PRESYNAPTIC CA2+ CALMODULIN-DEPENDENT PROTEIN-KINASE-II - AUTOPHOSPHORYLATION AND ACTIVITY INCREASE IN THE HIPPOCAMPUS AFTER LONG-TERM BLOCKADE OF SEROTONIN REUPTAKE/

It is known that long-term treatment with antidepressants induces an e nhancement of neurotransmission in the pathway projecting from raphe n uclei to the hippocampus. In the case of selective serotonin (5-HT) re uptake inhibitors, this enhancement is due to a desensitization of pre synaptic 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 subsynap tosomal fractions from hippocampus and total cortex. Long-term treatme nt with two selective serotonin reuptake inhibitors (paroxetine and fl uvoxamine) and with a nonselective reuptake inhibitor (venlafaxine) in duces a large increase of kinase autophosphorylation in synaptic vesic les and synaptic cytosol in the hippocampus but not in synaptosomal me mbranes. No significant change was detected in total cortex. The chang e is not reproduced by the direct addition of the drugs to the phospho rylation system and is not elicited by acute treatment of the animals. The increase in autophosphorylation is not accounted for by neosynthe sis or translocation of the kinase to synaptic terminals. The change i s restricted to the kinase located inside the terminals and is not det ected in synaptosomal membranes, containing predominantly postsynaptic kinase, suggesting that only presynaptic kinase is affected. In the s ame fractions, the kinase activity is increased. These results are in agreement with reports suggesting a presynaptic effect for the SSRIs a nd disclose a new putative site of action for psychotropic drugs.