Neuropeptide receptors as entry points for developmental vulnerability to drug abuse

Traditional views in cellular neurobiology stipulate that neuropeptides, biologically active peptides cleaved from precursor proteins with substantial expression in the nervous system, modulate bidirectional synaptic neurotransmission in the adult brain by engaging mostly, if not exclusively, G protein-coupled receptors. Recent evidence also places neuropeptides into developmental processes, with both transient and permanent expression foci in the fetal nervous system contributing to neuronal fate choices, notably axonal growth and directional guidance. Neuropeptide receptors are partitioned within navigating growth cones, with the bulk of neuropeptides inducing steering decisions, at least in vitro. Thus, any developmental process that disrupts growth cone motility and biases guidance decisions might render neuropeptide signaling inadequate for neuronal circuit formation. We recognize maternal drug abuse during pregnancy as a major liability for neuropeptide signaling, because the most common psychoactive drugs alter neuropeptide levels, their molecular targets coexist with neuropeptide receptors in growth cones, and symptomatically, neuropeptide signaling is altered in neurodevelopmental disorders in children with either prenatal or adolescent drug exposure. Mechanistically, the epigenetic deregulation of neuropeptide expression is suggested. Thus, we propose that neuropeptide-sensitive developmental programs, chiefly neurogenesis and synaptogenesis, are susceptible to psychoactive drugs. Thus, any means to rescue or reinstate neuropeptide signaling could attenuate nervous system pathobiology in offspring passively subjected to substance abuse during pregnancy.