Presynaptic alpha2-adrenoceptors control excitatory, but not inhibitory, transmission at rat hippocampal synapses

1. The effects of noradrenaline on neurotransmission at rat hippocampal synapses were investigated by recording autaptic currents in single neurons isolated on glial microislands. Noradrenaline reduced excitatory, but not inhibitory, autaptic currents in a pertussis toxin-sensitive manner, but the amine did not affect glutamate-evoked currents. 2. The inhibition of excitatory autaptic currents by noradrenaline was half-maximal at 0. 11 +/- 0.06 microM. The alpha2-adrenoceptor agonists UK 14 304 and clonidine were equipotent to noradrenaline in reducing these currents, whereas the alpha1-adrenoceptor agonist methoxamine and the beta-adrenoceptor agonist isoprenaline (isoproterenol) were ineffective. The reduction of excitatory autaptic currents by noradrenaline was not altered by the alpha1-adrenergic antagonist urapidil or the beta-antagonist propranolol, but reduced by the alpha2-antagonist yohimbine. The subtype-preferring antagonists rauwolscine and phentolamine (both at 0.3 microM) caused 9-fold and 36-fold rightward shifts in the concentration-response curve for the noradrenaline-dependent reduction of excitatory autaptic currents, respectively. Prazosine (1 microM) did not affect this concentration-response curve. 3. Noradrenaline reduced voltage-activated Ca2+ currents in excitatory, but not in inhibitory, microisland neurons. For comparison, the GABAB agonist baclofen reduced both excitatory and inhibitory autaptic currents and diminished voltage-activated Ca2+ currents in both types of neurons. The inhibition of Ca2+ currents by noradrenaline was half-maximal at 0.17 +/- 0.05 microM, and UK 14 304 and clonidine were equipotent to noradrenaline in reducing these currents. The noradrenaline-induced reduction of Ca2+ currents was antagonized by yohimbine, but not by urapidil or propranolol; the subtype-preferring alpha2-adrenergic antagonists displayed the following rank order of activity: phentolamine > rauwolscine > prazosine. 4. Noradrenaline did not affect K+ currents and failed to alter the frequency of miniature excitatory postsynaptic currents measured in mass cultures of hippocampal neurons. 5. These results show that noradrenaline regulates transmission at glutamatergic, but not at GABAergic, hippocampal synapses via presynaptic alpha2-adrenoceptors of the alpha2A/D subtype. This inhibitory action involves an inhibition of voltage-activated Ca2+ currents, but no modulation of spontaneous vesicle exocytosis or of voltage-activated K+ currents.