An Experimental Medicine Investigation of the Effects of Subacute Pramipexole Treatment on Emotional Information Processing in Healthy Volunteers

Abstract

Treatment with the dopamine D2/D3 receptor agonist pramipexole has demonstrated promising clinical effects in patients with depression. However, the mechanisms through which pramipexole might alleviate depressive symptoms are currently not well understood. Conventional antidepressant drugs are thought to work by biasing the processing of emotional information in favour of positive relative to negative appraisal. In this study, we used an established experimental medicine assay to explore whether pramipexole treatment might have a similar effect. Employing a double-blind, parallel-group design, 40 healthy volunteers (aged 18 to 43 years, 50% female) were randomly allocated to 12 to 15 days of treatment with either pramipexole (at a peak daily dose of 1.0 mg pramipexole salt) or placebo. After treatment was established, emotional information processing was assessed on the neural level by measuring amygdala activity in response to positive and negative facial emotional expressions, using functional magnetic resonance imaging (MRI). In addition, behavioural measures of emotional information processing were collected at baseline and on drug, using an established computerized task battery, tapping into different cognitive domains. As predicted, pramipexole-treated participants, compared to those receiving placebo, showed decreased neural activity in response to negative (fearful) vs. positive (happy) facial expressions in bilateral amygdala. Contrary to our predictions, however, pramipexole treatment had no significant antidepressant-like effect on behavioural measures of emotional processing. This study provides the first experimental evidence that subacute pramipexole treatment in healthy volunteers modifies neural responses to emotional information in a manner that resembles the effects of conventional antidepressant drugs.

The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain

“…As per previous data, significant brain activations were observed in a network of regions ( 43 – 45 ), including the superior, middle and inferior frontal gyrus, paracingulate gyrus, frontal pole, pre-central gyrus, left and right putamen, left insular cortex, and left thalamus. These findings confirm that the task engaged brain areas implicated in the processing of both fear and happiness, similar to previous work with this version of the task ( 42 ). Unexpectedly, we did not see differential whole-brain activation related to face emotion (see Supplementary Figure 2 ), and there was a similar level of amygdala activation to both fearful and happy faces bilaterally (see Figure 3 ).…”

“…This task was modified from previous versions used within our laboratory ( 27 , 32 ) with block lengths and orders optimised for fMRI [see Ref. ( 42 ), full details are in Supplementary Material ]. Briefly, faces were presented rapidly for 100 ms in isolation and participants had to respond to indicate the assumed gender of the face as quickly as possible using a button press.…”

Enhanced Taste Recognition Following Subacute Treatment With The Dopamine D2/D3 Receptor Agonist Pramipexole in Healthy Volunteers

“…Pramipexole-treated participants correctly guessed their treatment allocation in 61.9% of cases and placebo-treated participants in 84.2% of cases (Fisher’s exact test: P < .01). The assessor correctly guessed treatment allocation in 71.4% of cases for pramipexole-treated participants and 84.2% of cases for placebo-treated participants (Fisher’s exact test: P < .01) (also see Martens et al, 2021 ).…”

“…Nausea is a common side effect of pramipexole treatment and was the only side effect that was observed significantly more often in participants who received pramipexole (13 out of 21 participants, i.e., 61.9%) compared with placebo (1 out of 19, i.e., 5.3%) [Fisher’s exact test: P < .01; a detailed overview of all side effects observed in this study sample, can be found in Martens et al (2021) ]. Thus, it could be the case that the experience of nausea drove the observed group differences in gustatory processing.…”

Catechol-O-methyltransferase activity does not influence emotional processing in men

“…There is also some evidence that COMT genotype influences patterns of functional connectivity during emotional processing (Opmeer et al, 2013;Vai et al, 2017; but see Surguladze et al, 2012). Notably, this disconnect between neural measures and behavioural effects has been observed within subjects, both in the specific case of COMT genotype (Kempton et al, 2009) and after other manipulations of dopamine function (Martens et al, 2021). It is possible that that measurements of quantitative biological traits, such as BOLD response, are more sensitive to the subtle effects of genetic variation than studies looking at overt behaviour (Meyer-Lindenberg and Weinberger, 2006).…”