Four hypothalamic peptides and their impact on drug-seeking behaviour: a prefrontal cortex view

The prefrontal cortex plays a critical role in regulating substance use disorder and is strongly implicated in inhibition of and relapse to drug-seeking. Within the prefrontal cortex, inhibitory interneurons make up tightly regulated microcircuits that moderate activity of pyramidal neurons and hence control output to downstream circuits including those important for addiction-related behaviours. These interneurons can be classed into subpopulations based on peptide expression, however the complexity of these subclasses is only beginning to be understood. In this review we focus on four peptides that have receptor expression on interneurons and pyramidal neurons in the PFC. All four peptides have well-known roles in mediating drug-seeking behaviours, however their function within the prefrontal cortex is less well defined. We will review evidence from preclinical animal models that cells expressing these receptors are recruited during addiction-related behaviours, and that direct pharmacological manipulation of these systems within the prefrontal cortex may lead to altered drug-seeking behaviours. In our view, a deeper understanding of activity of specific microcircuits within this region, and their effect on pyramidal neuronal output are critical for understanding and remediating specific behaviours relevant to substance use disorder. Uncovering function of cells populations that express these neuropeptides and their receptors may help to define these microcircuits, and hence to understand how and why these behaviours are altered following drug exposure.