Cognitive performance of juvenile monkeys after chronic fluoxetine treatment

Abstract

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility test, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment.

Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex

“…In vivo , the attention-enhancing effects of prefrontal ACh release have been extensively studied (Arnold et al, 2002 ; Parikh et al, 2007 ; Gritton et al, 2016 ), but the adverse behavioral effects of 5-HT on attention tasks are less well understood (Ramaekers et al, 1995 ; Riedel et al, 1999 , 2005 ; Schmitt et al, 2002 ; Wingen et al, 2008 ; Golub et al, 2017 ). Recent work raises the concept that 5-HT may subvert top-down cortical signaling in favor of sensory processing (Lottem et al, 2016 ).…”

“…For example, some types of focused task attention can be difficult to disrupt in people with autism, a condition associated with low 5-HT levels in brain (Dougherty et al, 2013 ; Adamsen et al, 2014 ; Muller et al, 2016 ). Conversely, increases in 5-HT may contribute to adverse consequences of selective 5-HT reuptake inhibitors on attention (Ramaekers et al, 1995 ; Riedel et al, 2005 ; Graf et al, 2013 ; Golub et al, 2017 ). Taken together, our electrophysiological and optogenetic results suggest a potential cellular mechanism underlying the opposing influences of ACh and 5-HT on attention: these modulators exert opposite neurophysiological effects on the excitability of layer 6 pyramidal neurons in prefrontal cortex.…”

“…Brain serotonergic activity has the opposite effect on attention than ACh. Increased 5-HT levels negatively affect performance on attention tasks (Ramaekers et al, 1995 ; Riedel et al, 1999 , 2005 ; Schmitt et al, 2002 ; Wingen et al, 2008 ; Graf et al, 2013 ; Golub et al, 2017 ), while reductions in 5-HT enhance attention (Schmitt et al, 2000 ; Gallagher et al, 2003 ; Wingen et al, 2007 ). While it has been suggested that ACh and 5-HT can alter performance in the same attentional task (Jäkälä et al, 1992 ), it is not yet clear that there is a direct cortical interaction between these two modulatory systems in attentional processes (Steckler and Sahgal, 1995 ).…”

Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children

“…Sustained attention was sensitive to fluoxetine in our nonhuman primate project ( 8 ). An automated Continuous Performance Test (CPT) was used to evaluate sustained attention at the end of the dosing period.…”

“…Macaque monkeys are prominent models for childhood because of the extended juvenile period between infancy and puberty when advanced cortical functions mature under the influence of complex social systems. The review integrates findings from eight published studies of different endpoint domains ( 1 – 8 ) with current issues in pediatric psychopharmacology.…”