Prefrontal Cortical Opioids and Dysregulated Motivation: A Network Hypothesis

Loss of inhibitory control over appetitively motivated behavior occurs in multiple psychiatric disorders, including drug abuse, behavioral addictions, and eating disorders with binge features. In this opinion article, novel actions of μ-opioid peptides in the prefrontal cortex (PFC) that could contribute to inhibitory control deficits will be discussed. Evidence has accrued to suggest that excessive intra-PFC μ-opioid receptor (μ-OR) signaling alters the PFC response to excitatory drive, resulting in supernormal and incoherent recruitment of multiple PFC output pathways. Affected pathways include functionally opposed PFC→hypothalamus ‘appetitive driver’ and PFC→striatum ‘appetitive limiter’ projections. This network perturbation engenders disorganized, impulsive appetitive responses. Evidence supporting this hypothesis from human imaging and animal studies will be discussed, and combinatorial drug treatments targeting μ-ORs and specific PFC subcortical targets will be explored.

TrendsAbnormal opioid signaling in the brain is thought to contribute to motivational dysregulation in drug and ‘behavioral’ addictions (e.g., binge eating, pathological gambling). Opioid actions have been extensively studied in subcortical sites (e.g., the nucleus accumbens, Acb), but not in the cortex.Recent studies suggest that the prefrontal cortex (PFC) is a key anatomical substrate for opioid-driven food and alcohol bingeing, and food impulsivity.Recent findings suggest that dysregulated motivated behavior emerges when cortical opioid signaling disrupts the balance between PFC→hypothalamus ‘motivation driver’ and PFC→Acb ‘limiter’ circuits.Improved knowledge of opioid-responsive cortical→subcortical circuitry could aid the development of poly-drug strategies that block opioid receptors along with PFC-targeted subcortical neurochemical systems.