Looking at lithium: molecular moods and complex behaviour.
ABSTRACT Lithium and other mood-stabilizing drugs are used for the management of bipolar mood disorders and, to a lesser extent, for augmentation of other psychoactive drugs. Lithium also has neuroprotective properties that may be useful for treatment of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Over the years, lithium has been shown to inhibit inositol monophosphatases and glycogen synthase kinase 3, but the relevance of such enzyme inhibition to the therapeutic effects of lithium has remained difficult to assess. Here, we provide an overview of recent advances in the identification of molecular mechanisms involved in the regulation of behavior by lithium. We also highlight recent findings suggesting that lithium could exert some of its behavioral effects by acting on a dopamine receptor regulated signaling complex composed of Akt, protein phosphatase 2A, and the multifunctional protein scaffold beta-arrestin 2.
- SourceAvailable from: Stefano Espinoza[Show abstract] [Hide abstract]
ABSTRACT: The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on cAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as β-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors.
Article: MicroRNAs and depression[Show abstract] [Hide abstract]
ABSTRACT: With an estimated life-time prevalence of 15 to 17% and an incapacitating illness in 50% of cases, depressive spectrum disorders represent a heavy public health burden. Despite considerable efforts to underpin the molecular and cellular changes associated with depressive states, a global understanding of the pathophysiology of major depressive disorders (MDD) is still lacking. It is now acknowledged that deficits in synaptic plasticity, such as those resulting from chronic stress, can set the stage for the onset of depression. As a corollary, antidepressants balance neurotransmitter systems and help restore neuronal activity. In recent years, microRNAs have emerged as key protagonists in numerous physiopathological conditions including CNS function and disease. This review summarizes the current evidence for an involvement of microRNAs in the pathophysiology of depression and their contribution to the action of antidepressants.Neurobiology of Disease 12/2011; 46(2):272-8. DOI:10.1016/j.nbd.2011.12.035 · 5.20 Impact Factor
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ABSTRACT: Multifunctional scaffolding protein beta-arrestins (βArr) and the G protein-receptor kinases are involved in the desensitization of several G protein-coupled receptors (GPCR). However, arrestins can also contribute to GPCR signaling independently from G proteins. In this review, we focus on the role of βArr in the regulation of dopamine receptor functions in the striatum. First, we present in vivo evidence supporting a role for these proteins in the regulation of dopamine receptor desensitization. Second, we provide an overview of the roles of βArr2 in the regulation of extracellular-signal-regulated kinases/MAP kinases and Akt/GSK3 signaling pathways downstream of the D1 and D2 dopamine receptors. Thereafter, we examine the possible involvement of βArr-mediated signaling in the action of dopaminergic drugs used for the treatment of mental disorders. Finally, we focus on different potential cellular proteins regulated by βArr-mediated signaling which could contribute to the regulation of behavioral responses to dopamine. Overall, the identification of a cell signaling function for βArr downstream of dopamine receptors underscores the intricate complexity of the intertwined mechanisms regulating and mediating cell signaling in the basal ganglia. Understanding these mechanisms may lead to a better comprehension of the several roles played by these structures in the regulation of mood and to the development of new psychoactive drugs having better therapeutic efficacy.Frontiers in Neuroanatomy 09/2011; 5:58. DOI:10.3389/fnana.2011.00058 · 4.18 Impact Factor