Decynium-22 Enhances SSRI-Induced Antidepressant-Like Effects in Mice: Uncovering Novel Targets to Treat Depression
ABSTRACT Mood disorders cause much suffering and lost productivity worldwide, compounded by the fact that many patients are not effectively treated by currently available medications. The most commonly prescribed antidepressant drugs are the selective serotonin (5-HT) reuptake inhibitors (SSRIs), which act by blocking the high-affinity 5-HT transporter (SERT). The increase in extracellular 5-HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low-affinity, high-capacity transporters for 5-HT in brain [i.e., organic cation transporters (OCTs) and plasma membrane monoamine transporter], which may limit the ability of SSRIs to increase extracellular 5-HT. Decynium-22 (D-22) is a blocker of these transporters, and using this compound we uncovered a significant role for OCTs in 5-HT uptake in mice genetically modified to have reduced or no SERT expression (Baganz et al., 2008). This raised the possibility that pharmacological inactivation of D-22-sensitive transporters might enhance the neurochemical and behavioral effects of SSRIs. Here we show that in wild-type mice D-22 enhances the effects of the SSRI fluvoxamine to inhibit 5-HT clearance and to produce antidepressant-like activity. This antidepressant-like activity of D-22 was attenuated in OCT3 KO mice, whereas the effect of D-22 to inhibit 5-HT clearance in the CA3 region of hippocampus persisted. Our findings point to OCT3, as well as other D-22-sensitive transporters, as novel targets for new antidepressant drugs with improved therapeutic potential.
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ABSTRACT: Metformin, the most widely prescribed anti-diabetic drug, requires transporters to enter tissues involved in its pharmacologic action including liver, kidney and peripheral tissues. Organic cation transporter 3 (OCT3, SLC22A3), expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared to wildtype mice (p < 0.001), indicating an important role of OCT3 in tissue distribution and elimination of the drug. Following oral doses, a significantly lower bioavailability was observed in knockout compared to wildtype mice (0.27 versus 0.58, p < 0.001). Importantly, metformin's effects on oral glucose tolerance were reduced in knockout compared with wildtype mice (30% versus 12% reduction, p < 0.05) along with its accumulation in skeletal muscle and adipose tissue (p < 0.05). Further, the effect of metformin on phosphorylation of AMP activated protein kinase, AMPK, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3(-/-) mice. Additional analysis revealed that an OCT3 3'UTR variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin, and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action. The American Society for Pharmacology and Experimental Therapeutics.Molecular pharmacology 04/2015; 88(1). DOI:10.1124/mol.114.096776 · 4.12 Impact Factor
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ABSTRACT: This chapter brings together the work of several leading laboratories, each an outstanding example of integrative approaches to complex diseases of the central nervous system. Cognitive dysfunction and negative symptoms associated with schizophrenia are believed to result from hypofunction of the mesocortical dopaminergic projections to prefrontal cortex (PFC). Noradrenergic targets for the augmentation of dopaminergic function in PFC show promise to improve cognitive deficits as well as negative symptoms. Serotonergic targets for the modulation of mesocortical dopaminergic neurotransmission include 5-HT2A and 5-HT1A receptors. The hallmark of Parkinson's disease is the destruction of nigrostriatal dopaminergic neurons. l-DOPA, a metabolic precursor of dopamine, is the standard of treatment. However, the ectopic release of dopamine (DA) from serotonin neurons and the clearance of extracellular DA by the norepinephrine transporter in areas enriched with noradrenergic terminals contribute to extracellular DA produced by l-DOPA and offer opportunities to improve l-DOPA therapy. The high-affinity transporters for monoamines are the primary targets for antidepressant drugs. However, many patients experience suboptimal therapeutic benefit or fail to respond to treatment. Organic cation transporters and plasma membrane monoamine transporter serve an important function in regulating monoamine neurotransmission and hold potential utility as targets for the development of therapeutic drugs. Improved therapeutic approaches will arise from not only understanding how monoamines influence one another within the central nervous system as an integrated whole but also addressing the pathophysiology of specific core symptoms or distinct syndromal dimensions (cognitive impairment, motor slowing, and negative affect) regardless of disease classification, for example, psychotic, affective, and neurodegenerative.Advances in pharmacology (San Diego, Calif.) 01/2013; 68:167-97. DOI:10.1016/B978-0-12-411512-5.00009-9
- dressNature Reviews Drug Discovery 07/2013; DOI:10.1038/nrd4078 · 37.23 Impact Factor