Caffeine Regulates GABA Transport Homeostasis in the Adolescent Mouse Frontal Cortex via Adenosine A1 Receptor and PKC ‐Dependent Pathways

ABSTRACT Adolescence is a period of several brain changes, making it especially vulnerable to external influences. Abuse of psychoactive drugs, such as caffeine (CAFF), generates changes in cognitive functions. The main pharmacological targets of CAFF are mainly the A 1 R and A 2A R adenosine receptors, which can regulate GABA homeostasis. We therefore evaluated the influence of CAFF intake upon GABA uptake and release in the frontal cortex (FC) of adolescent Swiss mice and addressed the underlying mechanism. Mice were treated for 5 days with a subcutaneous injection of CAFF (10, 20, and 40 mg/kg) every 24 h, and the FC dissected out at 1 h after the last injection for measurement of [ 3 H]‐GABA uptake and release, cAMP accumulation, and density levels of GAT‐1, A 1 R, A 2A R, PKA, and PKC. Calcium (Ca 2+ ) imaging was performed on primary neuronal cultures treated with CAFF (200 μM). CAFF increased [ 3 H]‐GABA uptake at all doses studied, an effect reversed by incubation with the selective GAT‐1 uptake inhibitor, NO‐711 (10 μM). At 20 and 40 mg/kg, CAFF also increased [ 3 H]‐GABA release. CAFF also increased A 1 R, but not A 2A R levels. The influence of CAFF involves pPKC activity since CAFF enhanced the pPKC/PKC ratio, while the PKC‐inhibitor Gö 6983 (100 nM) reversed the facilitatory action of CAFF upon GABA transport and prevented the CAFF‐induced increase in the frequency of Ca 2+ transients in neuronal cell cultures. We conclude that CAFF alters GABAergic homeostasis in the FC, increasing GABA transport through PKC‐activity modulation. image