Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague‐Dawley rats

Abstract

Selective serotonin reuptake inhibitors (SSRIs) block the serotonin (5-HT) reuptake transporter (SERT) and increase synaptic 5-HT. 5-HT is also important in brain development; hence when SSRIs are taken during pregnancy there exists the potential for these drugs to affect CNS ontogeny. Prenatal SSRI exposure has been associated with an increased prevalence of autism spectrum disorder (ASD), and peripheral 5-HT is elevated in some ASD patients. Perinatal SSRI exposure in rodents has been associated with increased depression and anxiety-like behavior, decreased sociability, and impaired learning in the offspring, behaviors often seen in ASD. The present study investigated whether perinatal exposure to citalopram causes persistent neurobehavioral effects. Gravid Sprague-Dawley rats were assigned to two groups and subcutaneously injected twice per day with citalopram (10mg/kg; Cit) or saline (Sal) 6h apart on embryonic day (E)6-21, and then drug was given directly to the pups after delivery from postnatal day (P)1-20. Starting on P60, one male/female from each litter was tested in the Cincinnati water maze (CWM) and open-field before and after MK-801. A second pair from each litter was tested in the Morris water maze (MWM) and open-field before and after (+)-amphetamine. A third pair was tested as follows: elevated zero-maze, open-field, marble burying, prepulse inhibition of acoustic startle, social preference, and forced swim. Cit-exposed rats were impaired in the MWM during acquisition and probe, but not during reversal, shift, or cued trials. Cit-exposed rats also showed increased marble burying, decreased time in the center of the open-field, decreased latency to immobility in forced swim, and increased acoustic startle across prepulse intensities with no effects on CWM. The results are consistent with citalopram inducing several ASD-like effects. The findings add to concerns about use of SSRIs during pregnancy. Further research on different classes of antidepressants, dose-effect relationships, timing of exposure periods, and mechanisms for these effects are needed. It is also important to balance the effects described here against the effects of the disorders for which the drugs are given.

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open‐field activity in Sprague‐Dawley rats

“…Two studies showed that rats exposed to FLX (s.c.) from P0‐4 were hypoactive as adults (Ko et al, 2014; Lee and Lee, 2012). We found that 10 mg/kg CIT decreased offspring activity (Sprowles et al, 2016), a finding corroborated herein for CIT and FLX. In these studies, differences in exposure periods appear to be important, as shorter exposures appear to increase activity and longer exposures decrease offspring activity.…”

“…Approximately 62% of children with ASD exhibit intellectual impairment (Centers for Disease Control and Prevention, 2012). Our data showed that perinatal CIT exposure impaired spatial learning and memory (Schaefer et al, 2013; Sprowles et al, 2016).…”

“…Neonatal exposure to CIT and FLX (s.c.) induced hyperreactivity to novel auditory stimuli in rats (Rodriguez‐Porcel et al, 2011), and FLX exposure (s.c.) on P0‐4 in rats decreased PPI in adult offspring (Ko et al, 2014). We found that 10 mg/kg perinatal exposure to CIT resulted in startle hyperreactivity (Sprowles et al, 2016). The present results demonstrate that 5 mg/kg perinatal CIT and FLX also increased startle amplitude while it decreased PPI, results that are consistent with impaired sensorimotor gating.…”

“…Anxiety is often seen in ASD (Gillott et al, 2001; MacNeil et al, 2009; Olexová et al, 2016), and developmental exposure to SSRIs in rodents leads to increased anxiety‐like behavior (Ansorge et al, 2008, 2004; Bairy et al, 2007; Karpova et al, 2009; Noorlander et al, 2008; Olivier et al, 2011b; Sarkar et al, 2014; Soga et al, 2012; Zohar et al, 2016). We showed that perinatal exposure to 10 mg/kg CIT increased anxiety in open‐field and marble burying (Sprowles et al, 2016). The present data show that 5 mg/kg perinatal exposure to FLX and CIT increases marble burying, a test typically used to measure anxiety‐like behavior in rodents (Borsini et al, 2002; Njung'e and Handley, 1991).…”

“…Neonatal SSRI exposure increases anxiety (Ansorge et al, 2004), depression‐like behavior (Hansen et al, 1997) and anhedonia (Popa et al, 2008), but decreases aggression (Manhaes de Castro et al, 2001), sexual performance (Maciag et al, 2006a), and social behaviors (Rodriguez‐Porcel et al, 2011) in rodents. We recently reported that perinatal exposure to the SSRI, citalopram (CIT), increased anxiety, depression‐like behavior, and sensory reactivity (Sprowles et al, 2016) in rat offspring, effects consistent with an ASD‐like phenotype. Approximately 62% of children with ASD exhibit intellectual impairment (Centers for Disease Control and Prevention, 2012).…”