Overall, both inhibition of sodium channels and activity-dependent secretion contribute to the use-dependent action of the drugs. The present work, thus, suggests a mechanism wherein the presence of APDs in synaptic vesicles results in increased extracellular APD concentrations upon neuronal activity, leading to autoinhibitory feedback on synaptic

transmission. While the therapeutic effect of APDs starts soon after application, it usually reaches its maximum after 4–6 weeks (Agid et al., 2003; Leucht et al., 2005). The effects on synaptic transmission reported here, which are based on the accumulation of the drugs, might contribute to the slow development of the full therapeutic action of the drugs because tissue accumulation occurs within the same time range (Kornhuber et al., 1999). Accordingly, accumulation and secretion Enzalutamide molecular weight effects could explain the beneficial effects of electroconvulsive therapy (ECT) during APD treatment, which are not observed when ECT is performed without APD therapy (Falkai et al., 2005). In light of our findings (Figures 3 and 4), the concentration of APDs available locally is likely to be increased Selleckchem GDC 0068 acutely upon ECT-induced seizures. Physiologically, precisely mediated negative

feedback inhibition of neocortical pyramidal cells is necessary for the generation of synchronized high-frequency oscillations, which are related to attention and perception, and whose disturbance has been linked to the pathophysiology of schizophrenia (Uhlhaas and Singer, 2010). Such a deficit in synchronization

has, for example, been found in psychotic patients prior to antipsychotic Parvulin treatment (Gallinat et al., 2004) and chronically ill patients (Ferrarelli et al., 2010; Uhlhaas et al., 2006). The autoinhibition of synaptic transmission described here by the secretion of accumulated APDs could be beneficial to the generation of synchronized neuronal oscillations in schizophrenia. Our data underline the importance of measuring the neuronal oscillation patterns of unmedicated patients, or patients free of symptoms after sufficient antipsychotic therapy and in an already accumulated drug state. If the secretion of APDs and the associated selective modulation of synaptic transmission were important for the treatment of schizophrenia, then one could further speculate that an enriched environment (Oshima et al., 2003; Tost and Meyer-Lindenberg, 2012) is useful for patients under medication, whereas it would harm the psychotic, not yet treated patient. Taken together, our study proves the concept of APD accumulation first suggested by Rayport and Sulzer (1995) and defines synaptic vesicles as organelles that exert accumulation- and use-dependent inhibitory functional effects.