Psychopharmacology (2009) 205:689–698 self-rated drowsiness and PPI, but the present VAS measures may not be adequately sensitive to detect meaningful inter-individual differences in alertness and are not designed to assess attentional states. In a recent study with ten clinically normal adults, higher doses of pramipexole (0.25–0.50 mg) caused sedation and im- paired cognitive performance in sedation-sensitive tasks (Hamidovic et al. 2008). However, because directed attention is associated with higher PPI levels in normal humans (Filion et al. 1993), it would be counter-intuitive to explain the observed PPI increases based on attention- impairing effects of pramipexole. Confirmation that the present doses of pramipexole were bioactive came from increases in self-rated drowsiness, consistent with a number of reports with higher doses of pramipexole (Samuels et al. 2006a, b; 2007; Hamidovic et al. 2008). The lack of pramipexole effects on measures, such as “queasiness” or “happiness,” and on autonomic measures (e.g., pupil dilation), suggests that the doses in this study were physiologically low (Samuels et al. 2006a, b; 2007; Hamidovic et al. 2008) and raises the possibility that different effects on PPI might have been detected at higher doses. Such a prediction would be consistent with the present study in rodents, which demonstrated an inverted U dose function for pramipexole’s effects on PPI (i.e., it increased PPI at low doses and reduced PPI at high doses). Conceivably, low doses of pramipexole might preferentially activate presynaptic receptors or a combina- tion of pre- and post-synaptic receptors, making it difficult to determine whether the observed increase in PPI reflected functional decreases or increases in forebrain D3 stimula- tion (Samuels et al. 2006b). The nature of most studies using systemic drug administration is that the precise mechanisms of drug effects remain a matter of speculation. If we posit that the PPI-enhancing effects of pramipexole in humans reflect activation of post-synaptic forebrain D3 receptors, it would be difficult to account for PPI deficits observed in schizophrenia (Braff et al. 1978) or several other neuro- psychiatric disorders (cf. Braff et al. 2001; Swerdlow et al. 2008) based solely on overactivity of D3 neurotransmis- sion. On the other hand, if we posit that these effects of pramipexole reflect its action at presynaptic DA receptors that reduce forebrain DA “tone” (Samuels et al. 2006b), then the observed increases in PPI might be loosely consistent with PPI-enhancing effects of DA receptor antagonists in previous reports (Swerdlow et al. 2006; Vollenweider et al. 2006; Csomor et al. 2008). A strong caveat to such a connection—between PPI-enhancement by putative presynaptic effects of pramipexole and post- synaptic receptor-blocking effects of antipsychotics—is that these effects of antipsychotics are moderated by both personality dimensions (Swerdlow et al. 2006) and baseline 697 PPI (Vollenweider et al. 2006; Csomor et al. 2008), neither of which moderate the present effects of pramipexole. Certainly, one might imagine that the PPI-enhancing effects of drugs acting pre- vs. post-synaptically could both reflect reduced DAergic “tone,” yet be moderated by different biological factors. It is also conceivable that different patterns of pramipexole effects might have emerged had the 40 subjects in this study been stratified based on different polymorphisms for the D3 receptor (Roussos et al. 2008a). With the absence a clear understanding of whether the present drug effects reflect pre- vs. post-synaptic actions of pramipexole (or some combination thereof) and a lack of genetic information on D3 receptor polymorphisms among our subjects, we can still conclude from the present data that: (1) D3 receptors do appear to regulate PPI in clinically normal humans; (2) activation of these receptors by low doses of pramipexole enhances long-interval PPI; and (3) these effects appear to be independent of physiological variables that moderate other forms of DAergic regulation of PPI. It would be reasonable to consider whether such an effect could be used as a basis for predicting therapeutic sensitivity to D3 stimulation in clinical populations. Acknowledgements This study was supported by MH58903. The authors are grateful to Maria Bongiovanni for manuscript preparation and Dr. Martin Weber for technical assistance. 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