Decoupling Dopamine Synthesis from Impulsive Action, Risk-related Decision-Making, and Propensity to Cocaine Intake: A Longitudinal [¹⁸F]-FDOPA PET Study in Roman High- and Low-avoidance Rats

Abstract

Impulsive action and risk-related decision-making (RDM) are two facets of impulsivity linked to a hyperdopaminergic release in the striatum and an increased propensity to cocaine intake. We previously showed that with repeated cocaine exposure, this initial hyperdopaminergic release is blunted in impulsive animals, potentially signaling drug-induced tolerance. Whether such dopaminergic dynamics involve changes in dopamine (DA) synthesis as a function of impulsivity is currently unknown. Here, we investigated the predictive value of DA synthesis for impulsive action, RDM, and the propensity to take cocaine in a rat model of vulnerability to cocaine abuse. Additionally, we assessed the effects of cocaine intake on these variables. Rats were tested sequentially in the rat Gambling Task (rGT) and were scanned with positron emission tomography and [¹⁸F]-FDOPA to respectively assess both impulsivity facets and striatal DA synthesis before and after cocaine self-administration (SA). Our results revealed that baseline striatal levels of DA synthesis did not significantly predict impulsive action, RDM, or a greater propensity to cocaine self-administration (SA) in impulsive animals. Besides, we showed that impulsive action, but not RDM, predicted higher rates of cocaine-taking. However, chronic cocaine exposure had no impact on DA synthesis nor affected impulsive action and RDM. These findings indicate that the hyperresponsive DA system associated with impulsivity and a propensity for cocaine consumption, along with the reduction in this hyperresponsive DA state in impulsive animals with a history of cocaine use, might not be mediated by dynamic changes in DA synthesis.

Significance statement Impulsive behaviors are associated with a heightened presynaptic dopamine (DA) function and vulnerability to the rewarding effects of cocaine. However, with repeated drug exposure, the initially high DA release decreases, probably reflecting the development of drug tolerance. Whether such DA dynamics involve changes in DA synthesis is currently unknown. Using in vivo neuroimaging in rats before and after chronic cocaine use, our study reveals that DA synthesis does not predict impulsivity or vulnerability to cocaine, nor is it affected by chronic drug exposure. Our results suggest that the heightened presynaptic function underlying impulsivity and the cocaine-induced tolerance to drugs depend on alternative mechanisms to DA synthesis, such as those controlling DA reactivity to stimulation and DA reuptake.