European Review for Medical and Pharmacological Sciences 2021; 25: 4514-4519 Converging dopaminergic neurotoxicity mechanisms of antipsychotics, methamphetamine and levodopa

N. ZAREIFOPOULOS1, M. SKALTSA1, A. DIMITRIOU1, M. KARVELI1, P. EFTHIMIOU2, M. LAGADINOU2, A. TSIGKOU3, D. VELISSARIS4

1Department of Psychiatry, General Hospital of Nikea and Pireus Hagios Panteleimon, Patras, Greece 2Emergency Department, University General Hospital of Patras, Patras, Greece 3Department of Architecture, University of Patras School of Engineering, Patras, Greece 4Department of Internal Medicine, University of Patras School of Medicine, Patras, Greece

Abstract. – OBJECTIVE: Drugs affecting do- transmission may exert long-term effects which paminergic neurotransmission may exert toxic reverse slowly upon discontinuation, if at all. and beneficial effects that persist after discon- Until the nature of these changes is clear it tinuation by modulating gene expression in key would be best to utilize drugs which affect do- brain regions. Drug addiction, cravings and the paminergic neurotransmission cautiously espe- tardive symptoms associated with chronic expo- cially if prolonged treatment is required. sure to antipsychotics are among the most com- mon processes attributed to long-term dopami- Key Words: nergic neurotoxicity. The purpose of this review Akathisia, Aripiprazole, Dopamine agonist, Drug was to investigate the mechanisms of dopa- abuse, Haloperidol, L-DOPA, Tardive dyskinesia. minergic neurotoxicity induced by neuroleptic drugs, dopamine agonists, levodopa, stimulants and known dopaminergic neurotoxins MATERIALS AND METHODS: A PubMed Abbreviations search for each of the dopaminergic compounds in question was carried out. The heterogenous AC: adenyl cyclase, C1: Mitochondrial electron transfer nature of the relevant preclinical studies pre- chain complex 1, HPP+: Haloperidol phenylpyridinium cluded a systematic review, so a narrative re- ion, DAT: dopamine transporter, MPP+: 4-methyl-1-phe- view was carried out. nyl-pyrydinium ion, ROS: reactive oxygen species, RESULTS: The dopaminergic neurotoxins VMAT: vesicular monoamine transporter. 6-oxidopamine and 1-methyl-4-phenyl-tetrahy- dropyridine (MPTP) promote oxidative stress and inhibit mitochondrial function, while their Introduction affinity for the dopamine transporter ensures they are attain toxic intracellular concentrations exclusively in dopaminergic neurons. Stimu- Monoaminergic neurotransmission is of great lants which inhibit the vesicular monoamine clinical interest as it is implicated in the patho- transporter such as amphetamine and its de- physiology of multiple illnesses and underlies rivatives promote oxidative stress by greatly in- the mechanism of action of most drugs affecting creasing intracellular dopamine concentrations the central nervous system (CNS)1. Psychoactive and enabling dopamine autooxidation. Antipsy- chotics increase dopamine release and turnover drugs produce tolerance to their acute effects after by blocking autoinhibitory D2 receptors and constant exposure and in drugs for which a delayed lead to upregulation of post-synaptic D2 recep- response is the norm the mechanism leading to the tors. Dopamine agonists may slow the progres- development of tolerance may be more relevant to sion of Parkinson’s disease by reducing dopa- their therapeutic action than any acute effect2. mine turnover, but downregulation of D2 recep- Recently interest in the neurotoxicity of both tors may underlie their behavioural toxicity. CONCLUSIONS: Though the mechanisms therapeutic compounds and drugs of abuse has have not been completely elucidated yet, it been renewed in an attempt to understand the seems drugs which affect dopaminergic neuro- clinical implications of chronic exposure and

4514 Corresponding Author: Nicholas Zareifopoulos, MD; e-mail: [email protected] Antipsychotics, methamphetamine and levodopa dopaminergic neurotoxicity perhaps shed light on the pathophysiology of mitochondrial complex I, it tends to autooxidise neurodegenerative disease3. Adult neurogenesis is in high concentrations producing free radicals limited, so there is a valid concern that centrally in the process8. The compound 5,7-dihydroxy- active drugs may induce undesirable effects that tryptamine has the same effects in serotonergic persist long after discontinuation by inducing cell neurons. Its use in animals leads to behavioral death4. Objective of this review is to shed light on disinhibition and increased responses to stress9. the possible mechanisms underlying the neuro- Methamphetamine, a potent psychomotor stim- toxicity of dopaminergic drugs and their clinical ulant has been established as neurotoxic for all implications. monoaminergic neurons10. It is regarded as a monoamine releasing agent as it induces mono- amine release at the synaptic terminals in the ab- Materials and Methods sence of an action potential. It binds to the DAT, NET and SERT, activates the trace amine associ- A literature search was conducted on the ated receptor 1 (TAAR1), reversibly inhibits both PubMed database for each substance and drug isoforms of MAO and is a substrate of the vesic- class separately. The search returned 7846 ar- ular monoamine transporter (VMAT). Methylen- ticles. The heterogenous nature of the studies dioxymethamphetamine (MDMA) induces sero- precluded a systematic review, so this article is tonin release to an even greater extent and exerts structured as a narrative review of the available distinct psychological effects. Its interaction with preclinical evidence on the mechanisms underly- VMAT may be involved on both its neurotoxic- ing the neurotoxicity of dopaminergic drugs. ity and the intensity of its effects as it displaces monoamines from synaptic vesicles into the cyto- plasm, from where they are transported into the Results synaptic cleft by DAT and NET11,12. The extreme elevation in cytoplasmic dopamine concentration Mechanisms of appears to be responsible for its neurotoxic effect, Monoaminergic Neurotoxicity as in high concentrations dopamine may autooxi- Oxidative stress is the common pathway by dise non-enzymatically generating free radicals13. which selective neurotoxins destroy monoami- The depletion of neurotransmitters in the synapse nergic neurons. The most notorious of these is also contributes to post-acute adverse effects. It 1-methyl-4-phenyl-tetrahydropyridine (MPTP), is unclear whether neurotoxicity is a direct ex- which was discovered in the 1980s as a contami- tension of the pharmacological action of amphet- nant of a clandestinely synthesized opioid analog amines or if it occurs mostly as a consequence of of pethidine. Patients exposed to the drug devel- high dose binge use, as chronic administration of oped symptoms of Parkinson’s disease. The motor low doses is well tolerated. In vivo experiments in symptoms of Parkinson’s disease are attributed to other primates have demonstrated direct neuro- the loss of dopaminergic inputs from the substan- toxic effects with reduced DAT and tyrosine hy- tia nigra to the striatum that disinhibits move- droxylase expression following single high dose ment5. The syndrome induced by MPTP was exposure and cell death has been observed with irreversible but treatable with levodopa. It was the addition of a high concentration of metham- subsequently discovered that MPTP was trans- phetamine and other monoamine releasing agents ported into dopamine neurons by the dopamine to medium14. Monoamine releasing agents with transporter (DAT), where it is oxidized by mono- no affinity for the VMAT do not appear to be amine oxidase B (MAO-B) into a pyridinium neurotoxic even though they have similar subjec- cation (MPP+). MPP+ functions as a mitochon- tive effects15. Efavirenz may function similarly to drial toxin by inhibiting complex I of the electron MDMA and methamphetamine while also direct- transport chain thus greatly increasing oxida- ly interacting with serotonin receptors; it has not tive stress. Inhibition of either MAO-B or DAT been proven to be neurotoxic either16. during exposure prevents the effect of MPTP6,7. MPTP is considered a selective dopaminergic neu- Clinical Syndromes of Monoaminergic rotoxin and the phenotype it produces is consid- Neurotoxicity ered a valid animal model of Parkinson’s disease. As dopamine is a particularly reactive sub- 6-hydroxydopamine is another substance used stance which promotes oxidative stress in exces- for the same purpose. Apart from inhibiting the sive concentrations, it has been hypothesised that

4515 N. Zareifopoulos, M. Skaltsa, A. Dimitriou, M. Karveli, et al drugs which increase dopamine turnover are neu- serious and potentially irreversible sequelae31. rotoxic while those reducing dopamine turnover Therapeutic use of levodopa leads to peak dose are neuroprotective17. The first dopamine agonists dyskinesias once the drug attains its maximal were ergot derivatives which were also non-se- concentration which gives way to bradykinesia lective serotonin agonists. The current first line until the next dose is given17,32. This may be a agents, pramipexole and ropinirole are relatively consequence of disease progression or it may be selective for D2 and D3. These also function as indicative of a downstream compensatory mech- presynaptic inhibitory autoreceptors, the activa- anism33. Abrupt discontinuation of levodopa (typ- tion of which hyperpolarizes the dopaminergic ically iatrogenic) may manifest with psychiatric neuron and prevents dopamine release18,19. D2 apart from motor symptoms. A clinical presen- agonists decrease dopamine release and turn- tation similar to neuroleptic malignant syndrome over, a property which may be neuroprotective. has been associated with levodopa, dopamine ag- It may also contribute to their adverse effects, onist and irreversible MAO inhibitor discontinua- as initiation of treatment may be accompanied tion33-35. Dopamine agonists promote behavioural by dysphoria. MAO-B inhibitors (selegiline and addictions which may persist after cessation and a rasagiline) may be of use in Parkinson’s dis- withdrawal syndrome characterized by depressed ease both by increasing the availability of dopa- mood, agitation and anxiety has been report- mine and reducing the formation of free radicals ed36,37. A similar mechanism may underlie the during the oxidation of dopamine by MAO-B6,20. phenomenon of augmentation in restless leg syn- Antipsychotic drugs are D2 antagonists, affect- drome, in which treatment with a single PM dose ing dopamine turnover in the opposite manner of a dopamine agonist leads to the development of D2 agonists. Treatment initiation leads to of symptoms earlier during the day38. The tar- disinhibition of dopamine release and increase dive dyskinesia syndrome has been definitively of dopamine synthesis21,22. Euphoria has been linked to long term exposure to D2 antagonists31. reported with acute exposure to haloperidol Striatal D2 upregulation may enable dopamine which gives rise to extrapyramidal symptoms to exert supraphysiological responses even when and dysphoria over a few hours as dopamine the receptors are saturated. Supersensitivity to is depleted23. Antipsychotics may be transferred dopamine may underlie rebound psychosis upon into the synaptic vesicles, suggesting they could neuroleptic discontinuation and has been linked cause dopaminergic neurotoxicity in a manner to behavioural addictions and drug abuse39. similar to methamphetamine as well24. Butyro- phenones such as haloperidol are metabolized Pharmacokinetic Considerations to pyridinium metabolites in the liver, which The CNS toxicity of drugs is contingent upon are introduced into the brain by active trans- their ability to penetrate the blood brain barrier port and are concentrated in dopaminergic neu- (BBB) if they are administered peripherally. rons by binding to neuromelanin25. It has been Oxidopamine and 5,7-dHT do not cross the BBB hypothesised that these compounds may have so they are utilized in research by direct ad- similar toxicity to the pyridinium metabolite of ministration into the CNS or in cell cultures8,9. MPTP26. This has not been conclusively proven, MPTP does cross the BBB where it acts as a and one study27 suggested that haloperidol itself prodrug for the toxic MPP+ ion. The toxic moi- is more neurotoxic than its metabolites (Figure ety itself as a charged molecule is not expected 1)28. The concentration of these metabolites has to cross the BBB if administered peripherally6,7. however been correlated with the incidence of Antipsychotic drugs all cross the BBB readily tardive dyskinesia and akathisia29. Long term apart from benzamides (such as amisulpride exposure to antipsychotics has been associated and sulpiride), with brain concentrations far with diminished cortical volume, but it is un- exceeding those measured in blood plasma. The clear whether this can be attributed to the loss of half-life of individual drugs varies though it dopaminergic inputs from the ventral tegmental commonly exceeds 20 hours enabling once daily area. High concentrations of antipsychotic drugs dosing. As hydrophobic molecules they undergo added to medium lead to neuronal axon damage oxidative metabolism to inert forms in the liv- and cell death within days, but it is not clear er mediated by the cytochrome P450 enzymes whether this reflects their toxic action in vivo30. and the metabolites are subsequently conjugated Chronic exposure to antipsychotics, dopamine for biliary excretion40,41. Levodopa is an ami- agonists and levodopa has been associated with no-acid which is actively transported across

4516 Antipsychotics, methamphetamine and levodopa dopaminergic neurotoxicity

Figure 1. Schematic representation of the action of haloperidol, methamphetamine (METH) and MPTP (4-methyl- 1phenyl-tetrahydropyridine) in a dopaminergic synapse. Dopamine agonists have the opposite action of haloperidol, thus they downregulate D2 receptors and reduce dopamine synthesis and release. MAO (monoamine oxidase) inhibitors such as selegiline may be neuroprotective as they prevent the oxidation of dopamine which may lead to oxidative stress and also reduce dopamine turnover. the BBB and the intestinal wall by amino acid Conclusions transporters where it is decarboxylated to form dopamine. Half-life is 2-3 hours and it is always Neuronal cell death as a result of the direct administered alongside a peripheral DOPA de- influence or withdrawal of a psychotropic drug carboxylase inhibitor to limit peripheral conver- usually underlies the irreversible effects that may sion, thus minimising side effects and enabling be observed. Excitotoxicity is the mechanism a larger dose to reach the CNS17,32. Dopamine of neuronal cell death during epileptic seizures agonists utilized in the treatment of Parkinson’s and withdrawal of benzodiazepines or alcohol43, disease cross the BBB though bioavailability significantly contributing to the development of varies, and with half-lives ranging from 6-14 dementia44. It is not clear whether cell death is hours twice or thrice daily dosing is optimal42. implicated in the toxic effects of dopaminergic Methamphetamine and MDMA cross the BBB drugs but further research and extreme caution and undergo oxidative metabolism in the liver in their clinical use is required. We would rec- to amphetamine and MDA initially which are ommend against daily use of such agent unless similarly active and subsequently to inactive absolutely indicated (as in the treatment of Par- metabolites. A half-life of 5 hours for MDMA kinson’s disease). Indirectly acting drugs (includ- and 8-12 hours for methamphetamine coincides ing dopamine reuptake inhibitors and releasing largely with the duration of their effects13. agents) may be safer over the long term than sub-

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