Effect of apomorphine on cognitive performance and sensorimotor gating in humans.
BACKGROUND
Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level.


METHODS
Fifteen healthy male volunteers received apomorphine sublingually (2 mg), subcutaneously (0.005 mg/kg), and placebo in a balanced, double-blind, cross-over design. Outcome measures were plasma GH levels, performance on an AX continuous performance test, and prepulse inhibition of the acoustic startle. The relation between central outcome measures and apomorphine levels observed in plasma and calculated in the brain was modeled using a two-compartmental pharmacokinetic-pharmacodynamic analysis.


RESULTS
After administration of apomorphine, plasma GH increased and performance on the AX continuous performance test deteriorated, particularly in participants with low baseline performance. Apomorphine disrupted prepulse inhibition (PPI) on high-intensity (85 dB) prepulse trials and improved PPI on low intensity (75 dB) prepulse trials, particularly in participants with low baseline PPI. High cognitive performance at baseline was associated with reduced baseline sensorimotor gating. Neurophysiological measures correlated best with calculated brain apomorphine levels after subcutaneous administration.


CONCLUSIONS
The apomorphine challenge test appears a useful tool to assess dopamine receptor functioning at the forebrain level. Modulation of the effect of apomorphine by baseline performance levels may be explained by an inverted U-shape relation between prefrontal dopamine functioning and cognitive performance, and mesolimbic dopamine functioning and sensorimotor gating. Future apomorphine challenge tests preferentially use multiple outcome measures, after subcutaneous administration of apomorphine.
Schellekens
Arnt F A
AF
Department of Psychiatry, Radboud Medical Centre Nijmegen, 6500 HB Nijmegen, The Netherlands. a.f.a.schellekens@psy.umcn.nl
Grootens
K P
KP
Neef
C
C
Movig
Kris L L
KL
Buitelaar
J K
JK
Ellenbroek
B
B
Verkes
R J
RJ
D000286:Administration, Sublingual; D000328:Adult; D001058:Apomorphine / Q000008:administration & dosage / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D018592:Cross-Over Studies; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects*; D055815:Young Adult
D018491:Dopamine Agonists; D011954:Receptors, Dopamine; D013006:Growth Hormone; D001058:Apomorphine