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Early-life exposure to the SSRI paroxetine exacerbates depression-like behavior in anxiety/depression-prone rats
M E Glover1, P C Pugh1, N L Jackson1
1Department of Psychiatry and Behavioral Neurobiology, University of Alabama-Birmingham, USA.
Insights
Selective serotonin reuptake inhibitor (SSRI) antidepressants can affect offspring. This study shows low responder rats exposed perinatally to SSRIs exhibit increased anxiety, unlike high responders, revealing individual differences in susceptibility.
Area of Science:
- Neuroscience
- Developmental Psychology
- Pharmacology
Background:
- Selective serotonin reuptake inhibitors (SSRIs) are common antidepressants for pregnant women.
- Effects of prenatal SSRI exposure on child brain development and emotional health are not well understood.
- SSRIs may cause newborn withdrawal and increase toddler anxiety.
Purpose of the Study:
- To establish a rodent model for studying individual differences in susceptibility to perinatal SSRI exposure.
- To investigate the impact of prenatal paroxetine on offspring emotional behavior and brain gene expression.
- To identify neurobiological mechanisms underlying differential responses to SSRIs.
Main Methods:
- Utilized selectively bred High Responder (bHR) and Low Responder (bLR) rats, differing in novelty-seeking behavior.
- Administered paroxetine to pregnant bHR/bLR dams and assessed offspring behavior and gene expression.
- Conducted microarray analysis on offspring hippocampus and amygdala during critical developmental periods.
Main Results:
- Perinatal paroxetine exposure exacerbated anxiety-like behavior (increased immobility in Forced Swim Test) in bLR offspring.
- High risk-taking bHR offspring showed resistance to SSRI-induced behavioral changes.
- Significant gene expression changes related to neurogenesis, synaptic function, and metabolism were observed in bLR offspring brains.
Conclusions:
- The bLR/bHR rat model effectively demonstrates individual differences in susceptibility to perinatal SSRI effects.
- Genetic predisposition and temperament influence vulnerability to developmental SSRI exposure.
- Findings provide insights into the neurobiology of SSRI effects on the developing brain and emotional regulation.
Abstract:
Selective serotonin reuptake inhibitor (SSRI) antidepressants are the mainstay treatment for the 10-20% of pregnant and postpartum women who suffer major depression, but the effects of SSRIs on their children's developing brain and later emotional health are poorly understood. SSRI use during pregnancy can elicit antidepressant withdrawal in newborns and increase toddlers' anxiety and social avoidance. In rodents, perinatal SSRI exposure increases adult depression- and anxiety-like behavior, although certain individuals are more vulnerable to these effects than others. Our study establishes a rodent model of individual differences in susceptibility to perinatal SSRI exposure, utilizing selectively bred Low Responder (bLR) and High Responder (bHR) rats that were previously bred for high versus low behavioral response to novelty. Pregnant bHR/bLR females were chronically treated with the SSRI paroxetine (10 mg/kg/day p.o.) to examine its effects on offspring's emotional behavior and gene expression in the developing brain. Paroxetine treatment had minimal effect on bHR/bLR dams' pregnancy outcomes or maternal behavior. We found that bLR offspring, naturally prone to an inhibited/anxious temperament, were susceptible to behavioral abnormalities associated with perinatal SSRI exposure (which exacerbated their Forced Swim Test immobility), while high risk-taking bHR offspring were resistant. Microarray studies revealed robust perinatal SSRI-induced gene expression changes in the developing bLR hippocampus and amygdala (postnatal days 7-21), including transcripts involved in neurogenesis, synaptic vesicle components, and energy metabolism. These results highlight the bLR/bHR model as a useful tool to explore the neurobiology of individual differences in susceptibility to perinatal SSRI exposure.
