Dopamine D2/D3 receptor agonist quinpirole impairs spatial reversal learning in rats: investigation of D3 receptor involvement in persistent behavior
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Dopamine is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies.
We investigated the effects of systemic administration of the D2/D3 receptor agonist quinpirole (0.1, 0.3 mg/kg), the D2/D3 receptor antagonist raclopride (0.1, 0.3 mg/kg), the selective D3 antagonist nafadotride (0.3, 1.0 mg/kg), and combined administration of raclopride (0.1 mg/kg) or nafadotride (1.0 mg/kg) with quinpirole (0.3 mg/kg) on spatial discrimination and reversal learning.
Materials and methods
Rats were trained on an instrumental two-lever spatial discrimination and reversal learning task. Both levers were presented, only one of which was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a reversal was introduced.
None of the drugs altered performance during retention of the previously reinforced contingencies. Quinpirole (0.3 mg/kg) significantly impaired reversal learning by increasing both trials and incorrect responses to criterion in reversal phase, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, neither raclopride nor nafadotride when administered alone altered reversal performance. However, raclopride blocked the quinpirole-induced reversal deficit, whereas combined administration of nafadotride and quinpirole affected not only performance during the reversal but also the retention phase. The reversal impairment resulting from co-administration of nafadotride and quinpirole was associated with both perseverative and learning errors.
Our data indicate distinct roles for D2 and D3 receptors in the capacity to modify behavior flexibly in the face of environmental change.
KeywordsReversal learning Perseveration Learning Discrimination Dopamine Quinpirole Raclopride Nafadotride Obsessive-compulsive disorder Animal model
This work was supported by a Programme Grant from the Wellcome Trust (no. 076274/4/Z/04/Z) to TWR. The BCNI is funded by a joint award from the Medical Research Council and the Wellcome Trust. VB is supported by the Domestic Research Studentship, the Cambridge European Trusts, the Bakalas Foundation Scholarship, and the Oon Khye Beng Ch’ia Tsio Studentship from Downing College. AC is recipient of a postdoctoral fellowship from FIS-ISCIII. We thank David Theobald for preparing the drugs.
- Joel D, Avisar A, Doljansky J (2001) Enhancement of excessive lever-pressing after post-training signal attenuation in rats by repeated administration of the D1 antagonist SCH 23390 or the D2 agonist quinpirole, but not the D1 agonist SKF 38393 or the D2 antagonist haloperidol. Behav Neurosci 115:1291–300PubMedCrossRefGoogle Scholar
- Kontis D, Boulougouris V, Papakosta VM, Kalogerakou S, Papadopoulos S, Giannou H, Poulopoulou C, Tsaltas E (2008) Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive-compulsive disorder. Psychopharmacology (Berlin). doi: 10.1007/s00213-008-1241-5
- Modell JG, Mountz JM, Curtis GC, Greden JF (1989) Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neuropsychiatry 1:27–36Google Scholar