In vivo neurochemical profile of selectively bred high-responder and low-responder rats reveals baseline, cocaine- and novelty-evoked differences in monoaminergic systems

Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats have an exaggerated locomotor response to a novel environment, are more risk-taking, 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 the current study, we applied advanced in vivo microdialysis sampling in the nucleus accumbens of bHRs/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 bLRs. Furthermore, norepinephrine adrenergic receptor antagonist terazosin (10 μM) into the nucleus accumbens abolished the bHR response 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. distinct neurochemical signaling patterns between bHRs and bLRs upon to These identify a interactions in shed light on In summary, our findings provide further evidence for differences in the dopamine system in the NAc of bHRs and bLRs, and demonstrate, for the first time, a role for NE signaling via α 1ARs in the NAc in the distinct behavioral phenotypes of these bred lines. Importantly, we demonstrate “true” baseline differences in neurochemical signaling in the NAc, with bHRs showing elevated dopamine and NE. Furthermore, administration of an α 1AR antagonist, terazosin, rendered bHRs more bLR-like, attenuating the locomotor response to novelty and diminishing the relationship between dopamine and NE. Taken together, these findings highlight a role for α 1ARs in the behavioral phenotype of bHR rats, with data to suggest that antagonizing these receptors depresses dopamine activation. Thus, these data further support a role for dopamine and NE in mediating individual differences in response to novelty. Future studies will investigate additional aspects of co-regulation of dopamine and NE and other adrenergic receptor systems of this unique genetic animal model as potential targets for the treatment of addiction and other impulse control disorders.