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Impact of insulin and insulin resistance on brain dopamine signalling and reward processing – An underexplored mechanism in the pathophysiology of depression?
2023, Neuroscience and Biobehavioral ReviewsType 2 diabetes and major depressive disorder (MDD) are the leading causes of disability worldwide and have a high comorbidity rate with fatal outcomes. Despite the long-established association between these conditions, the underlying molecular mechanisms remain unknown.
Since the discovery of insulin receptors in the brain and the brain’s reward system, evidence has accumulated indicating that insulin modulates dopaminergic (DA) signalling and reward behaviour. Here, we review the evidence from rodent and human studies, that insulin resistance directly alters central DA pathways, which may result in motivational deficits and depressive symptoms. Specifically, we first elaborate on the differential effects of insulin on DA signalling in the ventral tegmental area (VTA) - the primary DA source region in the midbrain - and the striatum as well as its effects on behaviour. We then focus on the alterations induced by insulin deficiency and resistance. Finally, we review the impact of insulin resistance in DA pathways in promoting depressive symptoms and anhedonia on a molecular and epidemiological level and discuss its relevance for stratified treatment strategies.
The substantia nigra in the pathology of schizophrenia: A review on post-mortem and molecular imaging findings
2023, European NeuropsychopharmacologyDysregulation of striatal dopamine is considered to be an important driver of pathophysiological processes in schizophrenia. Despite being one of the main origins of dopaminergic input to the striatum, the (dys)functioning of the substantia nigra (SN) has been relatively understudied in schizophrenia. Hence, this paper aims to review different molecular aspects of nigral functioning in patients with schizophrenia compared to healthy controls by integrating post-mortem and molecular imaging studies. We found evidence for hyperdopaminergic functioning in the SN of patients with schizophrenia (i.e. increased AADC activity in antipsychotic-free/-naïve patients and elevated neuromelanin accumulation). Reduced GABAergic inhibition (i.e. decreased density of GABAergic synapses, lower VGAT mRNA levels and lower mRNA levels for GABAA receptor subunits), excessive glutamatergic excitation (i.e. increased NR1 and Glur5 mRNA levels and a reduced number of astrocytes), and several other disturbances implicating the SN (i.e. immune functioning and copper concentrations) could potentially underlie this nigral hyperactivity and associated striatal hyperdopaminergic functioning in schizophrenia. These results highlight the importance of the SN in schizophrenia pathology and suggest that some aspects of molecular functioning in the SN could potentially be used as treatment targets or biomarkers.
Anticancer efficacy of endo- and exogenous potent ligands acting at dopaminergic receptor-expressing cancer cells
2022, European Journal of PharmacologyCancer is one of the most common and dreaded diseases affecting the vastness of society. Unfortunately, still some people die especially when cancer is not diagnosed and thus caught early enough. On the other hand, using available chemo- or radiotherapy may result in serious side effects. Therefore, cancer-specific medications seem to be the most desired and safe therapy.
Knowing that some cancers are characterized by overexpression of specific receptors on the cell surface, target-mediated drugs could serve as a unique and effective form of therapy. In line with this, recently dopaminergic receptors were presented important in cancer therapy as several dopaminergic ligands revealed their efficacy in tumor growth reduction as well as in apoptosis mediation. Unfortunately, the indication of whether DA receptor agonists or antagonists are the best choices in cancer treatment is quite difficult, since both of them may exert either pro- or anticancer effects.
In this review, we analyze the therapeutic efficacy of compounds, both of exogenous and endogenous origin, targeting dopaminergic receptor-expressing cancers.
TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition
2021, Biological PsychiatryMonoamine 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.
Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice.
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.
These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs.
Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system
2021, Pharmacology and TherapeuticsG protein-gated inwardly rectifying potassium channels (Kir3/GirK) are important for maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Coupled to numerous G protein-coupled receptors (GPCRs), they mediate the effects of many neurotransmitters, neuromodulators and hormones contributing to the general homeostasis and particular synaptic plasticity processes, learning, memory and pain signaling. A growing number of behavioral and genetic studies suggest a critical role for the appropriate functioning of the central nervous system, as well as their involvement in many neurologic and psychiatric conditions, such as neurodegenerative diseases, mood disorders, attention deficit hyperactivity disorder, schizophrenia, epilepsy, alcoholism and drug addiction. Hence, GirK channels emerge as a very promising tool to be targeted in the current scenario where these conditions already are or will become a global public health problem. This review examines recent findings on the physiology, function, dysfunction, and pharmacology of GirK channels in the central nervous system and highlights the relevance of GirK channels as a worthful potential target to improve therapies for related diseases.
Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology
2020, NeuropharmacologyAntipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects and nonadherence in others. We review the in vitro, pre-clinical, clinical and molecular imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clinical response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as weight gain, sedation and dysphoria. We review the neurobiology of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the positive symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and negative symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and negative symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunological approaches which may be disease modifying.
This article is part of the issue entitled ‘Special Issue on Antipsychotics’.