnant patients, even though the effect on the fetus isn’t fully known.

A working theory of depression implicates the neurotransmitter serotonin because many depressed patients experience relief when prescribed selective serotonin reuptake inhibitors (SSRIs).

Whatever its role in depression, serotonin is critical for healthy brain development and function.

While previous research has shown changes in behavior and brain structure with prenatal and early life exposure to SSRIs, Rahn et al. explored changes in brain activity.

After exposing mice to the SSRI fluoxetine during gestation and the first two weeks after birth, the team deployed optical imaging to examine the mouse brains exposed to fluoxetine and compare them to control mice.

In the resting state, the brains of both sets of mice were nearly identical. When their front paws were stimulated, the fluoxetine-exposed mice displayed abnormal brain activity in sensory areas.

This shows neurons

Changes in brain activity in mice exposed to SSRIs. The image is credited to Rahn et al., eNeuro 2019.

The effect was observed during adulthood in mice, suggesting this developmental exposure to SSRIs causes long-term changes to sensory processing.


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, however, is limited (Sternberg and Ridgway, 2003; Sun et al., 2013; Knaepen et al., 2014).

In animal studies, maternal stress replicates risk factors for depression as well as other psychosocial disorders (Weinstock, 20082017). Prenatal stress can influence the offspring’s neurodevelopment via multiple ways. 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 hypothalamo-pituitary-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).

The serotonin 1A receptor subtype (5-HT1AR) and glucocorticoid receptors (GR) are thought to be the main targets of prenatal stress (Van den Hove et al., 2006; Kiryanova et al., 2018). The serotonergic system and the HPA axis are closely interrelated (Andrews and Matthews, 2004; Wyrwoll and Holmes, 2012). GR are on neurons in the CNS regions classically associated with nociception and there is evidence that HPA axis directly influences nociception, particularly pre- and perinatally (Shagura et al., 2016; Zouikr et al., 2016).

In the last week of the rat fetal development, the levels of corticosteroids in the blood increase, peaking 1 day before term (Waddell and Atkinson, 1994). The expression of 5-HT1AR first appears in the rat during the initial stages of embryonic development of the hippocampus (Patel and Zhou, 2005). 5-HT1AR is highly expressed in the limbic system, prefrontal cortex (PFC), raphe nuclei, and spinal cord (Popova and Naumenko, 2013).

The former two CNS structures are of particular relevance in affective behavior and the etiology of depressive disorders (Liu et al., 2017), and the latter two, in pain processing and its modulation (Wang and Nakai, 1994).

Neuroanatomical and functional connections among these structures determine the integration of nociceptive and affective signals and the involvement of the descending serotonergic system that regulates nociceptive signals in pain and depressive behaviors (Chaouloff, 2000).

Since 5-HT1AR is involved in nociception (Granados-Soto et al., 2010) and psycho-emotional behavior (Savitz et al., 2009), changes in its activity in the prenatal period may manifest itself later in alteration of various types of adaptive behaviors (Knaepen et al., 20132014; Kiryanova et al., 20172018; Pawluski and Gemmel, 2018).

There is increasing evidence to suggest that the 5-HT1AR is involved in depression and the actions of antidepressant drugs (Savitz et al., 2009; Carr and Lucki, 2011; Richardson-Jones et al., 2011) and is an important target for the pharmacological treatment of disorders in the CNS (Lacivita et al., 2008; Berrocoso and Mico, 2009; Albert and Fiori, 2014; Turcotte-Cardin et al., 2019).

Of the selective serotonin reuptake inhibitors (SSRIs) used for the treatment of depression, fluoxetine is among those recommended for pregnant women (Kaihola et al., 2016). SSRIs cross the placental barrier (Pohland et al., 1989; Ewing et al., 2015), bind to the serotonin transporter (SERT) and block the presynaptic reuptake of serotonin (5-HT), thus increasing the level of 5-HT in the synaptic gap (Kiryanova et al., 2013).

Since 5-HT is a key regulator of early developmental processes in the CNS (Lauder, 1990), disruption of 5-HT balance in the fetus can affect its development and lead to altered adaptive behavior in later life. However, fluoxetine does not reduce the level of depression in all patients, so attempts have been made to improve its efficacy.

A number of clinical observations in adult patients suffering from depression suggest that the combination of 5-HTIA receptor agonists with SSRI’s improves therapeutic outcomes (Pierz and Thase, 2014; Wang et al., 2015). For instance, the antidepressant vilazodone (Stuivenga et al., 2019) integrates properties of a partial 5-HT1A receptor agonist with SERT blockade. Despite a number of positive results with the use of SSRIs in combination with agonists of 5-HT1A receptors in adult patients, there continues to be a need for a systematic study of results of the influence of such types of combination in animal models (Stuivenga et al., 2019).

It should be noted that our knowledge of the possible antinociceptive effect of SSRIs (Dharmshaktu et al., 2012; Zammataro et al., 2017; Barakat et al., 2018; Hamdy et al., 2018), as well as buspirone (Giordano and Rogers, 1992; Pavlaković et al., 2009; Haleem et al., 2018) is limited, and the available data are inconsistent.

Buspirone is widely used for treating generalized anxiety disorder (Albert and François, 2010; Albert and Fiori, 2014; Howland, 2015; Wilson and Tripp, 2018).

It is a full agonist at presynaptic 5-HT1A autoreceptors, where it initially inhibits synthesis and release of 5-HT. Repeated administration of buspirone inhibits the function of 5-HT1A autoreceptors and its feedback control over the synthesis and release of 5-HT (Haleem et al., 2018).

Buspirone is also a partial agonist at 5-HT1AR in the hippocampus and frontal cortex, where it is expressed as a heteroreceptor on GABAergic and glutamatergic neurons, and helps attenuate dysfunctional serotonergic transmission in depressed patients (Celada et al., 2013). Our previous work found that buspirone injected to pregnant rat dams that were stressed during pregnancy, attenuated the inflammatory pain response in the formalin test in the offspring of those dams (Butkevich and Vershinina, 2001).

The formalin test is widely used for assessment of antinociceptive effect of the drugs and induces reproducible and quantifiable pain behavior in two distinct phases with an interphase between them (Dubuisson and Dennis, 1977; Barr, 1998).

The first phase represents acute pain and is mediated in part by AMPA receptors whereas the second phase is thought to be more inflammatory and is mediated in part by NMDA receptors. The interphase is a period of dampened pain and is a transition between these two phases and may be mediated by descending inhibition from medullary sites to the spinal cord dorsal horn (Shields et al., 2010; Fischer et al., 20142015; Ishikura et al., 2015; Urien et al., 2017).

The formalin test is often used to study the different mechanisms of analgesia induced by various new drugs and the acute to chronic pain transition (Price et al., 2018; Zhang et al., 2018).

Most studies of prenatal exposure on behavior have so far focused on male offspring. Nonetheless, it is essential to include individuals of both sexes in research studies, especially given the sex differences in psychological disorders (Aloisi, 2017; Kundakovic and Jaric, 2017; Gemmel et al., 2019).

Data on sex differences in response to SSRIs for the management of chronic pain are limited. We included rats of both sexes in our investigations to determine better whether mechanisms responsible for the effects of fluoxetine and buspirone are sex-specific, which is important for subsequent drug development.

Previously, we showed that the chronic administration of fluoxetine to pregnant rat dams that were not stressed during pregnancy did not alter formalin-induced pain behavior or the level of depressive-like behavior in the forced swim test in adolescence (Butkevich and Mikhailenko, 2018). In the present study, we injected the drugs to pregnant rat dams stressed during pregnancy.

In view of the questions raised in the literature cited above, the present study compared the prenatal effects of a combination of fluoxetine and buspirone and of each drug alone on basal thermal pain, inflammatory pain-like behavior, and affective behavior. Based on the available clinical literature, we hypothesized that the prenatal effect of the combination of fluoxetine and buspirone would be more effective than of fluoxetine or buspirone alone in altering pain- and depressive-like behaviors of the offspring of dams that were exposed to prenatal stress. We tested this hypothesis in peri-adolescent male and female rats, during an important developmental epoch in which depression is often first evidenced and an age that we have previously studied (Butkevich and Vershinina, 2001; Butkevich et al., 2017).


Source:
SfN
Media Contacts:
Calli McMurray – SfN
Image Source:
The image is credited to Rahn et al., eNeuro 2019.

Original Research: Close access
“Maternal Fluoxetine Exposure Alters Cortical Hemodynamic and Calcium Response of Offspring to Somatosensory Stimuli”. Rachel M. Rahn, Susan E. Maloney, Lindsey M. Brier, Joseph D. Dougherty and Joseph P. Culver.
eNeuro doi:10.1523/ENEURO.0238-19.2019.

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