Facilitation of spontaneous glutamate release by antidepressant drugs in rat locus coeruleus

The effects of antidepressant drugs on spontaneous excitatory postsynaptic currents (EPSCs) were investigated in the mechanically dissociated rat locus coeruleus (LC) neurons which had their presynaptic nerve terminals attached. The membrane currents were recorded by the whole-cell patch-clamp technique. Desipramine, a tricyclic antidepressant, reversibly and concentration- dependently increased the frequency of spontaneous EPSCs, but did not alter their amplitude distribution. The inhibitors of high-voltage-activated Ca ²⁺ channels failed to block the facilitatory action of desipramine, while they inhibited the high K ⁺-induced facilitation of spontaneous EPSC frequency. The desipramine action was also observed in the absence of extracellular Ca ²⁺. Pretreatment of thapsigargin in Ca ²⁺-free solution fully inhibited the desipramine action, thus suggesting the involvement of Ca ²⁺ release from intracellular Ca ²⁺ stores at glutamatergic presynaptic nerve terminals. Imipramine and nortriptyline, other tricyclic antidepressants, and amoxapine, mianserin and fluoxetine, non-tricyclic antidepressants, also increased the EPSC frequency, while tranylcypromine, an inhibitor of monoamine oxidase, did not increase the glutamate release. The present results indicate that modulation of spontaneous glutamatergic transmission by tricyclic- and non-tricyclic-antidepressant drugs may regulate the excitability of LC neurons.