Paroxetine-Induced Increase in Activity of Locus Coeruleus Neurons in Adolescent Rats: Implication of a Countertherapeutic Effect of an Antidepressant

Abstract

Concern that antidepressant (AD) drugs, especially selective serotonin reuptake inhibitors and paroxetine (PAR) in particular, can increase suicidality during the early treatment of juvenile patients (children and adolescents) has created a dilemma for clinicians treating depressives. Though preclinical research cannot resolve controversy in this area, our present findings may provide insight into how AD drugs might, under certain conditions, exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidence indicates that the principle noradrenergic cell group in the brain, the locus coeruleus (LC), is over-active in depressives and that, conversely, effective AD treatments decrease activity of LC neurons. We report here that short-term (2 and 4 day) administration of PAR produces an increase in the activity of LC neurons (spontaneous firing rate and sensory-evoked responses) in young rats, contrary to the “therapeutic” decrease in activity typically observed in adult rats. Blood levels of PAR were lower in young rats than in adult rats, though similar low blood levels produced by a lower dose of PAR in adult rats failed to produce an increase in LC activity. Additionally, activity of young rats in the swim test was determined to assess depressive-like responses. The same dose/durations of PAR which produced the largest increases in LC activity in young rats produced decreases in swim-test activity, indicating that brief administration of PAR in young rats can promote, rather than reduce, the depressive state. These results offer a model which may help screen potential adjunctive treatments to avoid early adverse effects of ADs.

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

“…TH). In contrast, West et al (2010) reported that paroxetine-induced increases of LC activity in adolescent rats (PN45) was restricted to acute exposure (2-4 days), but was more similar to adult exposure (decreased LC activity) after longer-term treatment (8-14 days). This increased activity complements our results but, with the apparent difference in chronic vs acute exposure in the above mentioned study, it is apparent that the identification of critical windows of antidepressant sensitivity on neurodevelopment needs to be investigated further.…”

“…Increased LC firing when SSRIs were administered during adolescence (PN45) was interpreted as a possible explanation for the increased risk for suicide in younger populations taking SSRIs (West et al, 2010; Goodman et al, 2007). We extend these findings to earlier periods of neurodevelopment and suggest this earlier manipulation of the monoamine system may result in long lasting modifications of the NE-LC system in males.…”

“…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. It is still not clear how SSRI exposure during early brain development affects NE-LC function, but it appears that it is different than adult exposure and the brief exposure can have dramatic effects that are observed well into adulthood.…”

Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin

“…In adolescent rats, SSRIs early in treatment had the effect of increasing, rather than decreasing, LC activity and depression-like behavior. By contrast, tricyclics, which are not associated with increased risk of suicidality in adolescents, decreased LC activity in both adult and adolescent rats (West et al, 2010a; West et al, 2010b). …”

Prédire le suicide ou prédire l’imprévisible dans un monde incertain. Modèle du suicide selon l’apprentissage par renforcement

“…Cette augmentation de noradrénaline suggère une augmentation d'activité dans le LC et a été liée à des choix impulsifs (Eckhoff et al,, 2009) ainsi qu'à des changements comportementaux rapides en réponse à des challenges cognitifs, par la facilitation de la réorganisation dynamique des réseaux corticaux (Bouret et Sara, 2005). Cette hypothèse s'appuie aussi sur l'observation qu'une prise brève d'antidépresseur chez des jeunes rats augmente les décharges des neurones dans le LC, et est associé avec une péjoration de la dépression (West et al, 2010), suggérant par là que l'augmentation d'activité du LC puisse être associée aux effets secondaires du traitement antidépresseur sur l'humeur particulièrement chez les jeunes.…”