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Open Access Research

Immunization with DAT fragments is associated with long-term striatal impairment, hyperactivity and reduced cognitive flexibility in mice

Walter Adriani1*, Susanne Koot12, Sandra Columba-Cabezas1, Emilia Romano1, Domenica Travaglini1, Ruud van den Bos2, Oleg Granstrem3, Syed F Ali4 and Giovanni Laviola1

Author Affiliations

1 Dept. Cell Biology & Neurosciences, Istituto Superiore di Sanità, Rome, Italy

2 Dept. Neuroscience & Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center of Utrecht, Utrecht, the Netherlands

3 Dept. Neurology & Neurosurgery, I.P. Pavlov’s State Medical University and Geropharm Ltd, St. Petersburg, Russia

4 Neurochemistry Lab, Division of Neurotoxicology, National Center for Toxicological Research / FDA, Jefferson, AR, USA

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Behavioral and Brain Functions 2012, 8:54  doi:10.1186/1744-9081-8-54

Published: 28 November 2012

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.

Keywords:
Auto-antibodies to neuro-receptors; DAT; Delay of reward; Flexibility of choice behaviour; ADHD; OCD