The role of 5HTSubscript2C/Subscript receptor

Authors: J Alsiö S R O Nilsson F Gastambide R A H Wang S A Dam A C Mar M Tricklebank T W Robbins

Publish Date: 2015/05/26

Volume: 232, Issue: 21-22, Pages: 4017-4031

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Abstract

Reversal learning requires associative learning and executive functioning to suppress nonadaptive responding Reversallearning deficits are observed in eg schizophrenia and obsessivecompulsive disorder and implicate neural circuitry including the orbitofrontal cortex OFC Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involvedIn experiments 1–2 we used a novel 3stimulus task to investigate the effects of 5HT2Creceptor antagonism through SB 242084 01 05 and 10 mg/kg ip crosssite Experiment 3 assessed the effects of SB 242084 in 2choice reversal learning In experiment 4 we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen/muscimolinduced OFC inactivation In experiment 5 we tested the effect of intraOFC SB 242084 10 or 30 μg/side on performance in this taskIntraOFC 5HT2Creceptor antagonism decreases perseveration in novel touchscreen reversallearning paradigms for the rat Systemic 5HT2Creceptor antagonism additionally impairs late learning—a robust effect observed crosssite and potentially linked to impulsivity These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disordersPurposeful goaldirected behaviour requires flexible responding to altered reinforcement contingences In experimental animals such flexible responding is commonly assessed using an appetitive operant reversallearning paradigm in which initially learned reward contingencies are switched In order to successfully adapt and maximise the amount of reward earned subjects must not only learn to suppress selection of the previously rewarded responses but also to learn a novel association and to choose the previously unrewarded but now rewarded option In humans impaired cognitive flexibility has been observed across tasks in schizophrenic patients Tyson et al 2004 Jazbec et al 2007 Murray et al 2008 Ceaser et al 2008 Pantelis et al 2009 but reversallearning deficits stand out as a core feature of firstepisode psychosis Leeson et al 2009 Despite a growing literature on such impairment the study of cognitive function in the evaluation and development of novel antipsychotic treatments has only recently received due focus Moore et al 2013Much evidence implicates circuitry including the orbitofrontal cortex OFC ventral NAc and dorsal striatum DStr and the amygdala in reversal learning Clark et al 2004 In humans the OFC has been shown to be activated in fMRI studies of reversal learning Hampshire and Owen 2006 Chamberlain et al 2008 OFClesioned marmosets show selective reversal deficits in an intradimensional/extradimensional setshifting task Dias et al 1996 OFC lesion or inactivation has also repeatedly been found to impair simple or serial reversal learning in rodents Bussey et al 1997 Schoenbaum et al 2002 Chudasama and Robbins 2003 McAlonan and Brown 2003 Kim and Ragozzino 2005 GhodsSharifi et al 2008 Bissonette et al 2008 Burke et al 2009 Graybeal et al 2011

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