Ginovart, N. | Search bioRxiv

bioRxiv2023

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

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 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, is not mediated by dynamic changes in DA synthesis. Significance statementImpulsive 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.

neuroscience↗

bioRxiv2022

Concurrent measures of impulsive action and choice are partially related and differentially modulated by dopamine D1- and D2-like receptors in a rat model of impulsivity

Impulsivity is a multidimensional construct, but the relationships between its constructs and their respective underlying dopaminergic underpinnings in the normal population remain unclear. A large cohort of Roman high-(RHA) and low- (RLA) avoidance rats were tested for impulsive action and risky decision-making in the rat gambling task, and then for delay discounting in the delay discounting task to concurrently measure the relationships among the three constructs of impulsivity using a within-subject design. Then, we evaluated the effects of dopaminergic drugs on the three constructs of impulsivity, considering innate differences in impulsive behaviors at baseline. Risky decision-making and delay discounting were positively correlated, indicating that both constructs of impulsive choice are related. Impulsive action positively correlated with risky decision-making but not with delay discounting, suggesting partial overlap between impulsive action and impulsive choice. RHAs showed a more impulsive phenotype in the three constructs of impulsivity compared to RLAs, demonstrating the comorbid nature of impulsivity in a normal population. While amphetamine increased impulsive action and had no effects on risky decision-making regardless of baseline levels of impulsivity, it decreased delay discounting but only in high impulsive RHAs. Conversely, the D1R agonist SKF81297, D3R agonist PD128907 and D2/3R partial agonist aripiprazole decreased impulsive action irrespective of baseline levels of impulsivity, whereas D2/3R agonism with quinpirole decreased it exclusively in high impulsive RHAs. Risky decision-making was increased by SKF81297 and quinpirole but not PD128907 and aripiprazole, with quinpirole producing baseline-dependent effects, increasing risky decision-making only in low impulsive RLAs. Finally, while SKF81297, PD128907 and aripiprazole increased delay discounting irrespective of baseline levels of impulsivity, quinpirole decreased it in low impulsive RLAs only. These findings indicate that the acute effects of dopamine drugs were partially overlapping across dimensions of impulsivity, and that only D2/3R agonism showed baseline-dependent effects on the three constructs of impulsivity.

neuroscience↗