Journal of Psychopharmacology 2014, Vol. 28(10) 973–977 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114544774 jop.sagepub.com Introduction People with schizophrenia have well-documented attentional impairments, including inability to ignore irrelevant stimuli (Heinrichs and Zakzanis 1998; McGhie and Chapman, 1962; Morris et al., 2013). Consequently, Latent Inhibition (LI), a pro- cess of learning to ignore irrelevant stimuli seen in humans and animals, has a long history of application in animal models of the disorder (Lubow, 2010). LI is impaired learning of a conditioned stimulus (CS)–unconditioned stimulus (US) association in a group receiving pre-exposure to that stimulus without reinforce- ment (pre-exposed, PE), compared with a group without such pre-exposure (non-pre-exposed, NPE). Most studies in patients with schizophrenia, their relatives and psychometrically defined schizotypy find abnormal LI (either inappropriately present or absent depending on symptom profile) (Lubow, 2010, though see Swerdlow, 2010). Based on pharmacological data in rats, Weiner’s ‘two-headed’ model of LI suggests that there are two categories of abnormality in LI that are counteracted by antipsy- chotic drugs: one in which LI is high in controls and disrupted (e.g. by psychotomimetic D-amphetamine, called ‘disrupted LI’) and one in which it is low in controls and potentiated (e.g. by antipsychotics or psychotomimetics such as scopolamine, MK801 or ketamine, called ‘persistent LI’) (Weiner, 2003; Weiner and Arad, 2009). It has been suggested that disrupted and persistent LI reflect different attentional processes: failure to Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2)-deficient mice: Do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms? Matthew J O’Callaghan 1 , Cecilie Bay-Richter 1,+ , Colm MP O’ Tuathaigh 2,* , David M Heery 3 , John L Waddington 4 and Paula M Moran 1 Abstract Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd 2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner’s ‘two-headed’ model indicates that antipsychotics not only reverse LI disruption, ‘disrupted LI’, but also potentiate LI when low/absent in controls, ‘persistent’ LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd 2 -/-. Both drugs potentiated LI in wild-type but not in Drd 2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd 1 -/- and wild-type mice, indicating no such moderation in Drd 1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis. Keywords Antipsychotics, Drd-2 knockout mice, latent inhibition, haloperidol, clozapine 1 School of Psychology, University of Nottingham, Nottingham, UK 2 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland 3 School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK 4 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland + present address: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark * present address: School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland. Corresponding author: PM Moran, School of Psychology, University of Nottingham, Nottingham NG7 2RD, UK. Email: paula.moran@nottingham.ac.uk 544774JOP 0 0 10.1177/0269881114544774Journal of PsychopharmacologyO’Callaghan et al. research-article 2014 Short Report by guest on February 8, 2016 jop.sagepub.com Downloaded from