Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude.
Antagonists of the N-methyl-D-aspartate (NMDA) receptors such as ketamine, induce abnormalities in healthy subjects similar to those found in schizophrenia. However, recent evidence, suggests that most of the currently known NMDA antagonists have a broader receptor profile than originally thought. Besides exerting an antagonistic effect on NMDA receptors, they have agonistic effects on dopamine D2 receptors. Can haloperidol (D2 antagonist) counteract the disruptive effects of ketamine on psychophysiological parameters of human attention? In a randomized, double-blind, placebo-controlled experiment 18 healthy male volunteers received placebo/placebo, placebo/ketamine (0.3 mg/kg i.v.) and haloperidol (2 mg)/ketamine (0.3 mg/kg i.v.) on three separate test days, after which they were tested in an auditory selective-attention paradigm. Haloperidol/ketamine reduced task performance compared to placebo/placebo, while the task performance in these two treatments did not differ from placebo/ketamine. Furthermore, placebo/ketamine reduced processing negativity compared to both placebo/placebo and haloperidol/ketamine, while processing negativity did not differ between placebo/placebo and haloperidol/ketamine treatments. However, both placebo/ketamine and haloperidol/ketamine reduced P300 amplitude compared to placebo/placebo, while P300 amplitude did not differ between placebo/ketamine and haloperidol/ketamine treatments. The combined effects of haloperidol and ketamine reduced task performance, suggesting that this is dependent on dopaminergic D2 activity, probably in the prefrontal cortex. In addition, ketamine reduced both P300 amplitude and processing negativity. In contrast to the P300 amplitude, the disruptive effects of ketamine on processing negativity could be prevented by pretreatment with haloperidol. The current results suggest that ketamine reduced P300 amplitude by its antagonistic effect on glutamatergic activity, while it reduced processing negativity by its agonistic effect on dopaminergic D2 activity.
Oranje
Bob
B
Center for Neuropsychiatric Schizophrenia Research (CNSR), Faculty of Health Sciences, Copenhagen University, University Psychiatric Center Glostrup, Glostrup, Denmark.
Gispen-de Wied
Christine C
CC
Westenberg
Herman G M
HG
Kemner
Chantal
C
Verbaten
Marinus N
MN
Kahn
René S
RS
D000161:Acoustic Stimulation / Q000379:methods; D000328:Adult; D000339:Affect / Q000187:drug effects; D001288:Attention / Q000187:drug effects; D001519:Behavior / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003265:Contingent Negative Variation / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004311:Double-Blind Method; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D004585:Electrooculography / Q000379:methods; D018913:Event-Related Potentials, P300 / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006719:Homovanillic Acid / Q000097:blood; D006801:Humans; D007649:Ketamine / Q000097:blood / Q000494:pharmacology*; D008297:Male; D015999:Multivariate Analysis; D009483:Neuropsychological Tests; D011388:Prolactin / Q000097:blood; D011569:Psychiatric Status Rating Scales; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D055815:Young Adult
D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D011388:Prolactin; D006220:Haloperidol; D006719:Homovanillic Acid