Abstract

It is known that long-term treatment with antidepressants induces an enhancement of neurotransmission in the pathway projecting from raphe nuclei to the hippocampus. In the case of selective serotonin (5-HT) reuptake inhibitors, this enhancement is due to a desensitization of presynaptic 5-HT autoreceptors and a concomitant increase in 5-HT release in terminal areas. To investigate whether this effect is accompanied by adaptive changes in the molecular machinery regulating transmitter release at serotonergic terminals, autophosphorylation and activity of Ca2+/calmodulin-dependent protein kinase II were measured in subsynaptosomal fractions from hippocampus and total cortex. Long-term treatment with two selective serotonin reuptake inhibitors (paroxetine and fluvoxamine) and with a nonselective reuptake inhibitor (venlafaxine) induces a large increase of kinase autophosphorylation in synaptic vesicles and synaptic cytosol in the hippocampus but not in synaptosomal membranes. No significant change was detected in total cortex. The change is not reproduced by the direct addition of the drugs to the phosphorylation system and is not elicited by acute treatment of the animals. The increase in autophosphorylation is not accounted for by neosynthesis or translocation of the kinase to synaptic terminals. The change is restricted to the kinase located inside the terminals and is not detected in synaptosomal membranes, containing predominantly postsynaptic kinase, suggesting that only presynaptic kinase is affected. In the same fractions, the kinase activity is increased. These results are in agreement with reports suggesting a presynaptic effect for the SSRIs and disclose a new putative site of action for psychotropic drugs.