Paradoxical dopaminergic drug effects in extraversion: dose- and time-dependent effects of sulpiride on EEG theta activity

Abstract

Dopaminergic drugs frequently produce paradoxical effects depending on baseline performance levels, genotype, or personality traits. The present study for the first time aimed to specify the mechanisms underlying such opposite effects using the following recently reported scenario as an example: depending on the personality trait agentic extraversion (agentic facet, aE; i.e., assertiveness, dominance, ambition, positive emotionality) the selective dopamine D2 receptor antagonist sulpiride (200 mg) had opposite effects on resting posterior vs. anterior theta activity in the electroencephalogram (EEG). In order to better describe these opposite pharmaco-EEG effects and to generate hypotheses regarding the underlying mechanisms, we measured the EEG intermittently over 5 h in 80 healthy male volunteers extremely high or low in aE who had received either placebo or one of three doses of sulpiride (50, 200, or 400 mg). The findings suggest a model postulating stronger pre- vs. postsynaptic subreceptor effects in high aE individuals compared to low aE individuals. Future studies may now systematically apply the model to other examples of paradoxical dopaminergic drug effects and examine the molecular basis of individual differences in pre- vs. postsynaptic dopamine D2 subreceptor sensitivities and densities.

Trait Extraversion and Dopamine Function

“…They found that the modulatory effects of extraversion could be observed across three doses, albeit with varying time courses: introverts showed stronger sulpiride effects with smaller doses or early after administration, whereas extraverts showed sulpiride effects (opposite in direction) only for the larger doses and later after administration. Because at low blood plasma levels sulpiride is thought to primarily act on presynaptic autoreceptors and post-synaptic receptor blockade only prevails at higher blood levels, the observed pattern of opposite effects with variable time courses is consistent with stronger effects on pre-versus post-synaptic subreceptors in introverts relative to extraverts (Chavanon et al, 2013). It should also be emphasized that most of these dopamine challenge studies found that modulation of the pharmacological effects was specific to extraversion relative to other personality traits.…”

“…Extraversion has also been shown to strongly modulate the effects of the selective dopamine D2 receptor antagonist sulpiride on several EEG measures including the FRN , frontal EEG asymmetry , and posterior versus frontal theta activity (Chavanon, Wacker, & Stemmler, 2013;Wacker et al, 2006) -another putative EEG index of approach motivation (Walden, Pornpattananangkul, Curlee, McAdams, & Nusslock, 2014). In each of these studies, the positive association between extraversion and the EEG measure of interest observed under placebo was not only diminished but inverted by the dopamine antagonist.…”

“…In each of these studies, the positive association between extraversion and the EEG measure of interest observed under placebo was not only diminished but inverted by the dopamine antagonist. Notably, in an initial attempt to probe the role of dose-response relationships and pharmacokinetics, Chavanon et al (2013) varied the dose of the dopamine antagonist sulpiride and observed its effects on the EEG over several hours. They found that the modulatory effects of extraversion could be observed across three doses, albeit with varying time courses: introverts showed stronger sulpiride effects with smaller doses or early after administration, whereas extraverts showed sulpiride effects (opposite in direction) only for the larger doses and later after administration.…”

Openness to experience predicts dopamine effects on divergent thinking

“…This paradoxical effect was hypothesized to be due to prevalent blockage of presynaptic autoreceptors leading to enhanced dopamine neurotransmission (Kuroki, Meltzer, & Ichikawa, 1999). In previous studies with healthy participants, single doses of sulpiride have been well tolerated, and participants were usually not able to guess whether they received sulpiride or placebo (Chavanon, Wacker, & Stemmler, 2013;Wacker, 2018;Wacker et al 2013).…”

Laboratory-induced learned helplessness attenuates approach motivation as indexed by posterior versus frontal theta activity

“…Third, profiles of resting delta/theta current in the rACC have been associated with both anhedonia and blunted ventral striatal activation in response to monetary rewards, as indexed by functional magnetic resonance imaging (fMRI) (Wacker et al, 2009). Finally, pharmacological agents that affect dopaminergic activity, such as the dopamine antagonist sulpiride, which is designed to attenuate dopaminerelated activity, have been shown to modulate PFTA (Chavanon, Wacker, & Stemmler, 2013). For example, whereas unmedicated participants displayed a positive relationship between self-reported BAS sensitivity and PFTA, individuals who took a dopamine antagonist exhibited a negative relationship between BAS sensitivity and PFTA (Wacker et al, 2006).…”