Dopamine Enhances Item Novelty Detection via Hippocampal and Associative Recall via Left Lateral Prefrontal Cortex Mechanisms

Abstract

The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine.

Dopaminergic modulation of human inter-temporal choice: a diffusion model analysis using the D2-receptor-antagonist haloperidol

“…As reported in detail in our previous papers 28,29 , there were no significant group differences with respect to reported side-effects, subjective mood, heart rate or blood pressure relative to baseline. Likewise, groups did not differ with respect to the actual and guessed drug condition (Haloperidol vs.…”

“…Taken together, our data show that the D2 receptor antagonist Haloperidol attenuated temporal discounting and substantially shortened the non-decision time, as revealed by comprehensive computational modeling of choices and RTs using hierarchical Bayesian parameter estimation. In combination with Haloperidol increasing dorsal striatal responses in an unrelated task in our participants 29 , these data are best accounted for by a model in which low dosages of Haloperidol lead to an enhancement of phasic DA responses due to reduced feedback inhibition from D2 autoreceptors, leading to an augmentation of both low-level (non-decision time) and higher-level (temporal discounting) components of the value-based decision process.…”

“…In separate memory tasks performed by our participants during fMRI, we have previously reported substantial increases in task-related dorsal striatal activation in the Haloperidol vs. Placebo group during trial onset both for recognition 28 and associative recall 29 . This observation is compatible with a predominantly presynaptic effect of Haloperidol in the present study, leading to an overall increase in striatal dopaminergic signaling.…”

“…First, participants in the present study performed an unrelated memory task during fMRI directly prior to completing the temporal discounting task reported here. Those data revealed an overall main effect of drug condition on trial onset-related activity in caudate nucleus during recognition 28 and associative recall 29 (both effects were correlated 29 ), such that participants from the Haloperidol group showed a substantially elevated dorsal striatal response in relation to stimulus onset, as compared to the placebo group. This neural read-out was obtained prior to the temporal discounting task, but both the fMRI and temporal discounting time points were well within the time of maximum Haloperidol plasma levels 34 .…”

Dopamine Related Genes Differentially Affect Declarative Long-Term Memory in Healthy Humans

“…Along the same lines, research in animals could show that reward enhances hippocampal reactivation (Singer and Frank, 2009 ) and hippocampal DA regulates the persistence of long-term memory (Rossato et al, 2009 ). Finally, pharmacological modulation of the dopaminergic system in humans drives memory retrieval, which provides evidence for a role of DA in episodic memory retrieval (Clos et al, 2019a , b ). Concerning our findings, this suggests that polymorphisms affecting dopaminergic neuromodulation may relate to encoding, consolidation, and/or retrieval.…”