The serotonergic and noradrenergic systems of the hippocampus : their interactions and the effects of antidepressant treatments

Since the formulation of the monoaminergic hypotheses of depression, several investigations have established that the serotonin (5-HT) as well as the noradrenaline (NA) systems are altered by antidepressant treatments. In the last few years, several studies have indicated that interactions between these two systems might also be important in the mechanism of action of antidepressant drugs. We have thus undertaken: (1) to elucidate the nature of some interactions between the 5-HT and NA systems in the rat hippocampus using in vivo electrophysiology and in vitro superfusion techniques; and (2) to determine whether antidepressant treatments alter these interactions. It was found that NA tonically inhibits 5-HT neurotransmission via $ alpha sb2$-adrenergic heteroreceptors. In addition, the presence of 5-HT$ sb3$ receptors facilitating the release of NA was also documented in this brain region. These receptors were shown to be activated by elevated levels of endogenous 5-HT, but did not appear to be activated by basal levels of this neurotransmitter. Long-term administrations of antidepressant drugs commonly known to increase the synaptic concentration of NA, i.e. monoamine oxidase and NA reuptake inhibitors, were found to desensitize the $ alpha sb2$-adrenoceptors that inhibit the release of 5-HT. This effect was also produced by atypical antidepressant drugs that have $ alpha sb2$-adrenergic antagonist properties (e.g. mianserin and idazoxan), but not by other antidepressant treatments, (e.g. selective 5-HT reuptake inhibitors or electroconvulsive shocks). In contrast to $ alpha sb2$-adrenergic heteroreceptors, 5-HT$ sb3$ receptors that enhance the release of NA did not become desensitized following long-term treatments with drugs that elevate the synaptic concentration of their endogenous neurotransmitter. Rather, the responsiveness of these 5-HT$ sb3$ receptors became blunted following an antidepressant treatment (desipramine) that caused a large increase in the