The novel atypical antipsychotic olanzapine, but not the CCK-B antagonist LY288513, blocks apomorphine-induced disruption of pre-pulse inhibition Kurt Rasmussen a, *, Mary R. Gates b , James E. Burger b , Janet F. Czachura a a Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA b School of Pharmacy, Butler University, Indianapolis, IN, USA Received 23 September 1996; revised version received 23 December 1996; accepted 23 December 1996 Abstract Pre-pulse inhibition (PPI) of the acoustic startle response is the diminution of the startle response when the startle stimulus is preceded by a weaker, non-startle-eliciting stimulus. Deficits in PPI occur in animals following the administration of apomorphine and in schizophrenic patients. In this study, we examined the ability of the novel atypical antipsychotic olanzapine and the cholecystokinin (CCK)-B antagonist LY288513 to reverse the apomorphine-induced disruption of pre-pulse inhibition. Olanzapine (3.0 and 5.0 mg/kg, i.p.), but not LY288513 (1.0–100 mg/kg, p.o.), blocked apomorphine-induced disruption of PPI. These results indicate that olanzapine, but not LY288513, has dopamine antagonist properties in vivo and predict that olanzapine, but not LY288513, will have antipsychotic activity in man.  1997 Elsevier Science Ireland Ltd. All rights reserved Keywords: Olanzapine; Acoustic startle; Cholecystokinin; Schizophrenia; Antipsychotics; Apomorphine; LY288513 Pre-pulse inhibition (PPI) of the acoustic startle response is the diminution of the startle response to a stimulus (pulse) when it is preceded by a weaker, non- startle-eliciting stimulus (pre-pulse) [9]. PPI is disrupted in schizophrenic patients. Deficits in PPI also occur in animals following the administration of apomorphine, N- methyl-D-aspartic acid (NMDA) antagonists, 5-hydroxy- tryptamine (5-HT)-1A agonists, 5-HT-2A agonists, and serotonin releasing agents [7,10,19,22]. The apomor- phine-induced disruption of PPI can be blocked by anti- psychotic drugs [11,18] with a potency that correlates with their D2 receptor affinity and clinical antipsychotic potency [22]. Therefore, blockade of apomorphine- induced disruption of PPI has been hypothesized to be predictive of clinical antipsychotic activity [22]. Olanzapine (LY170053) is a novel thienobenzodiaze- pine antipsychotic that has been demonstrated to have an atypical antipsychotic profile in clinical trials [2]. Olanza- pine has high affinity for D 1 ,D 2 ,D 3 and D 4 dopamine, serotonin (5-HT) 2A , 5-HT 2C and 5-HT 3 , a 1 adrenergic, his- tamine 1 , and muscarinic receptors [3] and has been shown to antagonize dopamine, serotonin, a-adrenergic, and muscarinic receptors in vivo [4,6,12,20]. While olanzapine has been reported to block the disruption of PPI by the NMDA antagonists phencyclidine (PCP) and MK-801 [1], its effects on apomorphine induced disruption of PPI have never been reported. LY288513 is a diphenylpyrazolidinone CCK-B antago- nist that has been hypothesized to have anxiolytic and antipsychotic potential in man [8,15]. The rationale for the use of CCK-B antagonists in schizophrenia is based on studies showing that diphenylpyrazolidinone, benzo- diazepine (e.g. L-365,260), and quinazolinone (e.g. LY247348) CCK-B antagonists decrease the activity of midbrain dopamine neurons [14–16]. These actions of CCK-B antagonists on dopamine neurons have been shown to be mediated through feedback projections from forebrain cites [17]. In an effort to further examine the antipsychotic potential of CCK-B antagonists, we also examined the effects of LY288513 on apomorphine induced disruption of PPI. Male Long–Evans rats (Harlan Sprague–Dawley, Indianapolis, IN, USA) weighing 350–450 g were used Neuroscience Letters 222 (1997) 61–64 0304-3940/97/$17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(97)13346-8 * Corresponding author. Tel.: +1 317 2761687; fax: +1 317 2765546; e-mail: rasmussen_kurt@lilly.com