Selective Blockade of Dopamine D3 Receptors Enhances while D2 Receptor Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex
Authors:
- 26 October 2011
- journal article
- Published by Springer Nature in Neuropsychopharmacology
- Vol. 37 (3) , 770-786
Abstract
Dopamine D3 receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D3 vs D2 receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D3 receptor antagonist, S33084 (0.04–0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D3 receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D2 receptor antagonist, L741,626 (0.16–5.0 mg/kg), or with the dopamine D3 agonist, PD128,907 (0.63–40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63–2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63–2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D3 receptors enhances both SND and NOR, whereas D3 receptor activation or antagonism of dopamine D2 receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D3 receptor antagonism.Keywords
This publication has 88 references indexed in Scilit:
- D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortexProceedings of the National Academy of Sciences, 2011
- Causal role of the prefrontal cortex in top-down modulation of visual processing and working memoryNature Neuroscience, 2011
- Alterations of Cortical GABA Neurons and Network Oscillations in SchizophreniaCurrent Psychiatry Reports, 2010
- Top-down control of visual attentionCurrent Opinion in Neurobiology, 2010
- A role for dopamine D2 receptors in reversal learningNeuroscience, 2009
- Using the MATRICS to guide development of a preclinical cognitive test battery for research in schizophreniaPharmacology & Therapeutics, 2009
- The prefrontal cortex and the executive control of attentionExperimental Brain Research, 2008
- A neurocognitive animal model dissociating between acute illness and remission periods of schizophreniaPsychopharmacology, 2008
- Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortexLearning & Memory, 2007
- Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SARBioorganic & Medicinal Chemistry Letters, 2007