Figure 2: Neuronal overexpression of adenosine A_2A receptor (A_2AR) disrupts HPA-axis function.

(a) GR protein and (b) mRNA levels are decreased in the hippocampus (n = 5) of Tg(CaMKII-hA_2AR) compared to WT animals, and (c) CRH mRNA levels are increased in the hypothalamus (n = 5) of Tg(CaMKII-hA_2AR) compared to WT animals, calculated using a unpaired Student’s t-test. (d) Corticosterone levels evaluated at 8 AM and 8 PM are elevated in Tg(CaMKII-hA_2AR) and do not oscillate in a circadian manner (n = 6–9); Results were analysed with a two-way ANOVA followed by a Bonferroni post hoc. *P < 0.05 compared to WT, ^#P < 0.05 compared with WT at AM. High frequency stimulation (HFS: 100 Hz, 1s) was used to evaluate synaptic plasticity in hippocampal rat slices according to scheme depicted in lower panel (f). (e) At 32 °C, Tg(CaMKII-hA_2AR) animals present a lower post-tetanic potentiation (PTP) and no effect on long term potentiation (LTP). (f) At 30.5 °C, Tg(CaMKII-hA_2AR) animals present higher LTP magnitude which was rescued by one-month oral administration of an A_2AR selective antagonist, KW 6002 (5mg/Kg/day). LTP and PTP magnitudes were quantified in (g). *P < 0.05 unpaired Student’s t test, compared to WT; and are presented as mean ± SEM of (n = 6–11) experiments; ^#P < 0.05 using one-way ANOVA, followed by a Bonferroni post hoc and (h) Input/Output (I/O) curve corresponding to fEPSP slope evoked by different stimulation intensities (0.6 – 3 mA). There is a shift to the left in the curve from Tg(CaMKII-hA_2AR) animals. (i) Short-term reference memory, using the modified Y-maze test. Impairments in Tg(CaMKII-hA_2AR) animals were rescued by oral KW6002 administration (n = 10–16). Results were analysed with a one-way ANOVA followed by a Bonferroni post hoc and are presented as mean ± SEM of n experiments. *^,#P < 0.05 compared to Novel (N) arm.