Caffeine increases cortical activation and the rate and selectivity of information processing (Fredholm et al. 1999), in humans especially in the elderly (Ryan et al. 2002). Caffeine exerts these actions most probably through antagonism of the adenosine A₁ and A_2A receptors (Fredholm et al. 1999), activated by ambient adenosine levels, which are increased with ageing. Hippocampal gamma oscillations are associated with memory (Herrmann et al. 2004) and are reduced with ageing (Vreugdenhil & Toescu, 2005). Here we assess the effect of caffeine and selective adenosine receptor antagonists on spontaneous and kainate-evoked gamma oscillations. Slices (400 µm thick) of the mouse ventral hippocampus were kept at 32°C under interface conditions. Recording electrodes were placed in stratum radiatum of CA3c; intracellular recordings were made from pyramidal neurons in CA3c. In some slices spontaneous gamma oscillations were recorded, otherwise gamma oscillations were induced by addition of 50 nM kainate. Deviation from normal development of power in the gamma range was taken as effect. Caffeine (50 µM) boosted kainate-induced gamma to 225±29% of control levels (n=9, P<0.01), without affecting the dominant frequency. Similarly, 50 µM caffeine boosted spontaneous gamma oscillations to 332±111% of control levels (n=9, P<0.05), whereas higher concentrations slightly reduced the effect. In some slices without noticeable activity caffeine induced gamma oscillations. The selective A₁ receptor antagonist 8-CPT (5 µM) boosted spontaneous gamma oscillations by 341±22% (n=6, P<0.01) times control levels,. Addition of 50 µM caffeine on top of 8-CPT-boosted spontaneous gamma caused a small reduction in gamma power, which could be mimicked by the selective A_2A receptor antagonist ZM241385 (50 nM). However ZM241385 alone had no significant effect. 8-CPT-boosted spontaneous gamma oscillations were resistant to the muscarinic receptor antagonist atropine (5 µM), discarding an A₁ receptor antagonist-induced increase in acetylcholine release (n=6). Intracellular recordings (n=3) showed that 8-CPT caused a 3-5 mV depolarisation, which was associated with a 5-10% increase in input resistance, suggesting the closure of a potassium conductance (O’Kane & Stone, 2004). However, the slow after-hyperpolarisation was not affected by 8-CPT. These observations indicate that selective A₁ receptor antagonists can induce and/or boost spontaneous gamma oscillations in CA3, by mediating a tonic postsynaptic depolarisation and are therefore potential candidates for cognition-enhancing treatment, especially in the elderly.