Sigma(2)-receptor regulation of dopamine transporter via activation of protein kinase C.
ABSTRACT The elucidation of the mechanisms underlying sigma(2)-receptor activation and signal transduction is crucial to the understanding of sigma(2)-receptor function. Previous studies in our laboratory have demonstrated sigma(2)-receptor-mediated regulation of the dopamine transporter (DAT) as measured by amphetamine-stimulated release of [(3)H]dopamine (DA) from both rat striatal slices and PC12 cells. The regulation of the DAT in the PC12 cell model was dependent upon activation of Ca(2+)/calmodulin-dependent kinase II. We have now studied the second messenger systems involved in sigma(2)-receptor-mediated regulation of amphetamine-stimulated [(3)H]DA release in rat striatal slices, including Ca(2+)/calmodulin-dependent kinase II, protein kinase C, and sources of calcium required for the enhancement of release produced by sigma(2)-receptor activation. The Ca(2+)/calmodulin-dependent kinase II inhibitors 1-[N,O-bis-(5-isoquionolinesulfonyl)]-N-methyl-L-tyrosyl-4-phenylpiperazine and N-[2-[[[3-(4'-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-benzenesulfonamide phosphate did not significantly affect the (+)-pentazocine-mediated enhancement of amphetamine-stimulated [(3)H]DA release. However, we found that an inhibitor of protein kinase C, 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl)-1H-pyrrole-2,5-dione, blocks the (+)-pentazocine-mediated enhancement in rat striatal slices. The protein kinase C activator phorbol 12-myristate 13-acetate, but not the inactive isophorbol 4 alpha,9 alpha,12 alpha,13 alpha,20-pentahydroxytiglia-1,6-dien-3-one, enhanced the amphetamine-stimulated [(3)H]DA release comparable to the enhancement seen by (+)-pentazocine alone. Additionally, the L-type voltage-dependent calcium channel inhibitor nitrendipine or prior treatment with thapsigargin, but not the N-type voltage-dependent calcium channel omega-conotoxin MVIIA, attenuated the (+)-pentazocine-mediated enhancement. Together, these data suggest that activation of sigma(2)-receptors results in the regulation of DAT activity via a calcium- and protein kinase C-dependent signaling mechanism.
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ABSTRACT: Methamphetamine interacts with sigma (σ) receptors and AC927, a selective σ receptor ligand, protects against methamphetamine-induced dopaminergic neurotoxicity. In the present study, the effects of AC927 on methamphetamine-induced hyperthermia and striatal serotonergic neurotoxicity were evaluated. Male, Swiss Webster mice were injected (i.p.) every 2 h, for a total of four times, with one of the following treatments: Saline+Saline; Saline+Methamphetamine (5 mg/kg); AC927 (5, 10, 20 mg/kg)+Methamphetamine (5 mg/kg); or AC927 (5, 10, 20 mg/kg)+Saline. Pretreatment with AC927 (10 mg/kg) significantly attenuated methamphetamine-induced striatal serotonin depletions, striatal serotonin transporter reductions, and hyperthermia. At the doses tested, AC927 itself had no significant effects on serotonin levels, serotonin transporter expression, or body temperature. To evaluate the effects of higher ambient temperature on methamphetamine-induced neurotoxicity, groups of mice were treated at 37 °C. Overall, there was an inverse correlation between the body temperature of the animals and striatal serotonin levels. Together, the data suggest that AC927 (10 mg/kg) protects against methamphetamine-induced neurotoxicity. The reduction of methamphetamine-induced hyperthermia by AC927 may contribute to the observed neuroprotection in vivo.Pharmacology Biochemistry and Behavior 03/2011; 98(1):12-20. · 2.82 Impact Factor
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ABSTRACT: More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.Psychopharmacology 08/2004; 174(3):301-19. · 4.06 Impact Factor
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ABSTRACT: Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse. Low and high dose administration of METH leads to locomotor stimulation, and dopaminergic and serotonergic neurotoxicity, respectively. The behavioral stimulant and neurotoxic effects of METH can contribute to addiction and other neuropsychiatric disorders, thus necessitating the identification of potential pharmacotherapeutics against these effects produced by METH. METH binds to σ receptors at physiologically relevant concentrations. Also, σ receptors are present on and can modulate dopaminergic and serotonergic neurons. Therefore, σ receptors provide a viable target for the development of pharmacotherapeutics against the adverse effects of METH. In the present study, CM156, a σ receptor ligand with high affinity and selectivity for σ receptors over 80 other non-σ binding sites, was evaluated against METH-induced stimulant, hyperthermic, and neurotoxic effects. Pretreatment of male, Swiss Webster mice with CM156 dose dependently attenuated the locomotor stimulation, hyperthermia, striatal dopamine and serotonin depletions, and striatal dopamine and serotonin transporter reductions produced by METH, without significant effects of CM156 on its own. These results demonstrate the ability of a highly selective σ ligand to mitigate the effects of METH.Neuropharmacology 01/2011; 61(5-6):992-1000. · 4.11 Impact Factor