Modulating sensorimotor gating in healthy volunteers: the effects of desipramine and haloperidol.
In schizophrenia both an involvement of a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity have been suggested. In addition, patients suffering from schizophrenia show reduced sensorimotor gating and reduced habituation. If there is a causality between these neurotransmitters and these processes, then either a reduction in dopaminergic activity or an enhanced noradrenergic activity in healthy volunteers would result in reduced sensorimotor gating and reduced habituation. In the present study, a group of 12 healthy male volunteers was tested four times in a prepulse inhibition (PPI) paradigm 2.5 h following administration of placebo/placebo, placebo/desipramine (50 mg), placebo/haloperidol (2 mg) and desipramine (50 mg)/haloperidol (2 mg). A significant reduction of percentage PPI was found in all active treatments compared with placebo/placebo, while no treatment effects on habituation were found. Furthermore, a significant increase in heart rate was found in both desipramine treatments, from 120 min following oral intake onwards. Both desipramine and haloperidol reduced PPI, which suggests that an enhanced noradrenergic activity and a reduced dopaminergic activity lead to a reduction in sensorimotor gating. Since reduced sensorimotor gating is found in schizophrenia, these results supply further evidence for a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity in schizophrenia. Furthermore, the combination of haloperidol and desipramine did not have a synergistic effect on PPI, which indicates an interaction between the compounds. The site for this interaction is most likely located in the prefrontal cortex, since evidence is accumulating that extracellular dopamine concentration is regulated by noradrenergic terminals, particularly in the frontal areas of the brain. Since no effects on habituation were found, this suggests that neither enhanced noradrenergic nor decreased dopaminergic activity is involved in this process.
Department of Psychopharmacology, Faculty of Pharmaceutical Sciences, Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, The Netherlands. B.Oranje@cnsr.dk
Bob
B
Oranje
René S
RS
Kahn
Chantal
C
Kemner
Marinus N
MN
Verbaten
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004576:Electromyography; D006185:Habituation, Psychophysiologic / Q000187:drug effects*; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007266:Inhibition, Psychological; D008297:Male; D011597:Psychomotor Performance / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D014150:Antipsychotic Agents; D006220:Haloperidol; D003891:Desipramine