The entorhinal cortex is a highly seizure-prone region of the limbic system. Removal of Mg²⁺ from the perfusate surrounding entorhinal cortex slices generates spontaneous seizure-like events (SLEs) that develop into continuous epileptiform activity resembling status epilepticus (Zhang et al. 1995). Here we show that the inhibitory actions of the endogenous neuromodulator adenosine (Dunwiddie, 1999) can reverse the development of this latter type of continuous epileptiform activity.

Horizontal combined hippocampal entorhinal cortex slices (500 µm thick) were prepared from humanely killed female Wistar rats (~200 g). Wedges of the entorhinal cortex (2-3 mm wide) were transferred to a two-compartment chamber that was continuously perfused (2-2.5 ml min^-1) with a solution containing (mM): NaCl 135, KCl 3, NaH₂PO₄ 1.25, MgCl₂ 1, CaCl₂ 2, glucose 10 and NaHCO₃ 26, pre-equilibrated with 95 % O₂-5 % CO₂ at room temperature. Withdrawal of Mg²⁺ led to the appearance of repetitive SLEs. Drugs were applied via the perfusate and changes in frequency and duration of the SLEs were measured before and after drug application. Values stated are means ± S.E.M.

Adenosine (10 µM) reduced the frequency of SLEs by 28 ± 4 % (n = 36, P < 0.001, Student’s paired t test), whereas the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 10 nM) increased the frequency of the events dramatically by 515 ± 79 % (n = 12, P < 0.001, paired t test) and converted the SLEs to a pattern of continuous epileptiform activity. In approximately 10 % of the slices SLEs spontaneously converted to a similar type of continuous pattern, with a mean change in frequency of 1351 ± 276 % (n = 13, P < 0.001, paired t test). Adenosine (30 µM), reversed this activity back to SLEs with a clear frequency reduction of 69 ± 3 % (n = 4, P < 0.01, paired t test). Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 1 µM), an adenosine deaminase inhibitor that increases extracellular adenosine levels, exerted a similar reversal, reducing the frequency of the continuous activity by 63 ± 8 % (n = 5, P < 0.05, paired t test) whilst DPCPX (0.1 µM) had no significant effect (n = 5).

Our results suggest that endogenous adenosine normally released during SLEs prevents the transition to a continuous pattern of epileptiform activity and that spontaneous transitions may be favoured when adenosine levels become depleted.

We acknowledge the support of the Epilepsy Research Foundation, UK.