Neonatal Exposure of Rats to Antidepressants Affects Behavioral Reactions to Novelty and Social Interactions in a Manner Analogous to Autistic Spectrum Disorders

Rodríguez‐Porcel, Federico; Green, Donald P.; Khatri, Nidhi; Harris, Sam; May, Warren; Lin, Rick C.S.; Paul, Ian A.

doi:10.1002/ar.21402

Cited by 67 publications

(97 citation statements)

References 35 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we do not suggest that the juvenile play behavior that we assess corresponds to a specific trait dimension of ASD, our findings are consistent with the possibility that dysregulation/dysfunction of the 5-HT system during early brain development may be the critical contributing factor in the etiology of ASD. This notion is also supported by the fact that the altered behaviors were observed in CTM-exposed rats but not in non-SSRI perinatally exposed animals (29,41), implicating a potential 5-HT linkage of social dysfunctioning seen in ASD (42).…”

Section: Discussionmentioning

confidence: 73%

Perinatal antidepressant exposure alters cortical network function in rodents

Simpson¹,

Weaver²,

Villers-Sidani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

180

174

View full text Add to dashboard Cite

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre-and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.S erotonin (5-HT) has long been postulated to play a trophic role in brain morphogenesis, including cell proliferation, migration, and differentiation. It is also known to be one of the first neurotransmitters to appear in the central nervous system (1, 2). An obvious question that can be raised relates to whether perinatal exposure to antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can affect cortical circuit development and function. Perhaps one of the most intriguing previous findings related to 5-HT and early cortical organization was the observation from immunohistochemical and 5-HT transporter (SERT) binding studies that, at postnatal days 2-14 (P2-P14), rodent primary sensory cortex (notably layer IV of visual, auditory, and somatosensory areas) is transiently innervated by aggregates of fine grainlooking 5-HT-containing processes (3)(4)(5). Surprisingly, it became clear that, in early brain development, 5-HT is taken up into glutamatergic thalamocortical terminals (6, 7) and used in combination with the 5-HT 1B receptor on layer IV afferents (8). At present, the functional implication of such transient 5-HT expression and targeting, namely the primary sensory thalamocortical afferents during early development, remains unknown.5-HT and Abnormal Brain Development. Interestingly, manipulations of rodent brain 5-HT levels during early development, either through increases (produced in SERT or monoamine oxidase knockout mice) or decreases (produced by parachlorophenylalanine or other treatments), have been shown to produce the downstream effect of interfering with the formation of the whisker (barrel) representation in the primary somatosensory cortex and promoting aggressive and/or anxiety-related behaviors (9-14). Furthermore, early-life modification of 5-HT levels has been shown to cause overreaction to auditory or tactile sensory stimulation (15) and abnormal response properties of cor...

show abstract

Section: Discussionmentioning

confidence: 73%

Perinatal antidepressant exposure alters cortical network function in rodents

Simpson¹,

Weaver²,

Villers-Sidani

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

180

174

View full text Add to dashboard Cite

show abstract

“…Though few studies have examined whether early FLX exposure affects social behaviours in rodents, the findings of those that have suggest these behaviours may be impaired. Aspects of social play are reduced considerably in male, but not female, adolescent rats following postnatal exposure to FLX [52]. Similar effects on the social play of male adolescent rats have also been observed following prenatal exposure [11], suggesting that this effect is consistent regardless of the period of exposure.…”

Section: Long-term Behavioural Outcomesmentioning

confidence: 81%

“…In adolescence, early exposure inhibits locomotion [23,41,50,51] and decreases novel object exploration [52]. Lisboa et al [35] observed decreased locomotion only in male mice, suggesting a difference in sensitivity between the sexes.…”

Section: Long-term Behavioural Outcomesmentioning

confidence: 99%

“…Similar effects on the social play of male adolescent rats have also been observed following prenatal exposure [11], suggesting that this effect is consistent regardless of the period of exposure. In adults, a test of preference for investigating a novel conspecific versus an inanimate object showed that adult male and female FLX-exposed rats had less of a preference for the conspecific [52], which could reflect reduced social motivation. Sexual behaviours in male rats are disrupted or decreased by postnatal FLX, administered either directly to the pup or indirectly via the dam's milk [26,52], but not following exposure throughout pregnancy and lactation in mice, though this treatment was found to reduce sexual motivation, as assessed by preference for investigating a receptive female over an adult male [57].…”

Section: Long-term Behavioural Outcomesmentioning

confidence: 99%

See 1 more Smart Citation

Long-Term Outcomes of Developmental Exposure to Fluoxetine: A Review of the Animal Literature

2013

View full text Add to dashboard Cite

During and following pregnancy, women are at high risk of experiencing depression, for which fluoxetine (FLX; brand names Prozac, Sarafem, Rapiflux) is the most commonly prescribed treatment. An estimated 1.4-2.1% of pregnant women use this medication, which inhibits the reuptake of serotonin and thereby increases serotonergic activity at the synapse. Serotonin acts as a cue guiding numerous neurodevelopmental processes, and changes in the concentration of serotonin can disrupt normal in utero brain development and organization in humans and other animals, thus providing a mechanism by which maternal intake of FLX might alter neural development and ultimately behaviour. Despite this possibility, long-term alterations of behaviour and the brain have not been well studied in individuals exposed to FLX during pregnancy or soon after birth, perhaps because conducting such studies beyond infancy presents significant challenges. To remedy this problem, many researchers have turned to modelling the effects of developmental FLX exposure in non-human animals, primarily rodents. The body of literature on this topic has expanded considerably over the past several years, yet a comprehensive review is lacking. In order to fill this gap, we have summarized the findings of those studies describing the long-term behavioural and neurophysiological effects of FLX exposure in non-human animals in early development. We also discuss methodological considerations and common shortcomings of research in this area. The precise nature of the long-term effects of developmental FLX exposure remains difficult to specify, as these effects appear to be highly variable and dependent on numerous factors. Overall, however, it is clear that early FLX exposure in non-human animals can alter the development of the brain in ways that are relevant to behaviour in adulthood, decreasing exploration and social interaction, and in some cases altering anxiety- and depression-like behaviours.

show abstract

“…Early antidepressant exposure in male rats results in long lasting behavioral effects, as well as a reduction in expression of the 5-HT synthetic enzyme (tryptophan hydroxylase) within the raphe nuclear complex and of the 5-HT transporter (SERT) within their cortical efferent fibers (Mirmiran et al, 1981; Maciag et al, 2006; Iniguez et al, 2010; Oberlander et al, 2009; Weaver et al, 2010, Rodriguez-Porcel et al, in press). In a recent study of adolescent (postnatal day-PN45) rats exposed to a SSRI, West et al (2010) reported that brief (2 or 4 days) treatment increased LC neuronal activity, suggesting an opposite effect compared to adult treatment.…”

Section: Introductionmentioning

confidence: 99%

Perinatal Citalopram Exposure Selectively Increases Locus Ceruleus Circuit Function in Male Rats

Darling

Alzghoul²,

Zhang³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (CTM) have been widely prescribed for major depressive disorder, not only for adult populations, but also for children and pregnant mothers. Recent evidence suggests that chronic SSRI exposure in adults increases serotonin (5-HT) levels in the raphe system and decreases norepinephrine (NE) locus coeruleus (LC) neural activity, suggesting a robust opposing interaction between these two monoamines. In contrast, perinatal SSRI exposure induces a long lasting down-regulation of the 5-HT-raphe system, which is opposite to that seen with chronic adult treatment. Therefore, the goal of the present investigation was to test the hypothesis that perinatal CTM exposure (20mg/kg/day) from postnatal day 1 to 10 (PN1-10) leads to hyperexcited NE-LC circuit function in adult rats (PN>90). Our single neuron LC electrophysiological data demonstrated an increase in spontaneous and stimulus-driven neural activity, including an increase in phasic bursts in CTM exposed animals. In addition, we demonstrated a corresponding immunoreactive increase in the rate limiting catalyzing catecholamine enzyme (tyrosine hydroxylase) within the LC and their neocortical target sites compared to saline controls. Moreover, these effects were only evident in male exposed rats, suggesting a sexual dimorphism in neural development after SSRI exposure. Taken together, these results indicate that administration of SSRIs during a sensitive period of brain development results in long-lasting alterations in NE-LC circuit function in adults and may be useful in understanding the etiology of pervasive developmental disorders such as autism spectrum disorder.

show abstract

Neonatal Exposure of Rats to Antidepressants Affects Behavioral Reactions to Novelty and Social Interactions in a Manner Analogous to Autistic Spectrum Disorders

Cited by 67 publications

References 35 publications

Perinatal antidepressant exposure alters cortical network function in rodents

Perinatal antidepressant exposure alters cortical network function in rodents

Long-Term Outcomes of Developmental Exposure to Fluoxetine: A Review of the Animal Literature

Perinatal Citalopram Exposure Selectively Increases Locus Ceruleus Circuit Function in Male Rats

Contact Info

Product

Resources

About