Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: implication of a countertherapeutic effect of an antidepressant.

Abstract

The 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. Although 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 evidences indicate that the principal noradrenergic cell group in the brain, the locus coeruleus (LC), is overactive in depressives and that, conversely, effective AD treatments decrease the activity of LC neurons. We report here that short-term (2 and 4 days) 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, although similar low blood levels produced by a lower dose of PAR in adult rats failed to produce an increase in LC activity. In addition, 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 that may help screen potential adjunctive treatments to avoid early adverse effects of ADs.