Neural mechanisms underlying stress-induced enhancement of cocaine craving behaviors

Abstract

Stress potentiates craving for addictive drugs including cocaine. To elucidate neural mechanisms underlying this effect of stress, we developed an experimental paradigm combining cocaine-induced conditioned place preference (CPP) with a restraint stress. Acute restraint stress exposure immediately before posttest significantly increased cocaine CPP scores. It has been suggested that the extracellular noradrenaline (NA) level is increased by stress in the laterodorsal tegmental nucleus (LDT), which sends cholinergic projections to dopamine (DA) neurons in the ventral tegmental area (VTA), and medial prefrontal cortex (mPFC), which receives DA input from the VTA. Thus, we investigated the roles of NA in these brain regions. Intra-LDT injection of an α2 or a β adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. In vitro whole-cell recordings revealed that α2 adrenoceptor stimulation reduced GABAergic inputs to LDT cholinergic neurons that were obtained from cocaine-, but not saline-, treated rats. On the other hand, α1, but not α2 or β, adrenoceptor stimulation excited mPFC pyramidal neurons. Intra-mPFC injection of an α1 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Additionally, chemogenetic silencing of mPFC excitatory neurons also reduced the stress-induced enhancement of cocaine CPP. These findings suggest that stress-induced increases in neuronal activity of the LDT and mPFC may contribute to the enhancement of cocaine craving.