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 mu-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 mu-opioid receptor (mu-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 -> hypo-thalamus '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 mu-ORs and specific PFC subcortical targets will be explored.