Ian A. Paul

Rationale Perinatal exposure of rats to selective serotonin reuptake inhibitors (SSRIs) produces sensory and social abnormalities paralleling those seen in autistic spectrum disorders (ASDs). However, the possible mechanism(s) by which this exposure produces behavioral abnormalities is unclear. Objective We hypothesized that the lasting effects of neonatal SSRI exposure are a consequence of abnormal stimulation of 5-HT_1A and/or 5-HT_1B receptors during brain development. We examined whether such stimulation would result in lasting sensory and social deficits in rats in a manner similar to SSRIs using both direct agonist stimulation of receptors as well as selective antagonism of these receptors during SSRI exposure. Methods Male and female rat pups were treated from postnatal days 8 to 21. In Experiment 1, pups received citalopram (20 mg/kg/day), saline, (±)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT; 0.5 mg/kg/day) or 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]-quinoxaline dimaleate (CGS-12066B; 10 mg/kg/day). In Experiment 2, a separate cohort of pups received citalopram (20 mg/kg/day), or saline which was combined with either N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo-hexanecarboxamide maleate (WAY-100635; 0.6 mg/kg/day) or N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1′-biphenyl-4-carboxamide (GR-127935; 6 mg/kg/day) or vehicle. Rats were then tested in paradigms designed to assess sensory and social response behaviors at different time points during development. Results Direct and indirect neonatal stimulation of 5-HT_1A or 5-HT_1B receptors disrupts sensory processing, produces neophobia, increases stereotypic activity, and impairs social interactions in manner analogous to that observed in ASD. Conclusion Increased stimulation of 5-HT_1A and 5-HT_1B receptors plays a significant role in the production of lasting social and sensory deficits in adult animals exposed as neonates to SSRIs.

Manipulation of serotonin (5HT) during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT) immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM). Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB) and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8–21. After animals reach adulthood (>90 days), OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs), these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

We have demonstrated that neonatal exposure to selective serotonin reuptake inhibitors has lasting effects on behavior and serotonergic neurons in Long Evans rats. Hyperserotoninemia and altered sensory processing are reported in autistic spectrum disorders (ASD). We hypothesized that early life exposure to SSRIs alters sensory processing, disrupts responses to novelty, and impairs social interactions in a manner similar to that observed in ASD. Male and female Long‐Evans rat pups were administered citalopram, buproprion, fluoxetine, or saline from postnatal day (P) 8–21. Rats were tested for response to a novel tone before weaning (P25). Later, rats were tested 2× for response to a novel object (P39), and to a novel conspecific (P78, P101). In addition, rats were assessed for juvenile play behaviors (P32–P34) and later, we assessed sexual response to an estrus female in male rats (P153–184). Antidepressant exposure increased freezing after tone, diminished novel object exploration, and reduced conspecific interaction up to 3× compared to saline exposed rats. Juvenile play was profoundly reduced in antidepressant‐exposed males when compared to saline exposed groups. Exposure to the SSRIs, but not bupropion disrupted male sexual behaviors. Moreover, specific male responses to female proceptive behaviors were disrupted in SSRI, but not bupropion exposed rats. We conclude that neonatal exposure to antidepressants in rats results in sensory and social abnormalities that parallel many of those reported in ASD. Anat Rec,, 2011.