Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia

Wright, Alesia M; Bempong, Jeffrey; Kirby, Michael; Barlow, Rebecca; Bloomquist, Jeffrey R.

doi:10.1016/s0006-8993(97)01551-5

Cited by 77 publications

(49 citation statements)

References 15 publications

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“…Haloperidol treatment may be neurotoxic [25,83] which may explain the cortical GM volume reduction. In a very recent study, Konopaske et al [84] found a significant 20.5% reduction in astrocyte numbers and a non-significant 12.9% reduction in oligodendrocytes in antipsychotic-exposed macaque monkeys.…”

Section: Mechanisms Of Antipsychotic Action On Brain Structurementioning

confidence: 99%

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

Smieskova

Fusar‐Poli²,

Allen³

et al. 2009

CPD

186

131

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Abstract:Despite a large number of neuroimaging studies in schizophrenia reporting subtle brain abnormalities, we do not know to what extent such abnormalities reflect the effects of antipsychotic treatment on brain structure. We therefore systematically reviewed cross-sectional and follow-up structural brain imaging studies of patients with schizophrenia treated with antipsychotics. 30 magnetic resonance imaging (MRI) studies were identified, 24 of them being longitudinal and six cross-sectional structural imaging studies. In patients with schizophrenia treated with antipsychotics, reduced gray matter volume was described, particularly in the frontal and temporal lobes. Structural neuroimaging studies indicate that treatment with typical as well as atypical antipsychotics may affect regional gray matter (GM) volume. In particular, typical antipsychotics led to increased gray matter volume of the basal ganglia, while atypical antipsychotics reversed this effect after switching. Atypical antipsychotics, however, seem to have no effect on basal ganglia structure.

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Section: Mechanisms Of Antipsychotic Action On Brain Structurementioning

confidence: 99%

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

Smieskova

Fusar‐Poli²,

Allen³

et al. 2009

CPD

186

131

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“…Although ASP ϩ was transported well by both hNET and hDAT, it was transported poorly by the human serotonin transporter (hSERT) (29 -31). Therefore, we designed alternative fluorescent substrates of hSERT based on the structure of 1-methyl-4-phenylpyridinium (MPP ϩ ), a known monoamine transporter substrate that has high-affinity for transport by the catecholamine transporters (32)(33)(34). Although a fluorescent analog of MPP ϩ has been marketed, it was only tested as a reagent for high-throughput screening (28,35).…”

mentioning

confidence: 99%

4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP+) Is a Fluorescent Substrate for the Human Serotonin Transporter

Solís

Zdravkovic

Tomlinson

et al. 2012

Journal of Biological Chemistry

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Serotonin (5HT) 3 plays a role in the regulation of many behaviors (1, 2), and disturbances in the serotonergic system are implicated in a myriad of diseases (3-7). Following neurotransmission the serotonin transporter (SERT) clears 5HT from the synaptic cleft (8 -10). Numerous antidepressants such as fluoxetine or citalopram inhibit re-uptake of 5HT by SERT (11), and drugs of abuse, such as 3,4-methylenedioxymethamphetamine (MDMA) induce reverse 5HT transport through the transporter (12). SERT is a member of the solute carrier 6 gene family consisting of numerous ion-coupled co-transporters, such as the norepinephrine and dopamine transporters (13)(14)(15). These transporters use the Na ϩ ionic electrochemical potential to concentrate substrates against their concentration gradient (15-18). Traditionally, co-transport is described by the alternating access model where ions and substrate are transported with a fixed stoichiometry (19, 20); however, a competing model describes a channel within the transporter capable of conducing currents mediated by substrate and ions. These substrate-induced uncoupled currents are found in many neurotransmitter transporters (21-25). Additionally, in the absence of substrate, a constitutive leak current exists, which, for SERT, can be uncovered with inhibitors such as fluoxetine (25).Traditionally, monoamine transporter activity has been assessed by radiolabeled uptake assays; however, these biochemical assays have poor temporal resolution and do not yield spatial information of the transport process. Conversely, fluorescent substrates of monoamine transporters are advantageous tools to study mechanistic properties of SERT because they provide a continuous signal that can be measured with single live-cell imaging. In addition to the temporal and spatial advantages of fluorescent substrates, their use is amenable for high-throughput screening (27,28).Previously, we characterized 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP ϩ ) as a fluorescent reporter for uptake activity for both the human norepinephrine transporter (hNET) and the human dopamine transporter (hDAT) and utilized it to study biophysical properties of hNET such as substrate-protein stoichiometry and substrate dwell time (29,30).

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“…The narrow therapeutic index is associated with the frequent occurrence of extrapyramidal side effects including acute dystonic reactions, akathisia, Parkinsonism, and, following chronic treatment, tardive dyskinesias (TD) that are slow to develop and often irreversible (Wright et al, 1998). The persistence of TD in many patients after discontinuation of HP therapy suggests that this condition may be related to a neuronal lesion induced by HP or a reactive metabolite(s) derived from it.…”

mentioning

confidence: 99%

Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

Kalgutkar

Taylor²,

Venkatakrishnan³

et al. 2003

Drug Metab Dispos

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ABSTRACT:As a plausible explanation for the large interindividual variability in the pharmacokinetics of the neuroleptic agent haloperidol, the contributions of CYP3A isozymes (CYP3A4 and the polymorphic CYP3A5) predominantly involved in haloperidol bioactivation to the neurotoxic pyridinium species 4-(4- Although, the neuroleptic agent haloperidol [HP 1 , 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol] is one of the most widely used antipsychotic drugs, a narrow therapeutic index and a large interindividual and interracial variability in pharmacokinetics results in the requirement of individualized HP dose optimization (Ulrich et al., 1998). The narrow therapeutic index is associated with the frequent occurrence of extrapyramidal side effects including acute dystonic reactions, akathisia, Parkinsonism, and, following chronic treatment, tardive dyskinesias (TD) that are slow to develop and often irreversible (Wright et al., 1998). The persistence of TD in many patients after discontinuation of HP therapy suggests that this condition may be related to a neuronal lesion induced by HP or a reactive metabolite(s) derived from it.ChlorophenylHP is extensively metabolized in the liver with only ϳ1% of the administered dose excreted in the urine (Forsman et al., 1977). Major biotransformation pathways of HP in humans have been extensively characterized (see Kudo and Ishizaki, 1999 for a review) and are summarized in Fig. 1. These include 1) glucuronidation of the 3 0 alcohol moiety (Someya et al., 1992); 2) reduction of the carbonyl group by cytosolic carbonyl reductase, which leads to reduced HP (Eyles and Pond, 1992); 3) reverse oxidation of reduced HP back to HP (Pan et al., 1998); 4) N-dealkylation leading to the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP) (Fang et al., 2001); 5) dehydration of 3 0 alcohol moiety to 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP) (Subramanyam et al., 1991a;Van der Schyf et al., 1994) , 1997). In contrast to earlier studies (Llerena et al., 1992;Viala et al., 1996) that suggested the involvement of cytochrome P450 (P450) 2D6 in HP metabolism to CPHP, HPTP, and HPP ϩ , recent reports have indicated that these pathways are almost exclusively catalyzed by CYP3A4 (Usuki et al., 1996;Fang et al., 2001).In view of the neurotoxic properties of 1-methyl-4-phenylpyridinium (MPP ϩ ), the monoamine oxidase-B-generated metabolite of the Parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine , the identification of MPP ϩ -like HPP ϩ and RHPP ϩ metabolites in significant quantities in the urine (Subramanyam et al., 1991b), plasma (Avent et al., 1997, and post-mortem brain samples (Eyles et al., 1997) in schizophrenic patients treated with HP is of neurotoxicological importance especially in the pathogenesis of HP-induced TD. Additional support for this proposal is evident from the observations that HPP ϩ displays MPP ϩ -like neurotoxicity in vivo as well as in vitro (Bloomquist et al., 1994).Although glucuronidat...

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Effects of haloperidol metabolites on neurotransmitter uptake and release: possible role in neurotoxicity and tardive dyskinesia

Cited by 77 publications

References 15 publications

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP+) Is a Fluorescent Substrate for the Human Serotonin Transporter

Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

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