We showed that retrieval of episodic information can be improved post learning by acute D2 antagonist administration. The retrieval-specific recognition enhancement of haloperidol is in agreement with previous reports of haloperidol-induced post-learning memory retrieval facilitation in the rat [22, 23] and with preliminary evidence of recognition impairments under decreased dopaminergic transmission in humans using a low-dose dopaminergic agonist [13]. However, the current retrieval-specific results go beyond this latter study where dopamine levels were not exclusively manipulated during retrieval and therefore the observed recognition deficit might also be due to dopaminergic effects on encoding. Inconclusive or absent retrieval performance effects of dopamine in other human pharmacological studies [11, 12, 14, 15] might likewise have resulted from a failure to constrain dopaminergic modulation to the retrieval phase specifically.

Of interest, the few human pharmacological studies that examined the retrieval effects specifically using dopamine agonists such as amphetamine, THC, or MDMA [16,17,18] observed increased false recognition under drug in the absence of retrieval accuracy effects. In contrast, our present results give no clear indication of a haloperidol effect on false alarm rates. These contradictory findings might be explained by a different impact on prefrontal retrieval monitoring mechanisms by these drugs. Specifically, while these dopamine agonists might target in particular frontal circuits linked with monitoring and false memory recognition [17], haloperidol has only marginal direct effects on frontal circuits but acts primarily on the striatum [37, 51]. Additionally, it should be noted that low-dose dopamine agonists can have likewise paradoxical effects due to the primary activation of the high-affinity presynaptic autoreceptors (e.g., [13, 40]) and therefore it cannot be excluded that these previously reported false recognition effects [16,17,18] result from decreased (rather than increased) dopaminergic neurotransmission.

Importantly, the fMRI data acquired in the present recognition study give an indication of the direction of the dopaminergic effects associated with the memory effects observed on the behavioral level. In particular, the increased striatal and SN/VTA activations indicate that haloperidol indeed potentiated dopamine release from the SN/VTA by blocking the presynaptic autoreceptors [37, 38, 43]. The resulting increased stimulation of (postsynaptic) dopamine receptors in the hippocampus and amygdala might have improved memory discrimination, possibly by augmenting the signal-to-noise ratio [52,53,54] of the mnemonic representation in these structures. This explanation is in accordance with the higher fMRI activity for retrieval success in these regions and in the dopaminergic midbrain under haloperidol. Still, it should be noted that the haloperidol-induced dopamine increase (e.g., [34, 35, 37]) as well as the tight correlation between dopaminergic stimulation and BOLD activity [38, 41,42,43] is thoroughly established in the striatum, but comparably less clear for the hippocampus or amygdala (though see [55, 56]). In contrast, the fMRI activity of memory confidence suggested that enhanced dopaminergic stimulation of frontostriatal networks under haloperidol resulted in behavioral impairments in metamemory for new decisions and probably also contributed to the decreased WM performance [31] in the haloperidol group. In particular, the unsystematically increased striatal activity across all confidence levels (“reduced confidence differentiation”) under haloperidol might have limited the dynamic response range of the striatum [52] to signal the previously reported linear increasing striatal confidence activity from low to high confidence [25] and altered striatal interactions with the PFC and ACC underlying metacognition. This frontostriatal metacognitive process seems to be more important for new decisions than for old decisions, as only the former were impaired under haloperidol. Of interest, an improvement of prefrontal metacognition for memory retrieval through the dopamine agonist l-dopa was reported by [57] while another recent study [58] did not observe an effect of dopamine on metacognition in a perceptual dot motion task. This could point to different mechanisms underlying the introspective metacognition in memory retrieval compared to perceptual metacognition (see also [59]).

Together, these data demonstrate that the dopaminergic modulation here has facilitating effects on midbrain–hippocampal memory retrieval, but detrimental effects on frontostriatally mediated metamemory. These opposing findings are in agreement with recently demonstrated dissociable brain mechanisms underlying recognition performance and memory confidence in non-human primates [60], as well as with long-established behavioral dissociations between memory accuracy and confidence in human cognitive studies (e.g., [61,62,63,64]). Beyond this dissociation, our findings might help to explain the presence of episodic memory [65] and metamemory [66] impairments in dopamine-related diseases, as well as offer new perspectives for the treatment of memory disorders.

Limitations

Our interpretation rests on the assumption that acute administration of 2 mg haloperidol will actually increase dopaminergic signaling. However, this effect has been directly demonstrated only in animals. Previous human fMRI studies using similar doses of haloperidol usually assumed that the drug decreases dopaminergic signaling (e.g., [67, 68]). It is possible that the effect of haloperidol is relatively dependent on the task and the kind of stimuli. Moreover, D2 antagonist effects on autoreceptor actions are certainly complex and not understood in all details. Depending on the state of the dopamine neurons and the exact stimulation pattern, regulation effects of the autoreceptors may vary and also feature additional components shaping the neuron’s activity [69]. Also, the observed memory effects might stem from interactions with other neurotransmitter systems (especially noradrenaline [23]) and be tightly linked to specific doses determining the amount of presynaptic vs. postsynaptic blockade [70]. Eventually, additional studies using multi-modal methodological approaches [71] will be necessary to resolve these contradictory drug findings as well to examine the specificity of dopaminergic effects on memory retrieval in more detail.

Finally, drug studies are prone to vascular baseline effects confounding the MR signal [72]. The critical fMRI group differences we report here for memory retrieval and confidence are well controlled for such potential baseline differences as we compared hit with CR trials and high with low confidence trials, respectively. General drug effects affecting the vascular reactivity should affect both conditions similarly and are therefore removed before the groups are compared. Still, future studies might consider to control these potential confounds more rigorously by, for example, measuring the baseline brain perfusion using arterial spin labeling and by recording and correcting for physiological parameters such as heart or breathing rate [72].

Funding and disclosure

This study was supported by a grant from the Deutsche Forschungsgemeinschaft to TS and NB (DFG SO 952/3-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to the University of Minnesota Center for Magnetic Resonance Research for providing the image reconstruction algorithm for the simultaneous multi-slice acquisitions. The authors declare no competing interests.