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Comparison of the Novel Antipsychotic Ziprasidone with Clozapine and Olanzapine: Inhibition of Dorsal Raphe Cell Firing And

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Comparison of the Novel Antipsychotic Ziprasidone with Clozapine and Olanzapine: Inhibition of Dorsal Raphe Cell Firing And Comparison of the Novel Antipsychotic Ziprasidone with Clozapine and Olanzapine: Inhibition of Dorsal Raphe Cell Firing and the Role of 5-HT1A Receptor Activation Jeffrey S. Sprouse, Ph.D., Linda S. Reynolds, M.S., John P. Braselton, B.S., Hans Rollema, Ph.D., and Stevin H. Zorn, Ph.D. a Ziprasidone is a novel antipsychotic agent which binds with bind to 1 receptors, antagonists of which inhibit serotonin 5 high affinity to 5-HT1A receptors (Ki 3.4 nM), in addition neuronal firing, this aspect of their pharmacology was to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at assessed with desipramine (DMI), a NE re-uptake blocker a these latter receptors, ziprasidone behaves as a 5-HT1A previously shown to reverse the effects of 1 antagonists on agonist in vitro in adenylate cyclase measurements. The raphe unit activity. DMI (5 mg/kg IV) failed to reverse the goal of the present study was to examine the 5-HT1A inhibitory effect of ziprasidone but produced nearly properties of ziprasidone in vivo using as a marker of complete reversal of that of clozapine and olanzapine. These central 5-HT1A activity the inhibition of firing of serotonin- profiles suggest a mechanism of action for each agent, a containing neurons in the dorsal raphe nucleus. In 5-HT1A agonism for ziprasidone and 1 antagonism for anesthetized rats, ziprasidone dose-dependently slowed clozapine and olanzapine. The 5-HT1A agonist activity 5 m raphe unit activity (ED50 300 g/kg IV) as did the reported here clearly distinguishes ziprasidone from 5 m atypical antipsychotics clozapine (ED50 250 g/kg IV) currently available antipsychotic agents and suggests that 5 m and olanzapine (ED50 1000 g/kg IV). Pretreatment this property may play a significant role in its m with the 5-HT1A antagonist WAY-100,635 (10 g/kg IV) pharmacologic actions. [Neuropsychopharmacology prevented the ziprasidone-induced inhibition; the same dose 21:622–631, 1999] © 1999 American College of of WAY-100,635 had little effect on the inhibition produced Neuropsychopharmacology. Published by Elsevier by clozapine and olanzapine. Because all three agents also Science Inc. KEY WORDS: Antipsychotic; 5-HT1A Agonist; by the shortcomings apparent in classical dopamine Dorsal raphe nucleus; Electrophysiology (DA) D2 receptor antagonists—low efficacy against neg- ative symptoms and high propensity for extrapyrami- The current wave of atypical antipsychotics in various dal side effects (EPS) (Meltzer 1995). While no single stages of clinical development has been spurred in part agent is ‘typical’ of these atypicals, clozapine shares several pharmacological features with other members of this class, in particular, high affinity for 5-HT recep- From the Department of Neuroscience, Central Research Divi- 2 sion, Pfizer Inc., Groton, CT. tors in addition to D2 sites (Altar et al. 1986; Meltzer et Address correspondence to: Dr. Jeffrey Sprouse, Department of al. 1989). Its superior efficacy and reduced EPS liability Neuroscience, Central Research Division, Pfizer Inc., Groton, CT has precipitated a re-evaluation of theories of schizo- 06340. Received December 3, 1998; revised April 19, 1999; accepted April phrenic pathology, resulting in a reinvigorated role for 29, 1999. serotonergic systems in both cause and treatment NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 5 © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00057-3 NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 5 Ziprasidone: Effects on Raphe Cell Firing 623 Table 1. Binding affinities of ziprasidone, clozapine and tivity in vitro (Seeger et al. 1995; Schmidt et al. 1998), lit- a a olanzapine for rat D2, 5-HT2A, 5-HT1A, and 1 receptors tle is known of the relevance of this activity in vivo or of K (nM) D 5-HT 5-HT a the comparative activities of clozapine and olanzapine. i 2 2A 1A 1 In the present study, the ability of ziprasidone, cloza- Ziprasidone 4.8 0.42 3.4 11 pine, and olanzapine to inhibit the spontaneous firing Clozapine 83 16 120 5.6 rate of serotonergic dorsal raphe neurons was used as Olanzapine 11 6.2 2800 19 an in vivo marker of 5-HT1A agonism. Blockade of inhi- a All data were compiled from Seeger et al. (1995), Howard et al. (1996), bition by pretreatment with the selective 5-HT1A antag- and Zorn et al. (1999). onist WAY-100,635 was employed to confirm mecha- a nism of action. Given the binding affinity for 1 sites noted for all three agents (Table 1) and the reported ability of a antagonists to suppress 5-HT unit activity (Sharma and Shapiro 1996). A focus on the 5-HT prop- 1 2 (Baraban and Aghajanian 1980), sensitivity to reversal erties of clozapine is thus justified, and yet the binding by desipramine (DMI), a NE re-uptake inhibitor, was affinity of clozapine to the 5-HT receptor (Table 1) 1A also assessed. A portion of this work was previously hints at the relative importance of this 5-HT subtype to presented in abstract form (Reynolds et al. 1997). the pharmacology of clozapine (Newman-Tancredi et al. 1996; Schotte et al. 1996). Recently reported interac- tions of 5-HT1A agonists with DA neurotransmission suggest that the relief of negative symptoms obtained MATERIALS AND METHODS with clozapine and its reduced risk of motor dysfunc- tion are due in part to its 5-HT1A agonist properties Electrophysiology (Sharma and Shapiro 1996). Extracellular single unit recordings were made in cho- Ziprasidone (Figure 1) is a novel antipsychotic agent, ral hydrate anesthetized male Sprague-Dawley rats chemically unrelated to any available antipsychotic (250–350 g) using standard electrophysiological tech- (Howard et al. 1996), with a unique combination of niques (Sprouse and Aghajanian 1987). Serotonin-con- pharmacological activities at serotonergic, dopaminer- taining neurons were identified on-line by their long gic, and adrenergic receptors and transporters (Seeger duration action potentials and slow rhythmic firing et al. 1995; Schmidt et al. 1998). The high affinity bind- rate. Cells with these characteristics in the dorsal raphe ing of ziprasidone for 5-HT1A, 5-HT1D, and 5-HT2C re- nucleus have been confirmed to be 5-HT neurons by in- ceptors, in addition to the 5-HT2A and D2 ones, differen- tracellular double-labeling (Aghajanian and Vander- tiates it from other antipsychotics such as clozapine and maelen 1982). Unit activity was integrated over 10-sec- its structural analog olanzapine, and places it outside ond periods and continuously plotted as a firing rate the already heterogeneous category of atypical antipsy- histogram. Compounds were administered I.V. in a vol- chotics. While ziprasidone possesses 5-HT1A agonist ac- ume of 1 ml/kg, and the effects on firing rate noted. Animal procedures were approved by the Institutional Animal Care and Use Committee. Drugs Ziprasidone (CP-88,059; 5-{2-(4-(1,2-benzisothiazol-3-yl)- piperazinyl)ethyl}-6-chloro-1,3-dihdro-2(1H)-indol-2-one hydrochloride hydrate), olanzapine (2-methyl-4-(4-methyl- 1-piperazinyl)-10H-thieno[2,3-B][1,5]benzodiazepine), desipramine, and WAY-100,635 (N-(2-(4-(2-methox- yphenyl)-1-piperazinyl)ethyl-N-(2-pyridinyl)cyclohex- ane-carboxamide trihydrochloride) were synthesized at Pfizer Inc., Central Research Division, Groton, CT. Cloz- apine (8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo- [b,e][1,4]-diazepine) was purchased from RBI (Natick, MA). Vehicles used for I.V. injections were 5% DMSO in acid/saline for ziprasidone, olanzapine, and clozapine, and acid/saline for desipramine and WAY-100,635. Figure 1. Structures of ziprasidone, clozapine, and olanza- Neither of these appeared to have any effect on firing pine. rate by themselves. 624 J.S. Sprouse et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 5 RESULTS drug administration; recovery was gradual and firing rates often did not return to baseline levels. Dose re- Inhibition of Serotonin-Containing Dorsal Raphe sponse curves reveal complete or nearly complete inhi- Cell Firing by Ziprasidone, Clozapine, bition for each drug at the highest dose tested (Figure and Olanzapine 3). Slowing of cell firing was dose-dependent with ED50 With a baseline period of stable cell firing established in values calculated to be 300 mg/kg for ziprasidone, 250 the dorsal raphe nucleus, bolus intravenous injection of mg/kg for clozapine, and 1000 mg/kg for olanzapine. ziprasidone, clozapine, or olanzapine caused a slowing Non-linear dose response analysis of the regression co- of unit activity (Figure 2). In general, the onset of the in- efficients corresponding to the slope of the linear por- hibition occurred within the first minute following tion of the curves yielded significant differences be- Figure 2. Rate histograms showing the effect of ziprasidone (top), olanzapine (middle), and clozapine (bottom) on the fir- ing of single dorsal raphe serotonergic neurons. In each case, firing was slowed shortly after the intravenous injection; recov- ery to the baseline rate was gradual and often incomplete. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 5 Ziprasidone: Effects on Raphe Cell Firing 625 a 1 receptor antagonism for clozapine and olanzapine. By themselves WAY-100,635 and DMI had minimal ef- fects on dorsal raphe neuronal firing (Figures 4 and 5). DISCUSSION Inhibition of serotonin neuronal firing by agents with appreciable affinity for 5-HT1A receptors has long been taken as a measure of 5-HT1A autoreceptor activation and, for the compound under study, central 5-HT1A ag- onism. Early work noted the ability of LSD and 5-HT it- self to slow neuronal firing (Aghajanian et al. 1972); later more selective 5-HT1A receptor agents, led in large part by 8-OH-DPAT, were employed to establish the re- ceptor subtype of the somatodendritic autoreceptors Figure 3.
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