Cyanuric acid induces dopaminergic dysfunction in the dorsomedial striatum and impairs extinction of operant responding by suppressing DRD1 receptor-dependent synaptic plasticity

Chronic exposure to the industrial contaminant cyanuric acid (CA) poses a significant neurotoxic risk, yet its potential effects on the dorsomedial striatum (DMS), a critical hub for goal-directed behavior, remain unexplored. This study employs a multimodal approach to investigate CA-induced DMS neurotoxicity and its cognitive sequelae. Adult male Sprague-Dawley rats received either systemic oral administration (20 mg/kg) or local intra-DMS microinjection (5 × 10⁻⁶ g/mL or 5 × 10⁻⁵ g/mL) of CA for four weeks, followed by a one-week washout. Biochemical assays revealed a selective, dose-dependent downregulation of dopamine D1 receptor (DRD1) protein expression in the DMS, with no changes in dopamine transporter, D2 receptor levels, or tissue dopamine homeostasis. Functionally, high-dose CA exposure (oral and intra-DMS) selectively impaired DMS-dependent operant extinction learning, evidenced by persistently high active lever presses, shortened response latencies, and shortened inter-press intervals during extinction testing, with total inactive lever presses unaltered across groups. These deficits were independent of alterations in locomotor activity, anxiety, or reward motivation. Crucially, intra-DMS infusion of the DRD1 agonist SKF-38393 completely reversed these behavioral deficits. At the synaptic level, CA abolished corticostriatal long-term potentiation (LTP) without affecting basal transmission or presynaptic release probability. This LTP impairment was similarly rescued by bath application of SKF-38393, suggesting that DRD1 hypofunction is a key mechanism underlying the observed synaptic plasticity deficits. This study provides the first evidence that the DMS is a novel and vulnerable target of CA neurotoxicity. The selective disruption of DRD1 signaling, resulting in corticostriatal synaptic plasticity deficits, represents a key mechanism linking the impairment in cognitive flexibility observed following CA exposure. These findings significantly expand the neurotoxic profile of CA, highlight the DMS as a critical substrate for environmental contaminant-induced cognitive dysfunction, and implicate DRD1 signaling as a potential therapeutic target.