The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice.
BACKGROUND
The psychotomimetic drug, phencyclidine, induces schizophrenia-like behavioural changes in both humans and animals. Phencyclidine-induced disruption of sensory motor gating mechanisms, as assessed by prepulse inhibition of the acoustic startle, is widely used in research animals as a screening model for antipsychotic properties in general and may predict effects on negative and cognitive deficits in particular. Dopamine (DA) stabilizers comprise a new generation of antipsychotics characterized by a partial DA receptor agonist or antagonist action and have been suggested to have a more favourable clinical profile.


OBJECTIVE
The aim of the present study was to investigate the ability of first, second and third generation antipsychotics to interfere with the disruptive effect of phencyclidine on prepulse inhibition in mice.


RESULTS
Aripiprazole blocked the phencyclidine-induced disruption of prepulse inhibition. The atypical antipsychotic clozapine was less effective, whereas olanzapine, and the typical antipsychotic haloperidol, failed to alter the effects of phencyclidine on prepulse inhibition.


CONCLUSIONS
The somewhat superior efficacy of clozapine compared to haloperidol may be explained by its lower affinity and faster dissociation rate for DA D2 receptors possibly combined with an interaction with other receptor systems. Aripiprazole was found to be more effective than clozapine or olanzapine, which may be explained by a partial agonist activity of aripiprazole at DA D2 receptors. In conclusion, the present findings suggest that partial DA agonism leading to DA stabilizing properties may have favourable effects on sensorimotor gating and thus tentatively on cognitive dysfunctions in schizophrenia.
Fejgin
Kim
K
Institute of Neuroscience and Physiology, Department of Pharmacology, The Sahlgrenska Academy, Göteborg University, P.O. Box 431, SE 405 30, Göteborg, Sweden.
Safonov
Sergej
S
Pålsson
Erik
E
Wass
Caroline
C
Engel
Jörgen A
JA
Svensson
Lennart
L
Klamer
Daniel
D
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects*; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D001569:Benzodiazepines; D000068180:Aripiprazole; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine