title: 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?
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 (Drd2 -/-) 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 Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. 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.
authors.affiliation: School of Psychology, University of Nottingham, Nottingham, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: O'Callaghan
authors.affiliation: School of Psychology, University of Nottingham, Nottingham, UK present address: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bay-Richter
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland present address: School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland.
authors.forename: Colm Mp
authors.initials: CM
authors.lastname: O'Tuathaigh
authors.affiliation: School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, Nottingham, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Heery
authors.affiliation: Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
authors.affiliation: School of Psychology, University of Nottingham, Nottingham, UK paula.moran@nottingham.ac.uk.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Moran
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D007266:Inhibition, Psychological; D007858:Learning / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D017447:Receptors, Dopamine D1 / Q000172:deficiency / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003024:Clozapine; D006220:Haloperidol
keywords: Antipsychotics; Drd-2 knockout mice; clozapine; haloperidol; latent inhibition