Serotonin 2A Receptors, Citalopram and Tryptophan-Depletion: a Multimodal Imaging Study of their Interactions During Response Inhibition

Abstract

Poor behavioral inhibition is a common feature of neurological and psychiatric disorders. Successful inhibition of a prepotent response in ‘NoGo' paradigms requires the integrity of both the inferior frontal gyrus (IFG) and the serotonergic system. We investigated individual differences in serotonergic regulation of response inhibition. In 24 healthy adults, we used 18F-altanserin positron emission tomography to assess cerebral 5-HT2A receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral and neural correlates of inhibition using intravenous citalopram and acute tryptophan depletion during functional magnetic resonance imaging. We adapted the NoGo paradigm to isolate effects on inhibition per se as opposed to other aspects of the NoGo paradigm. Successful NoGo inhibition was associated with greater activation of the right IFG compared to control trials with alternative responses, indicating that the IFG is activated with inhibition in NoGo trials rather than other aspects of invoked cognitive control. Activation of the left IFG during NoGo trials was greater with citalopram than acute tryptophan depletion. Moreover, with the NoGo-type of response inhibition, the right IFG displayed an interaction between the type of serotonergic challenge and neocortical 5-HT2A receptor binding. Specifically, acute tryptophan depletion (ATD) produced a relatively larger NoGo response in the right IFG in subjects with low 5-HT2A BPP but reduced the NoGo response in those with high 5-HT2A BPP. These links between serotonergic function and response inhibition in healthy subjects may help to interpret serotonergic abnormalities underlying impulsivity in neuropsychiatric disorders.

Effects of serotonin depletion on punishment processing in the orbitofrontal and anterior cingulate cortices of healthy women

“…A previous fMRI study assessing brain activation after ATD administration during response inhibition revealed serotonergic modulation of the right inferior PFC during inhibitory motor control (Rubia et al, 2005). Macoveanu et al (2013) showed that activation of the left inferior frontal gyrus (IFG) was greater after the administration of the SSRI citalopram than after an ATD challenge during No-Go trials. NoGo responses were larger after ATD administration in the right IFG in subjects with low neocortical 5-HT 2A BP p receptor binding and reduced in those with high 5-HT 2A BP p receptor binding.…”

Recent Insights into the Neurobiology of Impulsivity

“…Activation of the left inferior frontal gyrus during nogo was greater with citalopram administrations than with acute tryptophan depletion [37]. The inferior frontal gyrus during nogo trials displayed an interaction between type of 5HT challenge and neocortical 5HT 2A receptor binding, such that acute tryptophan depletion produced an increase in response during nogo trials in right inferior frontal gyrus in subjects with low 5HT 2A binding potential and a decrease in nogo response in those with high 5HT 2A binding potential as measured by positron emission tomography (PET) [37]. Taken together, findings suggest that there may be an optimal level of serotonin, or activation of the 5HT 2A receptor subtype, which allows for successful nogo responses.…”

The Center for Integrated Molecular Brain Imaging (Cimbi) database

“…Functional MRI (fMRI) in conjunction with various pharmacological challenges of the 5-HT system has been obtained with emotional faces task (Grady et al, 2013;Hornboll et al, 2013) or a gambling task (Macoveanu et al, 2013b, Macoveanu et al, 2013cMacoveanu et al, 2013a). fMRI has also been investigated in relation to genotype (Fisher et al, 2012) and bright light intervention .…”

“…Apart from standard screening blood tests, there are for some cohorts biochemical measures of serum brain derived neurotrophic factor (BDNF) (Klein et al, 2010;Trajkovska et al, 2007;Trajkovska et al, 2008), amino acids (Macoveanu et al, 2013a), and sex steroid hormones . In a large proportion of the Cimbi cohort saliva samples have been acquired overnight for determination of cortisol awakening response …”