Psychotropic drugs acting on monoamine neurotransmission are major pharmacological treatments for neuropsychiatric conditions such as schizophrenia, depression, bipolar disorder, Tourette syndrome, ADHD, and Alzheimer disease. Independent lines of research involving biochemical and behavioral approaches in normal and/or genetically modified mice provide converging evidence for an involvement of the signaling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behavior by dopamine and serotonin (5-HT). These signaling molecules have also received attention for their role in the actions of psychoactive drugs such as antidepressants, antipsychotics, lithium, and other mood stabilizers. Furthermore, investigations of the mechanism by which D2 dopamine receptors regulate Akt/GSK3 signaling strongly support the physiological relevance of a new modality of G protein-coupled receptor (GPCR) signaling involving the multifunctional scaffolding protein beta-arrestin 2. Elucidation of the contribution of multiple signaling pathways to the action of psychotropic drugs may provide a better biological understanding of psychiatric disorders and lead to more efficient therapeutics.

/pdf/akt-gsk3-signaling-in-the-action-of-psychotropic-drugs-4dnx9cvusl.pdf

Akt/GSK3 signaling in the action of psychotropic drugs.

For more than 60 years, the mood stabilizer lithium has been used alone or in combination for the treatment of bipolar disorder, schizophrenia, depression, and other mental illnesses. Despite this long history, the molecular mechanisms trough which lithium regulates behavior are still poorly understood. Among several targets, lithium has been shown to directly inhibit glycogen synthase kinase 3 alpha and beta (GSK3α and GSK3β). However in vivo, lithium also inhibits GSK3 by regulating other mechanisms like the formation of a signaling complex comprised of beta-arrestin 2 (βArr2) and Akt. Here, we provide an overview of in vivo evidence supporting a role for inhibition of GSK3 in some behavioral effects of lithium. We also explore how regulation of GSK3 by lithium within a signaling network involving several molecular targets and cell surface receptors [e.g., G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)] may provide cues to its relative pharmacological selectivity and its effects on disease mechanisms. A better understanding of these intricate actions of lithium at a systems level may allow the rational development of better mood stabilizer drugs with enhanced selectivity, efficacy, and lesser side effects.

/pdf/inhibition-of-gsk3-by-lithium-from-single-molecules-to-6a9zr9ct96.pdf

Inhibition of GSK3 by lithium, from single molecules to signaling networks

Lithium has been the gold standard in the treatment of bipolar disorder (BPD) for 60 y. Like lithium, glycogen synthase kinase 3 (GSK-3) inhibitors display both antimanic-like and antidepressant-like effects in some animal models. However, the molecular mechanisms of both lithium and GSK-3 inhibitors remain unclear. Here we show that the GSK-3 inhibitor AR-A014418 regulated α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-induced GluR1 and GluR2 internalization via phosphorylation of kinesin light chain 2 (KLC2), the key molecule of the kinesin cargo delivery system. Specifically, AMPA stimulation triggered serine phosphorylation of KLC2 and, subsequently, the dissociation of the GluR1/KLC2 protein complex. This suggests that GSK-3 phosphorylation of KLC2 led to the dissociation of AMPA-containing vesicles from the kinesin cargo system. The peptide TAT-KLCpCDK, a specific inhibitor for KLC2 phosphorylation by GSK-3β, reduced the formation of long-term depression. Furthermore, the TAT-KLCpCDK peptide showed antimanic-like effects similar to lithium's on amphetamine-induced hyperactivity, a frequently used animal model of mania. It also induced antidepressant-like effects in the tail suspension and forced swim tests, two commonly used animal models of depression. Taken together, the results demonstrated that KLC2 is a cellular target of GSK-3β capable of regulating synaptic plasticity, particularly AMPA receptor trafficking, as well as mood-associated behaviors in animal models. The kinesin cargo system may provide valuable novel targets for the development of new therapeutics for mood disorders.

https://www.pnas.org/content/pnas/107/25/11573.full.pdf

A kinesin signaling complex mediates the ability of GSK-3β to affect mood-associated behaviors

This is a short overview focusing on the biochemical interactions underlying the protective effects of lithium at the neuronal level. These include lithium modulation of autophagy, growth factors, excitotoxicity, and a variety of mechanisms underlying cell death, neurogenesis, and neuronal differentiation. All these effects represent the result of a multifaceted pharmacology, which is becoming more and more complex. Nonetheless, when trying to dissect the various mechanisms of action of lithium, two primary targets emerge: glycogen synthase kinase 3beta and phosphatidylinositol phosphatase. The numerous lithium effects on biochemical systems are placed downstream of these two main mechanisms. At several steps, these mechanisms interconnect to each other, thus making it difficult to keep distinct the biochemical cascades promoted by lithium. In this way, it is not surprising that, despite being described as different phenomena at the behavioral level, molecular mechanisms underlying the effects of lithium on mood, motor activity, and sensitization overlap with those responsible for neuroprotection and neurorestoration. It is likely that the ancestral role of this ion as a modulator of cell survival, cell growth, movement, and mood is the consequence of a few molecular mechanisms operating in different neuronal networks, where a variety of cascade events take place. This review is an attempt to elucidate the primary effects of lithium to interconnect the simpler targets to the most complex pharmacological effects.

Intracellular pathways underlying the effects of lithium.

Circadian clocks are driven by signals from the habitat to match the solar day and to reset their phase relative to local time A key function of the circadian clocks allows individuals to anticipate routine environmental conditions and to adjust their behaviors to the change of conditions In clinical practice mood, anxiety and alcohol use disorders are often comorbid conditions Clinical data have demonstrated that there are abnormalities in the circadian rhythms in patients with mood disorders and those with alcohol use disorders Recent findings of molecular genetics have yielded the first insight into the targets of interest Circadian clock gene variants are a fruitful target for elucidation of the pathogenesis The findings that have gained support indicate that genetic variants of RORA (rs2028122) and CRY1 (rs2287161) associate with depressive disorder, those of RORB (rs7022435, rs3750420, rs1157358, rs3903529) and NR1D1 (rs2314339) with bipolar disorder, and those of NPAS2 (rs11541353) and CRY2 (rs10838524) with seasonal affective disorder or winter depression Concerning anxiety disorders and alcohol use disorders, the current findings are preliminary and need further verification to explain the association of ARNTL2, being suggestive only, with social phobia (rs2306073) and with alcohol abuse (rs7958822, rs4964057)

Clock gene variants in mood and anxiety disorders.

The exact role of the enzyme glycogen synthase kinase 3β (GSK-3β) in mood disorders is still unknown. GSK-3β has been mapped to chromosome 3q13.3, a potential susceptibility locus for bipolar disorder. The -50T/C polymorphism, falling within the promoter region of the gene coding for GSK-3β, was previously reported to be associated with age at onset, therapeutic response to lithium salts and total sleep deprivation in bipolar patients. In the present study we investigated the association between the -50T/C polymorphism and both symptomatic and personality features in mood disorders. The sample comprised 365 inpatients affected by major depressive disorder and bipolar disorder, genotyped for the GSK-3β-50 polymorphism and assessed with the Operational Criteria Checklist for Psychotic Illness (OPCRIT). Ninety-five subjects were also evaluated with the Temperament and Character Inventory (TCI). The GSK-3β-50 polymorphism showed a positive association with delusional symptomatology and with the personality features linked to Self-Transcendence. Finally, GSK-3β-50 and personality showed an interactive effect on delusional scores. In conclusion, our findings support the role of GSK-3β-50 in both normal and psychopathological aspects of human cognition and further suggest a possible interaction between genes and personality in the liability to psychotic disorders.

Association between GSK-3β -50T/C polymorphism and personality and psychotic symptoms in mood disorders

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Association between GSK-3β -50T/C polymorphism and personality and psychotic symptoms in mood disorders