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

Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2011; 31(46):16709-15. DOI: 10.1523/JNEUROSCI.3736-11.2011
Source: PubMed


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 ceruleus (LC) neural activity, suggesting a robust opposing interaction between these two monoamines. In contrast, perinatal SSRI exposure induces a long-lasting downregulation 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 (20 mg/kg/d) from postnatal day 1 (PN1) to PN10 leads to hyperexcited NE-LC circuit function in adult rats (>PN90). 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. 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.

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    • "To lend further support, there should be some independent reason to expect that the LC-NE system in individuals with ASD is more prone to phasic activity. Recently, there has been work implicating the LC-NE system in ASD etiology in humans37 and animal models38. Further, there has been a suggestion that in ASD, the LC may indeed be in a persistent hyperphasic state26, thereby increasing performance on tasks that benefit from focussed attention and reduced distractibility, but decreasing performance on tasks that require shifts of attention3940. "
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    ABSTRACT: Research on the neural underpinnings of Autism Spectrum Disorder (ASD) has focussed primarily on impairments of social interaction and communication. Less is known though about the second diagnostic criterion of restricted behaviors and interests. Uniquely in this domain, alongside impairments stands an 'ASD advantage' characterised by superior performance on many visual tasks. We recently found that 2-year-olds with ASD dramatically outperform age-matched, typically developing controls on visual search. Here we use task-evoked, phasic pupil responses - a sensitive, involuntary measure of effort and a biomarker of the locus coeruleus-norepinephrine (LC-NE) system's modulation of attention - to isolate a causal factor: a 'hyperphasic' LC-NE system compels (here, advantageously) focussed attention. However, this focussed attention in other contexts may contribute to restricted behaviors and interests.
    Full-text · Article · Mar 2014 · Scientific Reports
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    • "Furthermore, after a single injection of 5HT into newborn rats, 5HT levels were reduced in the striatum of adult male rats and displayed increased sexual activity, while no obvious differences were detected in adult female rats (Csaba et al., 2003). Interestingly, perinatal exposure to CTM affected male locus coeruleus circuit function but was not seen in females (Darling et al., 2011). Because a variety of early-life 5HT-system manipulations produce a constellation of long-term and sex-specific effects, it is not surprising that we observed a sex-specific reduction of SERT-ir fiber density in the OB of only male rats after neonatal CTM exposure. "
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    ABSTRACT: 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.
    Full-text · Article · May 2013 · Frontiers in Cellular Neuroscience
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    • "However, the third trimester of human neurodevelopment is best modeled in neonatal mice and rats. In rats, neonatal SSRI exposure decreases synaptogenesis and elicits features consistent with depression [15] [16] [17]. This post-SSRI syndrome appeared to have a sexually dimorphic presentation with male mice affected more than females. "
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    ABSTRACT: . Selective serotonin reuptake inhibitor (SSRI) therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods . C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d) from P1–P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2) expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX). Metabolic rate was determined by indirect calorimetry. Results . In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions . SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome.
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