Neuromodulation of Dopamine D2 Receptors Alters Orbitofrontal Neuronal Activity and Reduces Risk-Prone Behavior in Male Rats with Inflammatory Pain

TL;DR

This study shows that modulating dopamine D2 receptors in the orbitofrontal cortex of rats with inflammatory pain can reduce risky decision-making behavior.

Contribution

The study identifies a novel role of dopamine D2 receptors in modulating risk-prone behavior in inflammatory pain conditions.

Findings

CFA-treated rats showed abnormal preference for uncertain rewards in a gambling task.

D2r ligands reversed risky behavior without affecting pain responses.

CFA treatment altered OFC receptor expression, including upregulated D1r and downregulated DH.

Abstract

Dopamine (DA) is believed to play a crucial role in maintaining the integrity of the rodent orbitofrontal cortex (OFC) networks during risk-based decision-making processes. Chronic pain conditions can lead to impaired DAergic signaling, which, in turn, may affect the motivational control of risk-based responses. Nevertheless, the neural mechanisms underlying this instability are poorly understood. In this study, we aimed to investigate whether this impairment is dependent on the activity of the DA D2 receptor (D2r). To address this hypothesis, we implanted bilateral matrices of multielectrodes into the OFC of male rats and recorded the neural activity while they performed a food-reinforced rodent gambling task (rGT). We evaluated behavioral performance and neural activity patterns before and after inducing a model of inflammatory pain – complete Freund’s adjuvant (CFA) model. Our findings revealed that rats treated with CFA exhibited an abnormal preference for the large/uncertain reward during rGT performance. This altered behavioral choice profile could be reversed by prior systemic administration of D2r ligands (0.05 mg/kg, quinpirole or raclopride), indicating a potential role of D2r in the decision-making process required for this task. The administration of these ligands at the specified dosages did not affect pain responses, but lead to a significant alteration of OFC neuronal activity that support goal-directed choice responses in the rGT. Finally, we found evidence that CFA-treated rats exhibit OFC functional changes, namely an upregulation of DA D1 receptor (D1r) and a downregulation of DA beta-hydroxylase (DH). These results demonstrate that the disruption of DAergic balance in the brain networks is crucial for the development of high-risk decision profiles during painful conditions.

The online version contains supplementary material available at 10.1007/s12035-025-04781-0.

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