Farmacologia Pa Traducir

A Model of Antipsychotic Action in Conditioned Avoidance: A Computational Approach Andrew Smith 1 , Ming Li 2 , Sue Becker 1 and Shitij Kapur* ,3 1 Psychology Department, McMaster University, Hamilton, Ontario, Canada; 2 Centre for Addiction and Mental Health, Toronto, Ontario, Canada; 3 Canada Research Chair and Professor of Psychiatry, University of Toronto, Vice President Research, Centre for Addiction and Mental Health, Toronto, Ontario, Canada The selective ability of antipsychotic drugs (APDs) to attenuate conditioned avoidance responding (CAR) has been recognized for over 50 years. However, most efforts to account for this finding have been either neurochemically oriented (focusing on the neuromodulator dopamine) or behavioral, with little effort invested in uniting the two within a computational model. In this paper we propose a comput ati ona l model, based on conc ept s from formal rei nfor cement lea rni ng the ory , whi ch accounts for the basic finding tha t noncataleptic doses of APDs disrupt avoidance without disrupting escape. The model formally separates out sensory, motor, and reward processes, and makes novel predictions pertaining to the dose- and time-dependent effects of APDs on response latencies Fpredictions which we verified in experimental studies using four different APDs (haloperidol, chlorpromazine, risperidone, and clozapine). The APD action in this model is most consistent with an effect on ‘expected future reward’ Fan idea closely linked to motivational drives and consis tent with sever al leadi ng theor ies of dopamine action. Neuropsychopharmacology (2004) 29, 1040–1049, advance online publication, 3 March 2004; doi:10.1038/sj.npp.1300414 Keywords: dopamine; schizophrenia; antipsychotics; modeling; neural networks; motivation; conditioned avoidance INTRODUCTION Conditi one d avoidance response (CA R) is one of mos t important pre clinical animal mode ls in the st udy of antip sychot ic drugs (APDs) (Kilts, 2001; Waden berg and Hicks , 1999). In a typical CAR experime nt, a rat is placed in a two- compar tment shut tl e box and presented wi th a neutral conditioned stimulus (CS) such as a light or tone, followed after a short delay by an aversive unconditioned stimulus (US), such as a foot-shock. The animal may escape the US when it arrives by running from one compartment to the other. However, after several presentations of the CS–US pair, the animal typicall y runs during the CS and before the onse t of the US, ther eby avoiding the US altogether. Ani mal s tre ated with low (noncatal ept ic) doses of APDs fail to perform avoidance responses to the CS, even though their escape res ponse to the shoc k itself is rela ti vely una ffe cte d (Ad er and Cli nk, 1957; Arnt, 198 2; Cook and Catania, 1964; Cook and Weidley, 1957; Courvoisier, 1956; Davidson and Weidley, 1976; Ponsluns, 1962). This selective disruption of avoidance is characteristic of all APDs, but nei the r anx iol ytic s nor antidepre ssa nts sho w thi s eff ect (Courvoisier, 1956; Morpurgo, 1965; Reynolds and Czudek, 1995). Furthermore, the ability of an APD to suppress CAR has been shown to be closely correlated with its clinical potency (with respect to its treatment of psychosis) (Arnt, 198 2; Jansse n et al , 1965) . Theref ore, suppression of av oi da nce in CAR is corre la ted wit h the specif ic anti - psych otic action of APDs. From a neurochemical perspective, it has been established that the blockade of the dopamine D2 receptor is strongly implicated APD-induced disruption of avoidance (Waden- berg et al , 2000, 2001). However, despite the fact that CAR has be en used to study AP Ds fo r ne ar ly 50 ye ar s, no consensus has been reached regarding the underl yin g behavioral or psychological processes. Early work proposed a rol e for APDs in inh ibit ing int ernal ‘fe ar’ or ‘an xie ty’ (Cook and Weidley, 1957; Davis et al , 1961; Hunt, 1956; Miller et al , 1957). Later work shifted the focus to the motor impairment effect of APDs (Beninger et al , 1980a, b; Cook and Catania, 1964; Fibige r et al , 1976; Grilly et al , 1984; Morpurgo, 1965; Ponsluns, 1962), and indeed the currently dominant explanation of APD-induced avoidance deficits is still the ‘motor initiation’ hypothesis (Aguilar et al , 2000; Ogren and Archer, 1994). Other suggestions have included an APD-i nduce d reduc tion in responsiveness to exter nal sti mul i (De ws and Morse , 196 1), a dec rease in sensor y aff erent sti mul ation (Ir win, 1958; Key , 196 1), a los s of Online publication: 24 January 2004 at http://www.acnp.org/citations/ Npp01210403504/default.pdf Received 30 October 2003; accepted 06 January 2004 *Corr espon dence: Dr S Kapur , Canada Research Chair and Profe ssor of Psychiatry, University of Toronto, Vice President Research, Centre for Addict ion and Mental Health, 250 Col leg e Str eet , Tor onto, Ontario, M5T 1R8 Canada, Tel: þ 1 416 979 6890, Fax: þ 1 416 260 4206, E-mail: [email protected] Neuropsychopharmacology (2004) 29, 1040–1049 & 2004 Natu re Publi shing Gro up All rights reserv ed 0893-13 3X/04 $25.00 www.neuropsychopharmacology.org

Farmacologia Pa Traducir

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