Modulation of appetitive motivation by prefrontal cortical mu-opioid receptors is dependent upon local dopamine D1 receptor signaling (2018)

Neuropharmacology. 2018 Sep 15;140:302-309. doi: 10.1016/j.neuropharm.2018.07.033.

Selleck RA1, Giacomini J2, Buchholtz BD3, Lake C3, Sadeghian K4, Baldo BA5.


Opioid neurotransmission has been implicated in psychiatric disorders featuring impaired control over appetitive motivation, such as addiction and binge-eating disorder. We have previously shown that infusions of the μ-opioid receptor (μOR) agonist DAMGO into the ventromedial prefrontal cortex (vmPFC) induced hyperphagia, increased motor activity, and augmented sucrose-reinforced responding in the task progressive ratio (PR) task, which assesses the motivational value of an incentive. These effects were not reproduced by intra-PFC infusion of a variety of dopamine (DA) agonists and antagonists, suggesting that manipulation of intra-PFC DA systems alone is not sufficient to reproduce μOR-like effects. Nevertheless, this does not rule out interactions between PFC DA and μ-opioid systems. Here we used intra-vmPFC drug cocktails containing DAMGO and SCH 23390 (a DA D1 receptor antagonist) to determine whether increases in appetitive motivation and motor activity elicited by intra-vmPFC μOR stimulation require intact signaling through vmPFC D1 receptors. Blockade of D1 receptors with SCH 23390 attenuated the enhancement of PR breakpoint, and increases in exploratory-like behavior and feeding initiation elicited by intra-vmPFC μOR stimulation. These results establish that intra-vmPFC D1 signaling is required for the expression of behavioral effects evoked by μOR stimulation within the PFC, and further suggest that D1 tone plays an enabling or permissive role in the expression of μOR -elicited effects. Simultaneous targeting of both μ-opioid and D1 systems may represent a more efficacious treatment strategy (compared to μOR blockade alone) for psychiatric disorders characterized by dysregulated appetitive motivation.

KEYWORDS: Dopamine D1 receptor; Feeding; Food motivation; Mu-opioid receptor; Prefrontal cortex; Rat