The International Journal of Neuropsychopharmacology

Thematic Section: Consequences of Developmental Exposure to Drugs, Hormones or Altered Environment

Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?

Emily Karangesa1, Kong M. Lia2, Craig Motbeya1, Paul D. Callaghana3, Andrew Katsifisa3 and Iain S. McGregora1 c1

a1 School of Psychology, University of Sydney, Australia

a2 Discipline of Pharmacology, Sydney Medical School, University of Sydney, Australia

a3 Australian Nuclear Science and Technology Organisation (ANSTO), Sydney, Australia

Abstract

Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11–12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19–20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down-regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX-induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans.

(Received August 18 2010)

(Reviewed October 11 2010)

(Revised January 03 2011)

(Accepted January 07 2011)

(Online publication February 18 2011)

Correspondence:

c1 Address for correspondence: Professor I. S. McGregor, School of Psychology A18, University of Sydney, Sydney, NSW 2006, Australia. Tel.: +61 2 9351 3571 Fax: +61 2 9351 8023 Email: iain@psych.usyd.edu.au

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