title: Immunization with DAT fragments is associated with long-term striatal impairment, hyperactivity and reduced cognitive flexibility in mice.
abstract: BACKGROUND
  Possible interactions between nervous and immune systems in neuro-psychiatric disorders remain elusive. Levels of brain dopamine transporter (DAT) have been implicated in several impulse-control disorders, like attention deficit / hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Here, we assessed the interplay between DAT auto-immunity and behavioural / neurochemical phenotype.
  
  
  METHODS
  Male CD-1 mice were immunized with DAT peptide fragments (DAT-i), or vehicle alone (VEH), to generate elevated circulating levels of DAT auto-antibodies (aAbs). Using an operant delay-of-reward task (20 min daily sessions; timeout 25 sec), mice had a choice between either an immediate small amount of food (SS), or a larger amount of food after a delay (LL), which increased progressively across sessions (from 0 to 150 sec).
  
  
  RESULTS
  DAT-i mice exhibited spontaneous hyperactivity (2 h-longer wake-up peak; a wake-up attempt during rest). Two sub-populations differing in behavioural flexibility were identified in the VEH control group: they showed either a clear-cut decision to select LL or clear-cut shifting towards SS, as expected. Compared to VEH controls, choice-behaviour profile of DAT-i mice was markedly disturbed, together with long-lasting alterations of the striatal monoamines. Enhanced levels of DA metabolite HVA in DAT-i mice came along with slower acquisition of basal preferences and with impaired shifting; elevation also in DOPAC levels was associated with incapacity to change a rigid selection strategy. This scarce flexibility of performance is indicative of a poor adaptation to task contingencies.
  
  
  CONCLUSIONS
  Hyperactivity and reduced cognitive flexibility are patterns of behaviour consistent with enduring functional impairment of striatal regions. It is yet unclear how anti-DAT antibodies could enter or otherwise affect these brain areas, and which alterations in DAT activity exactly occurred after immunization. Present neuro-behavioural alterations, coming along with an experimentally-induced rise of circulating DAT-directed aAbs, open the issue of a potential role for auto-immunity in vulnerability to impulse-control disorders.
authors.affiliation: Dept. Cell Biology & Neurosciences, Istituto Superiore di Sanità, Rome, Italy. Walter.Adriani@iss.it
authors.forename: Walter
authors.initials: W
authors.lastname: Adriani
authors.forename: Susanne
authors.initials: S
authors.lastname: Koot
authors.forename: Sandra
authors.initials: S
authors.lastname: Columba-Cabezas
authors.forename: Emilia
authors.initials: E
authors.lastname: Romano
authors.forename: Domenica
authors.initials: D
authors.lastname: Travaglini
authors.forename: Ruud
authors.initials: R
authors.lastname: van den Bos
authors.forename: Oleg
authors.initials: O
authors.lastname: Granstrem
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005106:Exploratory Behavior / Q000502:physiology; D006948:Hyperkinesis / Q000378:metabolism / Q000503:physiopathology*; D007114:Immunization; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D012201:Reward
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D010446:Peptide Fragments