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TAAR1-Dependent and -Independent Actions of Tyramine in Interaction with Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

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TAAR1-Dependent and -Independent Actions of Tyramine in Interaction with Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition Biological Psychiatry Archival Report TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition Ioannis Mantas, Theodosia Vallianatou, Yunting Yang, Mohammadreza Shariatgorji, Maria Kalomoiri, Elva Fridjonsdottir, Mark J. Millan, Xiaoqun Zhang, Per E. Andrén, and Per Svenningsson ABSTRACT BACKGROUND: Monoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. METHODS: Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice. RESULTS: Both antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild- type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states. CONCLUSIONS: These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs. https://doi.org/10.1016/j.biopsych.2020.12.008 Monoamine oxidase (MAO) is a mitochondrial enzyme that to induce monoamine release in an amphetamine-like manner plays a pivotal role in the intracellular inactivation of throughaninteractionwithVMAT2(7,10–12). Tyramine is gener- monoaminergic neurotransmitters. MAO inhibitors (MAOIs) ated by the AADC (aromatic L-amino acid decarboxylase)– have long been used for the treatment of Parkinson’sdis- mediated decarboxylation of tyrosine and is mainly colocalized ease, major depressive disorder, and anxiety (1,2). In with DA in nigrostriatal neurons (6,7,12). Tyramine can be addition, polymorphisms in MAO genes have been associ- degraded by both MAO isoforms, but MAOB predominates in ated with schizophrenia and personality disorders (3–5). dopaminergic pathways. The literature focuses on the fact that There are two MAO enzyme isoforms, MAOA and MAOB, MAOI-induced elevations of tyramine mediate severe peripheral which differ in their substrate specificity: serotonin (5-HT) side effects (13). The so-called tyramine syndrome in MAOI- and norepinephrine (NE) are primarily broken down by treated patients is characterized by a life-threatening elevation of MAOA, while dopamine (DA) is degraded by both MAOA blood pressure after the ingestion of tyramine-rich foods (13). and MAOB (2). MAO inhibition results in the accumulation Specifically, the monoamine-releasing properties of tyramine of 5-HT, NE, and DA along with trace amines (TAs), such cause an NE efflux from the postganglionic sympathetic nerve as tyramine (2). terminals (13). There is comparatively sparse knowledge on the TAs have low concentration in biological fluids compared with regulation and role of tyramine in modulating effects of MAOIs in classical monoamines. Parkinson’s disease is associated with the brain. high tyramine plasma levels, while major depressive disorder TAARs are GPCRs (G protein–coupled receptors) that displays low urine levels of the same TA (6–9). Tyramine is known belong to the rhodopsin subclass A of the GPCR superfamily SEE COMMENTARY ON PAGE 2 16 ª 2020 Society of Biological Psychiatry. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Biological Psychiatry July 1, 2021; 90:16–27 www.sobp.org/journal ISSN: 0006-3223 Biological Tyramine, TAAR1, and MAO Psychiatry (14,15). There is evidence that TAARs display Gs,Gq, and G13 METHODS AND MATERIALS coupling; interestingly, this can occur with the TA localized intracellularly rather than on the surface membrane (16–19). In Animals addition to binding TAs, such as tyramine, TAAR1 is activated Adult male and female WT and TAAR1-KO animals (29) were by several classes of psychoactive agents employed for both housed in temperature- and humidity-controlled rooms (20C, therapeutic and recreational purposes, notably amphetamine, 53% humidity) with a 12-hour light/dark cycle and access to methamphetamine, and MDMA (methylenedioxymethamphet- food pellets and water ad libitum. amine) (6,20–22). TAAR1 is expressed in the stomach, pancreas, and, along with TAAR5, in limbic and periventricular Behavioral Tests areas of the brain (7,14,23). TAAR1 is enriched in mono- aminergic perikarya, such as the ventral tegmental area (VTA), Adult male and female mice were randomized according to substantia nigra pars compacta (SNc), dorsal raphe nucleus, genotype and treatment and tested by videotracking in the fi and the nucleus of the solitary tract; it is also present in the open eld test and forced swim test. All behavioral tests were prefrontal cortex, entorhinal cortex, hypothalamus, and performed during the light cycle by experimenters blinded to amygdala (24,25). VTA and dorsal raphe neurons show a the genotype and treatment. The equipment and detailed robust increase of spontaneous firing after application of the protocols are described in the Supplement. TAAR1 selective antagonist EPPTB and in TAAR1-knockout (KO) mice compared with wild-type (WT) mice, suggesting Drugs that TAAR1 exerts an inhibitory tone on the activity of dopa- TCP, clorgiline, and rasagiline mesylate were dissolved in saline – minergic and serotonergic neurons (26 28). Accordingly, solution. Desipramine and pargyline were dissolved in 10% TAAR1-KO mice display behavioral hypersensitivity and more dimethyl sulfoxide solution. These chemicals were purchased pronounced increases in extracellular levels of monoamines from Sigma-Aldrich (St. Louis, MO). Drugs were administered in projection regions such as the nucleus accumbens, stria- intraperitoneally (i.p.). EPPTB and tyramine (Sigma-Aldrich) were tum, and cortex on exposure to psychostimulants (24,27,29). administered locally during fast analytical sensing technology Conversely, agonist stimulation of TAAR1 blunts actions of (FAST) recordings of glutamate neurotransmission. psychostimulants (27). The above observations underpin in- terest in TAAR1 as a potential target for novel classes of medication treating depression (antagonists) or psychotic Intrastriatal 6-Hydroxydopamine Lesioning disorders (agonists). Many compounds, both selective and To selectively denervate nigrostriatal DA neurons, but to pro- multitarget, have been generated to this end (30), and tect NE neurons, mice were pretreated with 25 mg/kg desi- encouraging observations have been acquired in experi- pramine (i.p.; Sigma-Aldrich) and 5 mg/kg pargyline (i.p.; mental and clinical studies (31). Most recently, the combined Sigma-Aldrich), anesthetized, placed in a stereotaxic frame, TAAR1/5-HT1A receptor agonist SEP-363856 showed anti- and injected with 1 mL of 6-hydroxydopamine (6-OHDA) solu- psychotic activity in patients with schizophrenia (31,32). tion into the striatum of the right hemisphere. The detailed Should these observations be corroborated in larger trials, procedure is described in the Supplement. SEP-363856 would become the first non–dopamine D2 re- ceptor antagonist available for the treatment of schizophrenia MAO Activity Assay (31,32). Despite the abovementioned observations supporting Fresh-frozen forebrain tissue was homogenized and used for the physiological, etiological, and therapeutic significance isolation of crude mitochondrial fraction. The isolated mito- of tyramine and TAAR1s, knowledge remains limited. chondrial fraction was used for MAOA and MAOB activity fi Previous studies have examined the role of TAAR1 under quanti cation using an Amplex Red Monoamine Oxidase fi conditions in which the synthesis and metabolism of Assay Kit (Thermo Fisher Scienti c, Waltham, MA), as detailed tyramine have not been directly perturbed. Here, we in the Supplement. decided to examine effects of tyramine and TAAR1 under conditions in which the levels of tyramine are elevated by MALDI–Mass Spectrometry Imaging of means of MAO inhibition. Taking advantage of a recently Neurotransmitters and Metabolites fl developed uoromethylpyridinium-based matrix assisted Fresh-frozen brain tissue sections collected for MALDI–mass laser desorption/ionization (MALDI) imaging method (33), spectrometry imaging (MSI) were thaw-mounted on indium tin fi we visualized and quanti ed tyramine, along with other oxide–coated glass slides (Bruker Daltonics GmbH, Bremen, monoamines and metabolites, in the striatum of both WT Germany). For MALDI-MSI of neurotransmitters and metabolites, and TAAR1-KO mice, following MAO inhibition. Mice were on-tissue derivatization was performed
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