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

Brain Research
A M WrightJ Bloomquist

Abstract

This research explored the effects of haloperidol (HP) metabolites on biogenic amine uptake and release, and compared them to those of MPTP and its toxic metabolite, MPP+. In synaptosome preparations from mouse striatum and cortex, the HP metabolites haloperidol pyridinium (HPP+), reduced haloperidol pyridinium (RHPP+), and haloperidol tetrahydropyridine (HPTP) inhibited the presynaptic uptake of dopamine and serotonin, with greater affinity for the serotonin transporter. HPP+ was the most potent inhibitor of dopamine uptake, and HPTP of serotonin uptake, both with IC50 values in the low micromolar range. RHPP+ was less active than the other metabolites, but was more active than the parent compound, HP. Inhibition of uptake was reversed when free drug was removed by centrifugation and then resuspension of the synaptosomes in fresh buffer, suggesting that inhibition of uptake was due to interaction with the transporters and was not due to irreversible cytotoxicity. HPP+ showed noncompetitive inhibition of both serotonin and dopamine uptake, suggesting that it has a relatively slow dissociation rate for its interaction with the transporter proteins. In experiments on amine release, HPP+ and HPTP were four-fold less potent than MP...Continue Reading

Citations

Feb 1, 2012·The Journal of Biological Chemistry·Ernesto SolisLouis J De Felice
Aug 30, 2020·Basic & Clinical Pharmacology & Toxicology·Ekramy ElmorsySoad Mosad
Jan 11, 2003·British Journal of Pharmacology·Stefania RuiuLuca Pani
Oct 10, 2008·Cerebral Cortex·Paul M ThompsonUNKNOWN HGDH Study Group
Jun 30, 2009·Schizophrenia Bulletin·P E RasserP M Thompson
Feb 14, 2013·Experimental and Therapeutic Medicine·Jaromir GumulecMichal Masarik
May 16, 2002·British Journal of Pharmacology·Pattipati S NaiduShrinivas K Kulkarni
Aug 15, 2013·Journal of Molecular Neuroscience : MN·Karamkolly R RekhaRamu Inmozhi Sivakamasundari
Oct 19, 2016·Neurochemical Research·Tafheem MalikDarakhshan Jabeen Haleem
Mar 8, 2005·Drug Metabolism Reviews·Shufeng ZhouYu-Zong Chen
Oct 21, 1999·European Journal of Pharmacology·I E De SouzaG E Meredith
Jan 25, 2003·Pharmacology, Biochemistry, and Behavior·Pattipati S NaiduShrinivas K Kulkarni
May 15, 2007·Pharmacology, Biochemistry, and Behavior·Darakhshan Jabeen HaleemMuhammad Abdul Haleem
Feb 9, 2017·ACS Chemical Neuroscience·Marshall W TylerStephen J Haggarty
May 14, 2008·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·C L Dalla CorteJ B T Rocha
Aug 18, 2010·Journal of Neuroscience Methods·Catherine E HaganJames O Schenk

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.