Treatment of
apnea of prematurity with methylxanthines like
caffeine,
aminophylline or
theophylline can evoke hippocampal
seizures. However, it is unknown at which interstitial brain concentrations methylxanthines promote such neonatal
seizures or interfere with physiological 'early network oscillations' (ENOs) that are considered as pivotal for maturation of hippocampal neural networks. We studied
theophylline and
caffeine effects on ENOs in CA3 neurons (CA3-ENOs) and CA3 electrical stimulation-evoked monosynaptic CA1 field potentials (CA1-FPs) in sliced and intact hippocampi, respectively, from 8 to 10-days-old rats. Submillimolar doses of
theophylline and
caffeine, blocking
adenosine receptors and
phosphodiesterase-4 (PDE4), did not affect CA3-ENOs, ENO-associated cytosolic Ca(2+) transients or CA1-FPs nor did they provoke seizure-like discharges. Low millimolar doses of
theophylline (⩾1mM) or
caffeine (⩾5mM), blocking GABAA and
glycine receptors plus sarcoplasmic-endoplasmic reticulum Ca(2+)
ATPase (SERCA)-type Ca(2+)
ATPases, evoked seizure-like discharges with no indication of cytosolic Ca(2+) dysregulation. Inhibiting PDE4 with
rolipram or
glycine receptors with
strychnine had no effect on CA3-ENOs and did not occlude seizure-like events as tested with
theophylline. GABAA receptor blockade induced seizure-like discharges and occluded
theophylline-evoked seizure-like discharges in the slices, but not in the intact hippocampi. In summary, submillimolar
methylxanthine concentrations do not acutely affect spontaneous CA3-ENOs or electrically evoked synaptic activities and low millimolar doses are needed to evoke seizure-like discharges in isolated developing hippocampal neural networks. We conclude that mechanisms of
methylxanthine-related seizure-like discharges do not involve SERCA inhibition-related neuronal Ca(2+) dysregulation, PDE4 blockade or
adenosine and
glycine receptor inhibition, whereas
GABA(A) receptor blockade may contribute partially.