Regulation of monoaminergic functions by GPCRs with a special emphasis on mental and movement disorders

Dysfunction of the brain’s monoaminergic system has been implicated in many human neurological and psychiatric disorders, such as Parkinson’s disease (PD), major depressive disorder (MDD) and schizophrenia. The monoamines that are most dysregulated in these diseases, are dopamine and serotonin. Monoamines act as signalling molecules through their receptors, which belong predominately to the G-protein coupled receptor (GPCR) superfamily¹. Most of the clinically employed drugs that are used to tackle these diseases, target directly or indirectly the monoaminergic class of GPCRs. This thesis aims to identify the role of four understudied GPCR-signalling related molecules (GPR88, TAAR1, p11 and NURR1) in animal models of PD, MDD and schizophrenia.

The main findings relate to the functions of GPR88, TAAR1, p11 and NURR1 in relationship to PD, MDD and schizophrenia. GPR88 has been suggested as crucial suppressor of striatal medium spiny neuron activity. We showed that loss of GPR88 facilitates L- dihydroxyphenylalanine treatment for PD by aiding its therapeutic efficacy without worsening its side effects. TAAR1 has been described as negative regulator of dopamine neurons firing rate. Herein, we report that TAAR1 deletion enhances the response of non-selective monoamine oxidase inhibitors but no other classes of antidepressants. Furthermore, we provide evidence that the antipsychotic action of the pioneering drug, SEP-856, depends in part on TAAR1 agonism. P11 is a small GPCR-adaptor protein that has been linked to MDD and antidepressant treatment response. In the current thesis, we demonstrate that loss of p11 causes an overt response to stress by triggering the activity of hypothalamic-pituitary-adrenal and sympathetic-adrenomedullary axes. Finally, NURR1 is a GPCR regulated transcription factor, which is linked to PD and schizophrenia as a consequence of its fundamental role in coordinating midbrain dopamine neuron development. In the present work, we describe the role of NURR1 in extra-dopaminergic brain structures such as striatum and claustrum. In detail, we show that induced striatal NURR1 is crucial for locomotor sensitization to L-DOPA. Moreover, we revealed that NURR1 is important factor for claustral neuron transcriptional identity without affecting the occurrence of hallucinogen states’ neural correlates.

Overall, we explored new avenues in the fields of neurology and psychiatry related molecular neurobiology. These findings may support future drug discovery research on PD, MDD and schizophrenia though the identification of novel pharmaceutical agents to treat these detrimental disorders. Thus, this body of work contributes to the better understanding of both the pharmacology and pathophysiology of mental and movement disorders.

List of scientific papers

I. Mantas I, Yang Y, Mannoury-la-Cour C, Millan MJ, Zhang X, Svenningsson P. Genetic deletion of GPR88 enhances the locomotor response to L-DOPA in experimental parkinsonism while counteracting the induction of dyskinesia. Neuropharmacology. 162, 107829 (2020).
https://doi.org/10.1016/j.neuropharm.2019.107829

II. Mantas I, Vallianatou T, Yang Y, Shariatgorji M, Kalomoiri M, Fridjonsdottir E, Millan MJ, Zhang X, Andrén PE, Svenningsson P. TAAR1-Dependent and - Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition. Biol Psychiatry. 90, 16-27 (2021).
https://doi.org/10.1016/j.biopsych.2020.12.008

III. Mantas I, Millan MJ, Di Cara B, Groenink L, Veiga S, Cistarelli L, Brocco M, Bertrand M, Svenningsson P, Zhang X. Trace Amine-Associated Receptor 1 Contributes to Diverse Functional Actions of O-Phenyl-Iodotyramine in Mice but Not to the Effects of Monoamine-Based Antidepressants. Int J Mol Sci. 22, 8907 (2021).
https://doi.org/10.3390/ijms22168907

IV. Saarinen M, Mantas I, Flais I, Ågren R, Sahlholm K, Millan MJ, Svenningsson P. TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5HT1A receptor agonist SEP-383856. [Manuscript]

V. Sousa VC, Mantas I, Stroth N, Hager T, Pereira M, Jiang H, Jabre S, Paslawski W, Stiedl O, Svenningsson P. P11 deficiency increases stress reactivity along with HPA axis and autonomic hyperresponsiveness. Mol Psychiatry. 26, 3253- 3265 (2021).
https://doi.org/10.1038/s41380-020-00887-0

VI. Mantas I, Zhang X, Fridjonsdottir E, Saarinen M, Tiklova K, Gillberg L, Li T, Andrén PE, Perlmann T, Svenningsson P. NURR1 regulates the response of striatal D1-neurons to subchronic treatment of L-DOPA. [Manuscript]

VII. Mantas I, Flais I, Saarinen M, Tiklova K, Yaghmaeian Salmani B, Gillberg L, Ågren R, Sahlholm K, Zhang X, Perlmann T, Hengerer B, Svenningsson P. NURR1 is master-regulator of claustrum identity but not of hallucinogenic-like states. [Manuscript]