Selective regulation of presynaptic calcium/calmodulin-dependent protein kinase II by psychotropic drugs

Background: Changes in neuroplasticity have been involved in the pathogenesis of psychiatric disorders as well as in psychotropic drug action. Calcium/calmodulin-dependent protein kinase II (CaM kinase II), an enzyme with a pivotal role in synaptic plasticity and cognitive functions, has been implicated in the action of anticonvulsants, benzodiazepines, and antidepressants, but little is known as to its role in the action of different drugs employed for treatment of psychiatric disorders. Methods: We studied the function and expression of CaM kinase H following chronic treatment of rats with two antidepressants, fluvoxamine and desipramine, a typical antipsychotic drug, haloperidol, and the typical medication for manic-depressive disorder, lithium. Results: Antidepressants significantly increased the kinase activity in presynaptic vesicles of frontal/prefrontal cortex. Haloperidol induced no change, whereas lithium significantly decreased the activity. Kinase activation by antidepressants was further demonstrated by increased phosphorylation of exogenously added recombinant synaptotagmin. Immunoreactivity of vesicular kinase ((alpha-isoform) was significantly increased by reuptake blockers but not by the two other drugs. Kinetic analysis showed that limiting value of enzymatic velocity (Vmax) of the kinase for substrate was also increased by reuptake blockers and decreased by lithium; however, neither messenger ribonucleic acid nor protein expression level of the kinase was increased in frontal/prefrontal cortex homogenates of antidepressant-treated rats, suggesting the involvement of local synaptic mechanisms. Conclusions: These findings show that functional regulation of presynaptic CaM kinase II is selectively affected by different psychotropic drugs, and suggest local synaptic mechanisms for pharmacological regulation of the kinase.