Innately low D2 receptor availability is associated with high novelty-seeking and enhanced behavioural sensitization to amphetamine.

High novelty-seeking has been related to an increased risk for developing addiction, but the neurobiological mechanism underlying this relationship is unclear. We investigated whether differences in dopamine (DA) D2/3-receptor (D2/3R) function underlie phenotypic divergence in novelty-seeking and vulnerability to addiction. Measures of D2/3R availability using the D2R-preferring antagonist [18F]Fallypride, and the D3R-preferring agonist [3H]-(+)-PHNO and of DA-related gene expression and behaviours were used to characterize DA signalling in Roman high- (RHA) and low-avoidance (RLA) rats, which respectively display high and low behavioural responsiveness both to novelty and psychostimulant exposure. When compared to RLA rats, high novelty-responding RHAs had lower levels of D2R, but not D3R, binding and mRNA in substantia nigra/ventral tegmental area (SN/VTA) and showed behavioural evidence of D2-autoreceptor subsensitivity. RHA rats also showed a higher expression of the tyrosine hydroxylase gene in SN/VTA, higher levels of extracellular DA in striatum and augmentation of the DA-releasing effects of amphetamine (Amph), suggesting hyperfunctioning of midbrain DA neurons. RHA rats also exhibited lower availabilities and functional sensitivity of D2R, but not D3R, in striatum, which were inversely correlated with individual scores of novelty-seeking, which, in turn, predicted the magnitude of Amph-induced behavioural sensitization. These results indicate that innately low levels of D2R in SN/VTA and striatum, whether they are a cause or consequence of the concomitantly observed elevated DA tone, result in a specific pattern of DA signalling that may subserve novelty-seeking and vulnerability to drug use. This suggests that D2R deficits in SN/VTA and striatum could both constitute neurochemical markers of an addiction-prone phenotype.