Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats have an exaggerated locomotor response to a novel environment, take more risks, are more impulsive, and more likely to exhibit compulsive drug-seeking behaviors. These phenotypic differences in addiction-related behaviors and temperament have previously been associated with differences in neurotransmitter signaling, including the mesolimbic dopamine system. In this study, we applied advanced in vivo microdialysis sampling in the nucleus accumbens of bHRs and bLRs to assess differences in basal and stimulated neurochemical efflux more broadly. We used liquid chromatography-mass spectrometry measurements of dialysate samples to quantify a panel of 17 neurochemicals, including dopamine, norepinephrine, serotonin, histamine, glutamate, GABA, acetylcholine, adenosine, DOPAC, 3-MT, HVA, 5-HIAA, normetanephrine, taurine, serine, aspartate, and glycine. We also applied a stable isotope labeling technique to assess absolute baseline concentrations of dopamine and norepinephrine in the nucleus accumbens. Finally, we investigated the role of norepinephrine tone in the nucleus accumbens on the bHR phenotype. Our findings show that bHRs have elevated basal and cocaine-evoked dopamine and norepinephrine levels in the nucleus accumbens compared to those of bLRs. Furthermore, norepinephrine signaling in the nucleus accumbens appeared to be an important contributor to the bHR phenotype because bilateral perfusion of the α1 adrenergic receptor antagonist terazosin (10 μM) into the nucleus accumbens abolished the response of bHRs to novelty. These findings are the first to demonstrate a role for norepinephrine in the bHR phenotype. They reveal a positive relationship between dopamine and norepinephrine signaling in the nucleus accumbens in mediating the exaggerated response to novelty and point to norepinephrine signaling as a potential target in the treatment of impulse control disorders.
Keywords: Dopamine; High responders; Mass spectrometry; Neurochemistry; Norepinephrine; Nucleus accumbens.