Segregation of caffeine reward and aversion in the rat nucleus accumbens shell versus core

Abstract

Caffeine, the most commonly consumed psychoactive drug in the world, is readily available in dietary sources, including soft drinks, chocolate, tea and coffee. However, little is known about the neural substrates that underlie caffeine's rewarding and aversive properties and what ultimately leads us to seek or avoid caffeine consumption. Using male Wistar rats in a place conditioning procedure, we show that systemic caffeine at a low intraperitoneal dose of 2 mg/kg (or 100 µM injected directly into the rostral, but not caudal, portion of the ventral tegmental area) produced conditioned place preferences. By contrast, high doses of systemic caffeine at 10 and 30 mg/kg produced conditioned place aversions. These aversions were not recapitulated by a caffeine analog restricted to the periphery. Both caffeine reward and aversion were blocked by systemic D1‐like receptor antagonism using SCH23390, while systemic D2‐like receptor antagonism with eticlopride had smaller effects on caffeine motivation. Most important, we demonstrated that pharmacological blockade of dopamine receptors using α‐flupenthixol injected into the nucleus accumbens shell, but not core, blocked caffeine‐conditioned place preferences. Conversely, α‐flupenthixol injected into the nucleus accumbens core, but not shell, blocked caffeine‐conditioned place aversions. Thus, our findings reveal two dopamine‐dependent and functionally dissociable mechanisms for processing caffeine motivation, which are segregated between nucleus accumbens subregions. These data provide novel evidence for the roles of the nucleus accumbens subregions in mediating approach and avoidance behaviours for caffeine.

Dopamine D1 and D2 Receptors Are Important for Learning About Neutral-Valence Relationships in Sensory Preconditioning

“…A more discriminatory impact on inhibitory D2 autoreceptors (as opposed to post-synaptic D2R) could, for example, play a role if these proved to be differentially sensitive to selective and non-selective dopamine receptor antagonists. Similarly, given what we know about other neural substrates of sensory preconditioning (Ward-Robinson et al, 2001;Coutureau et al, 2002;Holmes et al, 2018;Fournier et al, 2021;Kahnt and Schoenbaum, 2021), as well as the different roles of dopamine in striatal regions (e.g., Young et al, 1998;Li and McNally, 2015;Yee et al, 2020), there could be a more complicated interplay of dopaminergic involvement than can be teased out with systemic drug administration studies. Accordingly, central administration studies will be needed to help clarify this in the future.…”

Dopamine, behavior, and addiction

“…Caffeine Caffeine is self-administered by animals [148,162,163] and produces conditioned flavor preferences (low doses) or conditioned place aversions (high doses) in rats when injected intraperitoneally or directly into the VTA [164]. A dopamine antagonist injected into the shell of the ventral striatum blocks these place preferences, whereas the antagonist injected into the core of the ventral striatum blocks the conditioned aversive effects [165]. Volatized, inhaled caffeine increases extracellular dopamine levels in the nucleus accumbens shell [166].…”