Writing in Neuron that antipsychotics’ “functional consequences and the subcellular sites of their accumulation in nervous tissue have remained elusive,” researchers from Germany and Denmark find that antipsychotics accumulate in synaptic vesicles where, having reached sufficient concentration, are expelled into synaptic spaces when neurons are excited. The authors theorize that this period of accumulation accounts for “the slow development of the full therapeutic action of the drugs” which theoretically occurs within the same 4-6 week time range.
Tischbirek, C. Wenzel, E. et. al; “Use-Dependent Inhibition of Synaptic Transmission by the Secretion of Intravesicularly Accumulated Antipsychotic Drugs,” Neuron, released online June 7, 2012
Sanders, L. “Why Antipsychotics Need Time to Kick In,” Science News, June 6, 2012
Morton, A. Cousin, M; “The Best Things Come in Small Packages– Vesicular Delivery of Weak Base Antipsychotics,” Neuron, released online June 6, 2012
Note from Kermit Cole, “In the News” editor:
I have always found the search for an explanation for psychotropics’ supposed 4-6 week lag between the immediate and “therapeutic” effects interesting. I think that this has not, in fact, been the experience of many people and that, when it has, there are explanations other than merely physiological ones that could explain what occurs during this time. With some trepidation, I look forward to ideas that may explain what this study attempts to explain.
In the hope of a lively discussion, I am pasting the study’s discussion section and concluding remarks below.
During treatment, APDs and other psychotropic drugs accumulate in the brains of patients. In the present work, we studied the subcellular localization of APD accumulation in acidic organelles and identified functional consequences of this phenomenon. We demonstrated that accumulated APDs are secreted from synaptic vesicles upon exocytosis, leading to increased extracellular drug concentrations during neuronal activity. The secretion of APDs in turn was able to inhibit synaptic transmission in a use-dependent manner.
Increase of Extracellular Concentrations by Activity-Dependent Secretion of APDs
We found that synaptic transmission as measured by synaptic vesicle exocytosis was reduced by APDs in low micromolar concentrations. This concentration range raised our concerns because it has been convincingly demonstrated that the clinical efficacy of APDs correlates with effects observed for nanomolar concentrations (Seeman et al., 1976). Additionally, APDs acutely inhibit sodium channels in low micromolar concentrations (Figure 6), which in previous work were found unlikely to be achieved extracellularly during APD therapy (Baumann et al., 2004). Thus, instead of therapeutic benefits, continuously present micromolar APD concentrations were related mainly to side effects of the drugs (Ogata et al., 1989).
A major part of our study was, therefore, devoted to demonstrate that the accumulation of APDs in synaptic vesicles (Table 1; Figures 1 and 2) results in high APD concentrations within these confined compartments. Upon activity, synapses release their micromolar APD content into the synaptic cleft (Figure 3). We confirmed the activity-dependent release by in vitro fluorescence microscopy and in vivo data from experiments with freely moving rats treated with HAL. The released APDs have an inhibitory effect on signal propagation by promoting sodium channel inactivation (Figures 6 and 7). Even the extracellular HAL concentrations in the nanomolar range were sufficient to exert a use-dependent inhibitory action under prolonged stimulation (Figures 6 and 7). Accordingly, APD concentrations inhibiting sodium channels are likely to be reached at least locally during neuronal activity. 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.
Potential Implications of APD Accumulation and Secretion Affecting the Understanding of Therapeutic Actions of APDs
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 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 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 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. Although we found more pronounced inhibitory effects of APDs in striatal tissue (Figure 7), which hosts the receptors that bind the drugs in nanomolar concentrations (in this case DA receptors), our current results are limited with respect to other substance classes or synapse types. It will therefore be interesting to investigate the autoinhibitory effects of psychotropic drugs accumulated in synaptic vesicles on specific network activity profiles within cortical (Goto et al., 2010) and subcortical (Kellendonk, 2009) pathways as well as various neurotransmitter systems (Lisman et al., 2008), especially DA signaling, and differential effects of other classes of psychotropic drugs (Sulzer, 2011).
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