Background: Among psychostimulants, the dopamine transporter ligands amphetamine and cocaine display the highest addictive potential; the adenosine receptor antagonist caffeine is most widely consumed but less addictive. Psychostimulant actions of amphetamine were correlated with its ability to orchestrate ventral tegmental dopamine neuron activity with contrasting shifts in firing after single vs repeated administration. Whether caffeine might impinge on dopamine neuron activity has remained elusive.
Methods: Population activity of ventral tegmental area dopamine neurons was determined by single-unit extracellular recordings and set in relation to mouse behavior in locomotion and conditioned place preference experiments, respectively.
Results: A single dose of caffeine reduced population activity as did amphetamine and the selective adenosine A2A antagonist KW-6002, but not the A1 antagonist DPCPX. Repeated administration of KW-6002 or amphetamine led to drug-conditioned place preference and to unaltered or even enhanced population activity. Recurrent injection of caffeine or DPCPX, in contrast, failed to cause conditioned place preference and persistently reduced population activity. Subsequent to repetitive drug administration, re-exposure to amphetamine or KW-6002, but not to caffeine or DPCPX, was able to reduce population activity.
Conclusions: Behavioral sensitization to amphetamine is attributed to persistent activation of ventral tegmental area dopamine neurons via the ventral hippocampus. Accordingly, a switch from acute A2A receptor-mediated reduction of dopamine neuron population activity to enduring A1 receptor-mediated suppression is correlated with tolerance rather than sensitization in response to repeated caffeine intake.
Keywords: Adenosine receptor antagonists; VTA dopamine neurons; amphetamine; caffeine; psychostimulants.
© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.