Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats

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Abstract
Rationale Orbital/insular areas of the prefrontal cortex (PFC) are implicated in cocaine addiction. However, the role of dopamine D1 receptors in mediating cocaine self-administration in these sub-regions remains unknown. Objectives To define the role of the dorsal agranular insular (AId) sub-region of the PFC, we investigated the effects of D1 receptor manipulation on self-administration behavior maintained by cocaine and cocaine-related stimuli. Materials and methods Rats were trained to lever press for cocaine (1 mg/kg) under a fixed-interval 5-min (fixed-ratio 5:S) second-order schedule of reinforcement in the presence of conditioned light cues and contextual sound cues. Intra-AId infusions of vehicle, the D1-like receptor agonist SKF 81297 (0.1, 0.2, 0.4 μg/side) or the D1-like receptor antagonist SCH 23390 (1.0, 2.0, 4.0 μg/side), were administered prior to 1-h self-administration test sessions. Food-maintained responding under a second-order schedule was examined in separate rats to determine if pretreatment with D1 ligands produced general impairments in responding. Results Infusion of SKF 81297 (0.2 and 0.4 μg/side) reduced active lever responses during the first 30 min of 1-h test sessions, but did not influence cocaine intake. Infusion of 4.0 μg/side SCH 23390 reduced active lever responses and cocaine intake throughout the 1-h test sessions. Additionally, this dose of SCH 23390 disrupted food-maintained responding and intake. Conclusions D1 receptor agonists and antagonists in the AId have diverse consequences and time courses of action. D1 receptor stimulation in the AId may reduce the motivating influence of cocaine-related stimuli on responding whereas D1 receptor blockade in this PFC sub-region produces global disruptions in behavior.

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