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Table 2. Examples of the Effects of Antipsychotics in Preclinical Tests of Cognition

Test Compound Dosing Regime^a Dose(s) and Route Effects Subjects Reference(s)

Operant Responding (FR30/FI60s) haloperidol A/R 0.25 mg/kg IP^b operant response suppression after acute and repeated dosing; some tolerance to effects for clozapine and thioridazine only rat, male, SD Varvel, Vann, Wise, Philbin, & Porter, 2002¹⁶²

clozapine A/R 6.64 mg/kg IP

olanzapine A/R 2.40 mg/kg IP

quetiapine A/R 29.87 mg/kg IP

sertindole A/R 8.17 mg/kg IP

risperidone A/R 0.74 mg/kg IP

thioridazine A/R 22.14 mg/kg IP

remoxipride A 3.3–3.8 mg/kg IP

Prepulse Inhibition (PPI) reviews rat and mutant mouse models Geyer, Krebs-Thomson, Braff, & Swerdlow, 2001⁵⁴; Geyer, McIlwain, & Paylor, 2002⁷⁴

PPI clozapine A 5–20 mg/kg IP clozapine, olanzapine, and sertindole, but not risperidone, remoxipride, and haloperidol, potentiated the low level of PPI rats, male, Wistar Depoortere, Perrault, & Sanger, 1991⁷¹

olanzapine A 5–20 mg/kg IP

sertindole A 1–10 mg/kg IP

risperidone A 0.1–1 mg/kg IP

remoxipride A 1–10 mg/kg IP

haloperidol A 0.1–1 mg/kg IP

PPI risperidone A 0.25–1 mg/kg IP risperidone and clozapine improved PPI in all 3 strains, with the order of magnitude DBA2/J > 129S6SvEvTac > C57Bl/6J mice, male, DBA2/J, C57Bl/6J, 129S6SvEvTac Olivier, Leahy, Mullen, et al., 2001⁷²

clozapine A 1–0 mg/kg IP

PPI clozapine A/R 5 mg/kg SC, 1, 14, and 21 days clozapine improved PPI in Brattleboro (BB) rats after 1, 14, and 21 days and in Long Evans (LE) rats after 7, 14, and 21 days. rats, male, BB and LE Gartlon, Cilia, Shilliam, Staveley, Dawson, & Jones, 2004⁷⁰

PPI raclopride A 0.025–0.05 mg/kg raclopride reversed isolation rearing– induced deficits in PPI rats, male, HL or SD, isolation reared for at least 8 weeks from PND 21 Geyer, Wilkinson, Humby, & Robbins, 1993⁷⁵

PPI olanzapine A 2.5–5mg/kg IP both drugs reversed isolation rearing–induced deficits in PPI rats, male, SD, isolation reared for at least 8 weeks from PND 21 Bakshi, Swerdlow, Braff, & Geyer, 1998⁷⁶

quetiapine A 5 mg/kg SC

PPI clozapine A 5 mg/kg SC all drugs except haloperidol improved PPI in isolation-reared rats rats, male, HL, isolation reared for at least 8 weeks from PND 28 Cilia, Reavill, Hagan, & Jones, 2001⁷⁷; Cilia, Hill, Reavill, & Jones, 2005⁷⁹

risperidone A 0.3 and 1 mg/kg IP

olanzapine A 3 mg/kg SC

ziprasidone A 1 and 3.2 mg/kg PO

quetiapine A 10 and 32 mg/kg PO

haloperidol A 0.25 and 0.5 mg/kg PO

Auditory Evoked Potential (AEP) haloperidol A 1 mg/kg IP olanzapine and all doses of clozapine improved the processing of the AEP; haloperidol did not influence the response mice, male, DBA/2 Simosky, Stevens, Adler, & Freedman, 2003⁸²; Simosky, Stevens, & Freedman, 2004²⁰⁶

clozapine A 0.1–10 mg/kg IP

olanzapine A 0.033 mg/kg IP

AEP haloperidol R 0.5, 1, or 2mg/kg/day SC via osmotic minipump, 14 days olanzapine increased N40 (5mg/kg/day), P80 (1 and 2.5 mg/kg/day), and P20/N40 (1 and 5 mg/kg/day) amplitude; haloperidol had no effects mice, C57BL/6J, gender not given Maxwell, Liang, Weightman, et al., 2004⁸³

olanzapine R 1, 2.5, or 5mg/kg/day SC via osmotic minipump, 14 days

Latent Inhibition (LI) reviews Moser, Hitchcock, Lister, & Moran, 2000⁹¹; Weiner, Gaisler, Schiller, Green, Zuckerman, & Joel, 2000⁹²

LI haloperidol A 0.1 mg/kg IP haloperidol and clozapine enhanced LI under "no control LI" test conditions; clozapine, but not haloperidol, abolished LI under "control LI" test conditions rat, male, Wistar Shadach, Gaisler, Schiller, & Weiner, 2000⁹³

clozapine A 5 mg/kg IP

5-Choice Serial Reaction Time Task review Robbins, 2002⁹⁴

Attentional Set Shifting clozapine R 5 or 10 mg/kg BID, PO, 9 days clozapine had either no effect (5 mg/kg) or impaired performance (10mg/kg) relatively nonspecifically rat, male, HL D. Tait, V. Brown, D. N. C. Jones, unpublished data

Serial Reversal Learning clozapine A 5 mg/kg IP haloperidol disrupted performance at $≥$ 0.1 mg/kg; ziprasidone (2.5 mg/kg), clozapine (5mg/kg), and lamotrigine ( $≥$ 10mg/kg), but not haloperidol (0.05 mg/kg), attenuated phencyclidine (PCP) effects rat, female, HL, acute PCP treated Abdul-Monim, Reynolds, & Neill, 2003¹¹⁴; Idris, Repeto, Neill, & Large, 2005¹¹⁶

ziprasidone A 0.25–2.5 mg/kg IP

haloperidol A 0.01–0.25 mg/kg IP

lamotrigine A 5–25 mg/kg IP

Serial Reversal Learning clozapine A 5 mg/kg IP clozapine and olanzapine, but not chlorpromazine, attenuated subchronic PCP effects rat, female, HL, subchronic PCP treated Abdul-Monim, Reynolds, & Neill, 2003¹¹⁵

olanzapine A 1.5 mg/kg IP

chlorpro mazine A 2mg/kg IP

Delayed Nonmatch to Position (DNMTP) raclopride A 0.02–0.08 mg/kg SC all compounds, except sertindole, caused delay-independent impairments in choice accuracy rat, male, Wistar or LE Didriksen, 1995¹¹⁷

haloperidol A 0.01–0.04 mg/kg SC

clozapine A 0.63–2.5 mg/kg SC

sertindole A 0.04–1.25 mg/kg SC

risperidone A 0.1–0.4 mg/kg SC

DNMTP haloperidol C 0.01, 0.05, 0.2 micromoles SC, 20, 21, and 22 days some tolerance to effects of low doses of haloperidol and clozapine; sertindole caused impaired working memory on days 20 (0.7 umol) and 21 (3 umol) rat, male, Wistar Didriksen & Sams-Dodd, 1997¹²¹

clozapine C 0.9, 4, 15 umol SC, 20, 21, and 22 days

sertindole C 0.2, 0.7, 3 umol SC, 20, 21, and 22 days

DNMTP iloperidone A 0.03 and 0.1 mg/kg IP improved accuracy at long delays rat, male, HL Gemperle, McAllister, & Olpe, 2003¹¹⁹

clozapine A 0.1 and 0.3 mg/kg SC no effect

haloperidol A 0.003–0.03 mg/kg SC no effect

DNMTP haloperidol A 1–30 mg/kg PO all drugs reduced accuracy delay-independently and markedly increased missed trials rat, male, HL Pemberton, Martin, & Jones, 2003¹¹⁸, and unpublished

clozapine A 0.03–1 mg/kg PO

olanzapine A 0.3–10 mg/kg PO

aripiprazole A 0.3–10 mg/kg PO

Delayed Nonmatch to Sample haloperidol A 0.01–3 mg/kg PO olanzapine and risperidone reduced errors during retention; other drugs had no effects on accuracy rat, male, SD Wolff & Leander, 2003¹²⁰

clozapine A 3–50 mg/kg PO

olanzapine A 1–10 mg/kg PO

risperidone A 0.003–0.3 mg/kg PO

ziprasidone A 1–10 mg/kg PO

Novel Object Detection (NOD) clozapine A 1–10 mg/kg SC clozapine (3, but not 10 mg/kg) impaired NOD rat, male, SD Besheer, Short, & Bevins, 2001¹³⁰

sulpiride A 20–80 mg/kg IP sulpiride was without effect

Social Recognition haloperidol A 0.1–0.3 mg/kg IP clozapine and amisulpiride reversed the social recognition impairment in rat neonatally treated with PCP; haloperidol (0.125mg/kg, but not higher) was ineffective adult rat, male, Wistar Han, neonatally treated with PCP Terranova, Chabot, Barnoiun, Depoortere, Briebel, & Scatton, 2005¹³²

clozapine A 0.01–1 mg/kg IP

amisulpiride A 0.3–3 mg/kg IP

Social Recognition haloperidol A 0.075–0.15 mg/kg IP clozapine, amisulpiride, and haloperidol (0.125mg/kg, but not higher) improved social recognition impaired by parametric manipulation rat, male, Wistar Han Terranova, Chabot, Barnoiun, Depoortere, Briebel, & Scatton, 2005¹³²

clozapine A 0.01–0.1 mg/kg IP

amisulpiride A 0.1–3 mg/kg IP

Water Maze risperidone A 0.08–0.63 mg/kg SC impaired acquisition rat, male, Wistar Skarsfeldt, 1996¹³⁴

clozapine A 0.31–10 mg/kg SC impaired acquisition

olanzapine A 0.16–2.5 mg/kg SC impaired acquisition

ziprasidone A 0.31–5 mg/kg SC impaired acquisition

haloperidol A 0.005–0.08 mg/kg SC impaired acquisition

seroquel A 0.16–2.5 mg/kg SC no impairment

sertindole A 0.16–2.5 mg/kg SC no impairment

Water Maze clozapine A/R 122 µmol/kg PO, acute and 21 days impaired acquisition acutely, reduced after chronic rat, male, Wistar Didriksen, 2000¹³⁵

olanzapine A/R 2 and 8 umol/kg SC, acute and 21 days impaired acquisition after acute and repeated dosing

sertindole A/R 5.7 umol/kg PO, acute and 21 days no impairment after acute or repeated dosing

Water Maze haloperidol C 2mg/kg PO, 45 and 90 days haloperidol and olanzapine impaired acquisition after 90 days; haloperidol, not olanzapine, impaired retention after 90 days; risperidone slightly improved acquisition (trend to improvement for clozapine); a trend for improved retention with clozapine and risperidone rat, male, Wistar Terry, Hill, Parikh, Evans, Waller, & Mahadik, 2002¹³⁶; Terry, Hill, Parikh, Waller, Evans, & Mahadik, 2003¹³⁷

olanzapine C 10 mg/kg PO, 45 and 90 days

clozapine C 20 mg/kg PO, 45 and 90 days

risperidone C 2.5 mg/kg PO, 45 and 90 days

Radial Arm Maze (RAM) haloperidol A 0.04 mg/kg SC haloperidol and risperidone did not cause impairment; clozapine impaired at both doses rat, female, SD Addy & Levin, 2002¹²²; Addy, Pocivavsek, & Levin, 2005¹²³

clozapine A 1.25 and 2.5mg/kg SC

risperidone A 0.05 mg/kg SC

RAM olanzapine R 0.5 or 2mg/kg IP for 14 days olanzapine did not affect working or reference memory rat, male, SD He, Yang, Xu, Zhang, & Li, 2005¹²⁴

RAM haloperidol C 0.5 mg/kg/day PO, 75 days^c all drugs, except olanzapine, impaired acquisition and retention in both age groups rat, male, 3- and 18-month-old Fischer 344 Rosengarten & Quartermain, 2002¹²⁵

clozapine C 12.2 mg/kg/day PO, 75 days

olanzapine C 0.88 mg/kg/day PO, 75 days

risperidone C 0.45 mg/kg/day PO, 75 days

Passive Avoidance (PA) haloperidol A 0.025 0.4mg/kg IP haloperidol did not influence PA mouse, male, ddY Ichihara, Nabeshima, & Kameyama, 1988¹²⁷

sulpiride A 10–80 mg/kg IP low-dose sulpiride, but not higher doses, impaired PA

PA clozapine A 0.1–7.5 mg/kg IP all doses of clozapine disrupted PA; a low dose (0.1 mg/kg) attenuated the effects of scopolamine mouse, Swiss (gender not stated) Ninan & Kulkarni, 1996¹²⁸

PA haloperidol A/R 0.1 mg/kg SC, 1 or 20 days haloperidol impaired retention of PA rat, male, Wistar Drago, Contarino, Marino, et al., 1997¹²⁶

risperidone A/R 0.1–10 mg/kg SC, 1 or 20 days risperidone had no effect

^a A = acute (single), R = repeated (<21 days), C = chronic (>21 days).

^b ED₇₅ values for response suppression after acute dosing; dosed daily for 16 days (with exception of sertindole and remoxipride where ED₅₀ value given).

^c All drugs administered in the drinking water.

SD = Sprague-Dawley, PND = post natal day, HL = hooded Listar, SC = subcutaneous, IP = intraperitoneal, PO = per Os.

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Schizophrenia Bulletin