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

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, {type:entrez-protein,attrs:{text:S33084,term_id:420474,term_text:pir||S33084}}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 {type:entrez-protein,attrs:{text:S33084,term_id:420474,term_text:pir||S33084}}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.     

Heightened D3 Dopamine Receptor Levels in Cocaine Dependence and Contributions to the Addiction Behavioral Phenotype: A Positron Emission Tomography Study with [11C]-(+)-PHNO

The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D₂ receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D₃ receptor system has recently attracted considerable clinical interest, and D₃ antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D₃ receptor system in CD, using the positron emission tomography (PET) radiotracer [¹¹C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7–240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [¹¹C]-(+)-PHNO to assess D₃ receptor binding (BP_ND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [¹¹C]raclopride to assess D_2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [¹¹C]-(+)-PHNO BP_ND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [¹¹C]raclopride BP_ND was lower across the striatum in CD, consistent with previous literature in ⩾2 week abstinence. The data suggest that in contrast to a D₂ deficiency, CD individuals may have heightened D₃ receptor levels, which could contribute to addiction-relevant traits. D₃ upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.