Activation of the dynorphin-kappa opioid receptor (KOR) system produces a negative emotional state during drug withdrawal, thereby motivating continued cocaine-seeking behaviors. However, it is not clear whether dynorphin plays a functional role in the onset of compulsive cocaine-taking. Here, escalation of cocaine self-administration was significantly attenuated by pretreatment of a long-acting KOR antagonist, norbinaltorphimine (NBI), in long access (LgA; 6-hours) male rats, whereas there was no effect of NBI on short access (ShA; 1-hour) rats on a fixed or progressive ratio schedule of reinforcement. Additionally, optical density of prodynorphin was increased in the nucleus accumbens (NAc) core and shell, bed nucleus of the stria terminalis (BNST), central amygdala (CeA), and basolateral amygdala (BLA) of LgA rats compared to both ShA and drug-naïve rats. These results suggest dynorphin in the stress-sensitive extended amygdala (NAc shell, BNST, CeA), and BLA-NAc core circuitry mediating cue-controlled cocaine-taking may be associated with the onset of compulsive drug-taking.

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The therapeutic benefits attributed to activation of peripheral mechanoreceptors are poorly understood. There is growing evidence that mechanical stimulation modulates substrates in the supraspinal central nervous system (CNS) that are outside the canonical somatosensory circuits. This work demonstrates that activation of peripheral mechnoreceptors via mechanical stimulation (MStim) is sufficient to increase dopamine release in the nucleus accumbens (NAc), alter neuron firing rate in the ventral tegmental area (VTA) and increase membrane translocation of delta opioid receptors (DORs) in the NAc. Further, we demonstrate that these effects are dependent on DORs and acetylcholine receptors. Additionally, MStim can block neuronal markers of chronic ethanol dependence including ethanol-induced changes to VTA GABA neuron firing during withdrawal, and DA release profiles after reinstatement ethanol during withdrawal. These are presented in tandem with evidence that MStim also ameliorates behavioral indices of ethanol withdrawal. Finally, exercise, a modality that includes a mechanosensory component, is shown to alter expression of kappa opioid receptors (KORs) in the NAc. This change substantively depresses KORs influence over evoked DA release in direct contraversion to the effects of chronic ethanol. These changes translate into reduced drinking behavior.