Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex
- 695 Downloads
Disruption in cognition is characteristic of psychiatric illnesses such as schizophrenia. Studies of drugs that improve cognition might provide a better insight into the mechanisms underlying cognitive deficits.
We compared the effects of the antipsychotic drugs aripiprazole, olanzapine, and haloperidol on performance deficit in a test of divided and sustained visual attention, the five-choice serial reaction time task (5-CSRTT), which provides information on attentional functioning (accuracy of visual discrimination), response control (measured by anticipatory and perseverative responses) and speed.
The cognitive deficit was induced by infusion of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the rat medial prefrontal cortex (mPFC). In vivo microdialysis was used to compare the effects of aripiprazole, olanzapine and haloperidol on CPP-induced glutamate (GLU) and serotonin (5-HT) release in the mPFC of conscious rats.
Oral aripiprazole (1.0 and 3.0 mg/kg) and olanzapine (0.3 and 1.0 mg/kg), but not haloperidol (0.1 mg/kg), abolished the CPP-induced accuracy deficit and GLU release. Haloperidol and aripiprazole, but not olanzapine, reduced perseverative over-responding, while anticipatory responding was best controlled by olanzapine. However, these effects were not associated with changes in GLU release. No association was found between the effects of these antipsychotics on CPP-induced attentional performance deficits in the 5-CSRTT and 5-HT efflux.
The data confirm that excessive GLU release in the mPFC is associated with attentional deficits. Thus, suppression of GLU release may be a target for the development of novel antipsychotic drugs with greater effect on some aspects of cognitive deficits.
KeywordsAntipsychotics Cognitive deficits Glutamate release Medial prefrontal cortex NMDA receptor antagonists
This work was supported by a research grant from Brystol-Myers Squibb (Italy). Olanzapine was kindly donated by Eli-Lilly and Company (USA). We are grateful to JD Baggott for language editing. The authors have nothing to disclose.
Conflicts of Interest
- Assie MB, Carilla-Durand E, Bardin L, Maraval M, Aliaga M, Malfetes N, Barbara M, Newman-Tancredi A (2008) The antipsychotics clozapine and olanzapine increase plasma glucose and corticosterone levels in rats: comparison with aripiprazole, ziprasidone, bifeprunox and F15063. Eur J Pharmacol 592:160–166PubMedCrossRefGoogle Scholar
- Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) Effects of lesions to ascending noradrenergic neurones on performance of a 5-choice serial reaction task in rats; implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav Brain Res 9:361–380PubMedCrossRefGoogle Scholar
- Carli M, Baviera M, Invernizzi RW, Balducci C (2006) Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31:757–767PubMedCrossRefGoogle Scholar
- Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119PubMedCrossRefGoogle Scholar
- Higgins GA, Enderlin M, Homan M, Fletcher PJ (2003) The 5-HT2A receptor antagonist M100,907 attenuates motor and “impulsive-type” behaviours produced by NMDA receptor antagonism. Psychopharmacology 170:309–319Google Scholar
- Keefe RS, Seidman LJ, Christensen BK, Hamer RM, Sharma T, Sitskoorn MM, Lewine RR, Yurgelun-Todd DA, Gur RC, Tohen M, Tollefson GD, Sanger TM, Lieberman JA (2004) Comparative effect of atypical and conventional antipsychotic drugs on neurocognition in first-episode psychosis: a randomized, double-blind trial of olanzapine versus low doses of haloperidol. Am J Psychiatry 161:985–995PubMedCrossRefGoogle Scholar
- Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA (2007) Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 64:633–647PubMedCrossRefGoogle Scholar
- Kikuchi T, Tottori K, Uwahodo Y, Hirose T, Miwa T, Oshiro Y, Morita S (1995) 7-(4-[4-(2, 3-Dichlorophenyl)-1-piperazinyl]butyloxy)-3, 4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity. J Pharmacol Exp Ther 274:329–336PubMedGoogle Scholar
- Knauer CS, Campbell JE, Galvan B, Bowman C, Osgood S, Buist S, Buchholz L, Henry B, Wong EH, Shahid M, Grimwood S (2008) Validation of a rat in vivo [(3)H]M100907 binding assay to determine a translatable measure of 5-HT(2A) receptor occupancy. Eur J Pharmacol 591:136–141PubMedCrossRefGoogle Scholar
- Lucas G, Di Matteo V, De Deurwaerdere P, Porras G, Martin-Ruiz R, Artigas F, Esposito E, Spampinato U (2001) Neurochemical and electrophysiological evidence that 5-HT4 receptors exert a state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function. Eur J Neurosci 13:889–898PubMedCrossRefGoogle Scholar
- Morimoto T, Hashimoto K, Yasumatsu H, Tanaka H, Fujimura M, Kuriyama M, Kimura K, Takehara S, Yamagami K (2002) Neuropharmacological profile of a novel potential atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-benzothieno[2, 3-b][1, 5] benzodiazepine maleate). Neuropsychopharmacology 26:456–467PubMedCrossRefGoogle Scholar
- Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107PubMedCrossRefGoogle Scholar
- Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic PressGoogle Scholar
- Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ (1995) (1-(2, 5-dimethoxy-4 iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112PubMedGoogle Scholar
- Shimokawa Y, Akiyama H, Kashiyama E, Koga T, Miyamoto G (2005) High performance liquid chromatographic methods for the determination of aripiprazole with ultraviolet detection in rat plasma and brain: application to the pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 821:8–14PubMedCrossRefGoogle Scholar
- Stark AD, Jordan S, Allers KA, Bertekap RL, Chen R, Mistry Kannan T, Molski TF, Yocca FD, Sharp T, Kikuchi T, Burris KD (2007) Interaction of the novel antipsychotic aripiprazole with 5-HT1A and 5-HT 2A receptors: functional receptor-binding and in vivo electrophysiological studies. Psychopharmacology (Berl) 190:373–382CrossRefGoogle Scholar
- Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J (1997b) Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol 7:9–24PubMedCrossRefGoogle Scholar