Background Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated. Methods We evaluated a large cohort (n=49) of Roman high-(RHA) and low-(RLA) avoidance rats using single photon emission computed tomography to concurrently measure in-vivo striatal D2/3R availability and amphetamine- (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the dopamine-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex-vivo autoradiography in the same animals. Results We replicated a robust inverse relationship between impulsivity, as measured with the five-choice serial reaction time task, and D2/3R availability in ventral striatum (VST) and extend this relationship to D2/3R levels measured in dorsal striatum (DST). Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in DST and VST. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high impulsive/novelty-preferring RHA animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release. Conclusions Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, dopamine-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype.

A partial saturation protocol permits the non-invasive and time-efficient estimation of B and appK separately. Given the different biological phenomena that underlie these parameters, this method may be applied for the in-depth study of the dopaminergic system in translational molecular imaging studies. It can detect the biological variations in these parameters, dissociating the variations in receptor density (B) from affinity (1/appK), which reflects the interactions of the receptor with its endogenous ligand.

Roman high- (RHA) and low-avoidance (RLA) rats have been used as a model for drug-addiction, showing, respectively, high- and low-responding to psychostimulants, and low versus high dopamine D2/3 receptors (D2/3R) striatal density. Previous studies indicated a major involvement of D2/3R on reinstatement of cocaine seeking, although the respective role of the two receptor subtypes is not clear. Here, we investigated sensitivity to cocaine self-administration (SA) through a dose-response protocol in RHAs and RLAs, and reinstatement of drug-seeking behavior at 15 days and 5 weeks following withdrawal. Compared to RLAs, RHAs confirmed a higher vulnerability to cocaine SA that was not related to a difference in sensitivity to the drug, as highlighted by the dose-response analysis. Both at early and late withdrawal, RHAs showed higher susceptibility than RLAs to reinstatement of drug-seeking when cocaine was used as a primer, but the two sublines did not differ when primed with the D2/3R agonist quinpirole. Moreover, while the specific D2R antagonist L741,626 blocked, the specific D3R antagonist SB-277011A failed to impair cocaine-primed relapse. The higher vulnerability of RHA versus RLA rats to cocaine-primed relapse, which contrasts with their similar vulnerability to quinpirole-primed relapse, suggests that the different propensity of both sublines to relapse likely relies on presynaptic rather than postsynaptic mechanisms. Moreover, our study challenges the involvement of D3R in the mechanisms underlying relapse to cocaine addiction, at least in conditions that may involve high levels of dopaminergic stimulation, and supports a major role of postsynaptic D2R over D3R in the vulnerability to relapse.

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Rationale Risk factors for drug addiction include genetics, environment, and behavioral traits such as impulsivity and novelty preference (NP), which have been related to deficits in striatal dopamine (DA) D2/3-receptors (D2/3R) and heightened amphetamine (AMPH)-induced DA release. However, the influence of the early rearing environment on these behavioral and neurochemical variables is not clear. Objectives We investigated the influence of early rearing environment on striatal D2/3R availabilities and AMPH-induced DA release in relation to impulsivity, NP, and propensity to drug self-administration (SA) in “addiction-prone” Roman high- (RHA) and “addiction-resistant” Roman low-avoidance (RLA) rats. Methods Animals were reared post-weaning in either environmental enrichment (EE) or impoverishment (EI) and were assessed at adulthood for impulsivity, NP, and propensity to cocaine SA. EE and EI rats were also scanned using single-photon emission computed tomography to concurrently measure in vivo striatal D2/3R availability and AMPH-induced DA release. Results EE vs. EI was associated with heightened impulsivity and a lack of NP in both rat lines. Higher dorsal striatal D2/3R densities were found in RHA EE and higher AMPH-induced DA release in RLA EE. Both impulsivity and NP were negatively correlated to dorsal striatal D2/3R availabilities and positively correlated with AMPH-induced DA release in EI but not in EE. EE vs. EI was related to a faster rate of cocaine intake and elevated active timeout responses in RHAs. Conclusion Our results suggest non-monotonic, environment-dependent, relationships between impulsivity, NP, and D2/3R-mediated signaling, and suggest that EI vs. EE may decrease the reinforcing effects of psychostimulants in predisposed individuals.