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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