Repeated Cocaine Intake Differentially Impacts Striatal D2/3 Receptor Availability, Psychostimulant-Induced Dopamine Release, and Trait Behavioral Markers of Drug Abuse

Abstract

Current research indicates that altered dopamine (DA) transmission in the striatum contributes to impulsivity and novelty-seeking, and it may mediate a link concerning a higher susceptibility to drug abuse. Whether increased susceptibility to drug abuse results from a hyperdopaminergic or hypodopaminergic state is still debated. Here, we simultaneously tracked changes in DA D2/3 receptor (D2/3R) availability and amphetamine-(AMPH)-induced DA release in relation to impulsivity and novelty-seeking prior to, and following, cocaine self-administration (SA) in Roman high- (RHA) and low- (RLA) avoidance rats. We found that high-impulsive/high novelty-seeking RHA rats exhibited lower D2/3R availabilities and higher AMPH-induced DA release in the striatum that predicted higher levels of cocaine intake compared with RLAs. Cocaine SA did not alter striatal D2/3R availability or impulsivity in RHA or RLA rats. Critically, cocaine exposure led to a baseline-dependent blunting of stimulated DA release in high-impulsive/high novelty-seeking RHA rats only, and to a baseline-dependent increase in novelty-seeking in low-impulsive/low novelty-seeking RLA rats only. Altogether, we propose that susceptibility to drug abuse results from an innate hyper-responsive DA system, promoting impulsive action and novelty-seeking, and producing stronger initial drug-reinforcing effects that contribute to the initiation and perpetuation of drug use. However, with repeated cocaine use, a tolerance to drug-induced striatal DA elevations develops, leading to a compensatory increase in drug consumption to overcome the reduced reward effects.

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

“…However, despite continuous research, some debate still exists on the effects of cocaine on specific impulsivity facets. For instance, as shown in our data and consistent with several studies (Abbott et al, 2022;Dalley et al, 2005;Ferland and Winstanley, 2017;Urueña-Mendez et al, 2023), chronic cocaine exposure did not significantly alter impulsive action (but see also: (Caprioli et al, 2013;Dalley et al, 2007;Winstanley et al, 2009). In contrast, the evidence regarding RDM has been less consistent.…”

“…Importantly, we extended those findings by showing that impulsive action and RDM are not linked to variations in DA synthesis. Additionally, our study shows that chronic cocaine use does not affect impulsive action or RDM, nor decreased DA synthesis, even though similar cocaine exposure has proven sufficient to blunt striatal DA release (Urueña-Mendez et al, 2023). Altogether, our study indicates that alterations in DA synthesis are not the mechanism behind heightened-evoked DA release linked to impulsivity nor the mechanism underlying dopaminergic tolerance to psychostimulants.…”

“…Moreover, hyperdopaminergic release in impulsive animals predicts a higher propensity to cocaine self-administration (SA) (Urueña-Mendez et al, 2023). Together, these studies strengthen the view that increased presynaptic -rather than decreased postsynaptic-DA function might be the main dysregulation underlying impulsive behaviors, conferring greater vulnerability to cocaine abuse.…”

“…Another potential limitation of our study is the use of only one temporal window to evaluate the effects of cocaine on DA synthesis. Nevertheless, while cocaine withdrawal might affect DA function (Wu et al, 1999), potential changes in DA synthesis at later withdrawal time are improbable to underlie cocaineinduced tolerance to psychostimulants, as this effect has been observed from early withdrawal (Ferris et al, 2011;Siciliano et al, 2015;Urueña-Mendez et al, 2023). Finally, our study included only males, while the mechanisms controlling DA release may vary in females (Zachry et al, 2021), who are also reported as more vulnerable to cocaine intake than males (Knouse and Briand, 2021).…”

“…However, cocaine effects may vary depending on the impulsivity facet assessed. While several studies (Abbott et al, 2022;Dalley et al, 2005;Ferland and Winstanley, 2017;Urueña-Mendez et al, 2023) have reported no alterations in impulsive action shortly after cocaine withdrawal (but see: Dalley et al, 2007;Winstanley et al, 2009), research on RDM is scarce and has yielded mixed results. For instance, one study (Ferland and Winstanley, 2017) found impaired RDM exclusively in risky rats (i.e., those preferring high reward magnitude at higher punishment risk), while another study found impairments in nonrisky rats (Cocker et al, 2019).…”