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

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.