Persistence of Haloperidol in Human Brain Tissue

Kornhuber, Johannes; Schultz, Andreas; Wiltfang, Jens; Meineke, Ingolf; Gleiter, Christoph H.; Zöchling, Robert; Boissl, K.; Leblhuber, Friedrich; Riederer, Peter

doi:10.1176/ajp.156.6.885

Cited by 131 publications

(58 citation statements)

References 35 publications

(48 reference statements)

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“…Consequently, the final concentration of drug in the animals is likely to be much lower than the concentrations present on the NGM plates. Nonetheless, all three of these drugs inhibited nuclear localization of DAF-16::GFP at concentrations equivalent to those required to antagonize dopamine receptors in C. elegans under identical conditions (36) and similar to those reached with accumulation in tissues including the human brain (37,38). Thus, stimulation of Akt signaling and antagonism of dopamine receptors occur in the same concentration range in this species.…”

Section: Resultsmentioning

confidence: 55%

Antipsychotic Drugs Activate the C. elegans Akt Pathway via the DAF-2 Insulin/IGF-1 Receptor

Weeks

Dwyer

Aamodt

2010

ACS Chem. Neurosci.

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The molecular modes of action of antipsychotic drugs are poorly understood beyond their effects at the dopamine D2 receptor. Previous studies have placed Akt signaling downstream of D2 dopamine receptors, and recent data have suggested an association between psychotic illnesses and defective Akt signaling. To characterize the effect of antipsychotic drugs on the Akt pathway, we used the model organism C. elegans, a simple system where the Akt/forkhead box O transcription factor (FOXO) pathway has been well characterized. All major classes of antipsychotic drugs increased signaling through the insulin/Akt/FOXO pathway, whereas four other drugs that are known to affect the central nervous system did not. The antipsychotic drugs inhibited dauer formation, dauer recovery, and shortened lifespan, three biological processes affected by Akt signaling. Genetic analysis showed that AKT-1 and the insulin and insulin-like growth factor receptor, DAF-2, were required for the antipsychotic drugs to increase signaling. Serotonin synthesis was partially involved, whereas the mitogen activated protein kinase (MAPK), SEK-1 is a MAP kinase kinase (MAPKK), and calcineurin were not involved. This is the first example of a common but specific molecular effect produced by all presently known antipsychotic drugs in any biological system. Because untreated schizophrenics have been reported to have low levels of Akt signaling, increased Akt signaling might contribute to the therapeutic actions of antipsychotic drugs.

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Section: Resultsmentioning

confidence: 55%

Antipsychotic Drugs Activate the C. elegans Akt Pathway via the DAF-2 Insulin/IGF-1 Receptor

Weeks

Dwyer

Aamodt

2010

ACS Chem. Neurosci.

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“…Furthermore, haloperidol concentrations in the range between 8.9 and 226 mM have been shown in human post-mortem brain tissue. 49 In conclusion, various types of neuroleptics at therapeutic concentrations act as noncompetitive antagonists at the 5-HT 3 receptor. This effect, therefore, may contribute to the antipsychotic efficacy of such compounds and may constitute a not yet recognized pharmacological principle of neuroleptics.…”

Section: Discussionmentioning

confidence: 95%

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

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The serotonin type 3 (5-HT 3 ) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT 3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT 2 ) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT 3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na þ -inward currents through 5-HT 3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT 3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca 2 þ influx, measured as a change in intracellular Ca 2 þ concentrations ([Ca 2 þ ] i ). All neuroleptic drugs, but not risperidone, antagonized Na þ -and Ca 2 þ -inward currents evoked by 5-HT (10 lM for 2 s and 1 lM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC 50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT 3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na þ and Ca 2 þ currents. Since 5-HT 3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT 3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

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“…This scenario may well reflect our human data, as antipsychotic drugs were detectable in only two patients at the time of autopsy. Given a 6.8-week half-life of haloperidol in the human brain (Kornhuber et al, 1999), it seems that many patients were not taking medications for a number of weeks before death. The effects of clozapine seemed to be limited to increasing VAMP levels; SNAP-25 was unchanged.…”

Section: Antipsychotic Drug Effectsmentioning

confidence: 99%

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

Barakauskas

Beasley

Barr

et al. 2010

Neuropsychopharmacol

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Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of proteinprotein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein-protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P ¼ 0.015) and syntaxin was 26% lower (P ¼ 0.006) in the VMC. In contrast, in the same region, SNARE protein-protein interactions were higher in schizophrenia (P ¼ 0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P ¼ 0.003), syntaxin (mean 18%, P ¼ 0.010), and VAMP (mean 16%, P ¼ 0.001), whereas clozapine increased only the VAMP level (mean 13%, P ¼ 0.004). Neither drug altered SNARE protein-protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.

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Persistence of Haloperidol in Human Brain Tissue

Cited by 131 publications

References 35 publications

Antipsychotic Drugs Activate the C. elegans Akt Pathway via the DAF-2 Insulin/IGF-1 Receptor

Antipsychotic Drugs Activate the C. elegans Akt Pathway via the DAF-2 Insulin/IGF-1 Receptor

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

A Novel Mechanism and Treatment Target for Presynaptic Abnormalities in Specific Striatal Regions in Schizophrenia

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