Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction

Abstract

Cocaine is known to increase brain dopamine at supranormal levels in comparison to alternative nondrug rewards. According to the dopamine hypothesis of addiction, this difference would explain, at least in part, why the latter are eventually given up in favor of continued cocaine use during the transition to addiction. Though resting on solid neuroscientific foundations, this hypothesis has nevertheless proven difficult to reconcile with research on cocaine choice in experimental animals. When facing a choice between an intravenous bolus of cocaine and a nondrug alternative (e.g., sweet water), both delivered immediately after choice, rats do not choose the drug, as would be predicted, but instead develop a strong preference for the nondrug alternative, sometimes to the exclusion of continued drug use. Here we report converging evidence that reconciles this finding with the dopamine hypothesis of addiction. Briefly, our data suggest that cocaine is indeed supranormal in reward magnitude, as postulated by the dopamine hypothesis of addiction, but is less preferred during choice because its pharmacokinetics makes it an inherently more delayed reward than the alternative. Reframing previous drug choice studies in rats as intertemporal choice studies reveals that the discounting effects of delays spare no rewards, including supranormal ones, and that during choice, pharmacokinetics trumps pharmacodynamics. Finally, this study also reveals important gaps in our understanding of drug reward delays that need to be filled by future experimental and theoretical work.

Transcriptome profiling of the ventral pallidum reveals a role for pallido-thalamic neurons in cocaine reward

“…Nr4a1 knockdown did not impact water self-administration suggesting that the VPàMDT circuit may not be involved in learning action-outcome association for natural rewards. This circuit could thus be engaged in more complex, delayed rewards such as cocaine22 consistent with the role of MDT in working memory and behavioral perseverance 23 , and exemplified here with perseverative responding during drug-seeking after Nr4a1 overexpression. While the exact cognitive mechanisms altered by cocaine intake remain to be clarified, our work demonstrated a significant role for the VPàMDT circuit in addiction-like behaviors through Nr4a1-mediated structural plasticity.…”

Probing the decision-making mechanisms underlying choice between drug and nondrug rewards in rats

“…In contrast to saccharin, cocaine is generally selected with longer latencies during sampling, preventing the floor effect. Longer latencies to select cocaine could result from the ambivalent and anxiogenic effects of the drug [50][51][52][53] or from its delayed pharmacological effects on the brain [54]. Interestingly the gap between cocaine choice and sampling latencies was more pronounced in IND rats compared to CP rats.…”

The Effect of ROE on the PBV of Toll Road, Airport, Port, and Sub-Sector Companies in the Indonesia Stock Exchange

“…Methods and research to design. This type of research uses verification research with explanatory survey method used to test hypotheses (Canchy, Girardeau, Durand, Vouillac-Mendoza, & Ahmed, 2021;Ongan, Isik, & Ozdemir, 2020) and to explain phenomena in the form of relationships between variables. Research designed is a procedure that researchers use when selecting, collecting, and analyzing data as a whole.…”