Adenosine A₁ and A_2A receptors are not upstream of caffeine’s dopamine D₂ receptor‐dependent aversive effects and dopamine‐independent rewarding effects

Abstract

Caffeine is widely consumed throughout the world, yet little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversions to caffeine, but reveals dopamine blockadeinduced conditioned place preferences. These aversions are mediated by the dopamine D 2 receptor since knockout mice showed conditioned place preferences to doses of caffeine that C57Bl/6 mice found aversive. Further, these aversions appear to be centrally-mediated since a quaternary analogue to caffeine failed to produce conditioned place aversions. While the adenosine A 2A receptor is important for caffeine's physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A 2A receptor knockout mice showed stronger dopamine-dependent aversions to caffeine than C57Bl/6 animals, which partially obscured the dopamine-and A 2A receptor-independent preferences. Additionally, the A 1 receptor, alone or in combination with the A 2A receptor, does not seem to be important for caffeine's rewarding or aversive effects. Finally, excitotoxic lesions of the tegmental pedunculopontine nucleus revealed that this brain region is not involved in dopamine blockade-induced caffeine reward. This data provides surprising new information on the mechanism of action of caffeine, indicating that adenosine receptors do not mediate caffeine's appetitive and aversive effects. We show that caffeine has an atypical reward mechanism, independent of the dopaminergic system and the tegmental pedunculopontine nucleus and provide additional evidence in support of a role for the dopaminergic system in aversive learning.

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

“…We have elicited separately conditioned caffeine reward through low-dose systemic injections and intra-rVTA caffeine, or conditioned caffeine aversions through higher dose systemic injections by performing in vivo administration of caffeine in a place conditioning paradigm. While our study aligns generally with the findings reported previously by us and by others (Brockwell, Eikelboom, & Beninger, 1991;Patkina & Zvartau, 1998;Sturgess et al, 2010), there are several inconsistencies and F I G U R E 6 Intra-rVTA caffeine reward and systemic (10 mg/kg i.p.) caffeine aversion are both DA-dependent, but segregated in the NAc shell and NAc core, respectively.…”

“…This could be due to unknown compensatory mechanisms arising from transgenic manipulation. Nonetheless, downstream dopaminergic mechanisms were implicated in the aversive response to caffeine, as systemic pharmacological blockade of DA receptors reduced caffeine aversions (Sturgess et al, 2010). As caffeine may not act as an adenosine receptor antagonist to produce these motivational effects and does not bind directly to DA receptors as demonstrated by radioligand competitive binding assays (Watanabe & Uramoto, 1986), caffeine could be acting on an unknown receptor to produce a motivational response.…”

“…Most of these effects, including those involving motivation, have been attributed to its role as a competitive adenosine receptor antagonist (subtypes A 1 R and A 2A R) (Fredholm, Bättig, Holmén, & Zvartau, 1999; Higgins et al, 2007; Lazurus et al, 2011). However, despite the abundance of evidence implicating adenosine receptors in caffeine motivation (Bedingfield, King, & Holloway, 1998; El Yacoubi, Kedent, Parmentier, Costentin, & Vaugeois, 2005; Hilbert, May, & Griffin, 2013; Lazurus et al, 2011; Patkina & Zvartau, 1998), our group has demonstrated that the aversive effects of caffeine are spared in adenosine receptor mouse knockouts (KO) (Sturgess et al, 2010). Additionally, the rewarding effects of caffeine produced under conditions of dopamine (DA) receptor blockade in wild‐type C57BL/6 mice were reproduced in A 1 R KO, A 2A R KO and double KO mice, indicating that adenosine receptor subtypes neither individually nor in tandem are necessary.…”

Assessment of Sedative Effects of Passiflora edulis f. flavicarpa and Passiflora alata Extracts in Mice, Measured by Telemetry

“…Caffeine, a xanthine alkaloid, is naturally found in a lot of different plants worldwide and acts as a central nervous system and metabolic stimulant. The CNS stimulating effects of caffeine have been reported in numerous preclinical studies (Kuzmin et al, 2006;Popoli et al, 1996;Sturgess et al, 2010;Xu et al, 2009).…”

Nicotinic Acetylcholine Receptors in the Ventral Tegmental Area are Important Targets for Nicotine and Ethanol Co-dependence

“…The necessity of this DA system in the rewarding properties of benzodiazepines, barbiturates and caffeine is also questioned [29,31,32]. A rising hypothesis asserts that DA is not requisite for all rewarding effects of opiates, cannabis, cocaine and NIC.…”