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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.

ABSTRACT: Dopamine D(3) receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D(3) vs D(2) receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D(3) 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 D(3) receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D(2) receptor antagonist, L741,626 (0.16-5.0?mg/kg), or with the dopamine D(3) agonist, PD128,907 (0.63-40??g/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??g/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63-2.5??g/side) improvement in NOR, while intra-striatal injection (2.5??g/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??g/side) impairment of NOR. These observations suggest that blockade of dopamine D(3) receptors enhances both SND and NOR, whereas D(3) receptor activation or antagonism of dopamine D(2) 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 D(3) receptor antagonism.

SUBMITTER: Watson DJ

PROVIDER: S-EPMC3261029 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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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.

Watson David J G DJ Loiseau Florence F Ingallinesi Manuela M Millan Mark J MJ Marsden Charles A CA Fone Kevin C F KC

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20111026 3

Dopamine D(3) receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D(3) vs D(2) receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D(3) 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 gene ...[more]

PMID: 22030711

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Project description:Recognition memory provides the ability to distinguish familiar from novel objects and places, and is important for recording and updating events to guide appropriate behavior. The hippocampus (HPC) and medial prefrontal cortex (mPFC) have both been implicated in recognition memory, but the nature of HPC-mPFC interactions, and its impact on local circuits in mediating this process is not known. Here we show that novelty discrimination is accompanied with higher theta activity (4-10 Hz) and increased c-Fos expression in both these regions. Moreover, theta oscillations were highly coupled between the HPC and mPFC during recognition memory retrieval for novelty discrimination, with the HPC leading the mPFC, but not during initial learning. Principal neurons and interneurons in the mPFC responded more strongly during recognition memory retrieval compared with learning. Optogenetic silencing of HPC input to the mPFC disrupted coupled theta activity between these two structures, as well as the animals' (male Sprague Dawley rats) ability to differentiate novel from familiar objects. These results reveal a key role of monosynaptic connections between the HPC and mPFC in novelty discrimination via theta coupling and identify neural populations that underlie this recognition memory-guided behavior.SIGNIFICANCE STATEMENT Many memory processes are highly dependent on the interregional communication between the HPC and mPFC via neural oscillations. However, how these two brain regions coordinate their oscillatory activity to engage local neural populations to mediate recognition memory for novelty discrimination is poorly understood. This study revealed that the HPC and mPFC theta oscillations and their temporal coupling is correlated with recognition memory-guided behavior. During novel object recognition, the HPC drives mPFC interneurons to effectively reduce the activity of principal neurons. This study provides the first evidence for the requirement of the HPC-mPFC pathway to mediate recognition memory for novelty discrimination and describes a mechanism for how this memory is regulated.

Dataset Information

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.

Publications

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.

Similar Datasets

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