Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Pharm Pharmacol
2009 May 01;615:577-81. doi: 10.1211/jpp/61.05.0005.
Show Gene links
Show Anatomy links
Amitriptyline inhibits the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes.
Baik HJ, Lee SA, Washington JM, Zuo ZY.
???displayArticle.abstract???
Evidence suggests that glutamatergic systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. We have investigated the effects of amitriptyline, a tricyclic antidepressant, on the activity of the excitatory amino acid transporter type 3 (EAAT3), a protein that can regulate extracellular glutamate concentrations in the brain. EAAT3 was expressed in Xenopus oocytes. Using a two-electrode voltage clamp, membrane currents were recorded after application of 30 microM L-glutamate in the presence or absence of various concentrations of amitriptyline or after application of various concentrations of L-glutamate in the presence or absence of 0.64 microM amitriptyline. Amitriptyline concentration-dependently reduced EAAT3 activity. This inhibition reached statistical significance at 0.38-1.27 microM amitriptyline. Amitriptyline 0.64 microM reduced the pharmacokinetic parameter Vmax, but did not affect the pharmacokinetic parameter Km, of EAAT3 for L-glutamate. The amitriptyline inhibition disappeared after a 4-min washout. Phorbol-12-myristate-13-acetate, a protein kinase C activator, increased EAAT3 activity. However, 0.64 microM amitriptyline induced a similar degree of decrease in EAAT3 activity in the presence or absence of phorbol-12-myristate-13-acetate. Our results suggested that amitriptyline at clinically relevant concentrations reversibly reduced EAAT3 activity via decreasing its maximal velocity of glutamate transporting function. The effects of amitriptyline on EAAT3 activity may have represented a novel site of action for amitriptyline to increase glutamatergic neurotransmission. Protein kinase C may not have been involved in the effects of amitriptyline on EAAT3.
Abdel-Salam,
Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.
2003, Pubmed
Abdel-Salam,
Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.
2003,
Pubmed Andin,
Modulation of neuronal glutamate transporter rEAAC1 mRNA expression in rat brain by amitriptyline.
2004,
Pubmed Auer,
Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study.
2000,
Pubmed Billups,
Physiological and pathological operation of glutamate transporters.
1998,
Pubmed Cai,
Amitriptyline, desipramine, cyproheptadine and carbamazepine, in concentrations used therapeutically, reduce kainate- and N-methyl-D-aspartate-induced intracellular Ca2+ levels in neuronal culture.
1992,
Pubmed Danbolt,
Glutamate uptake.
2001,
Pubmed Dick,
Sodium channel blockade may contribute to the analgesic efficacy of antidepressants.
2007,
Pubmed Do,
Effects of volatile anesthetics on glutamate transporter, excitatory amino acid transporter type 3: the role of protein kinase C.
2002,
Pubmed
,
Xenbase Duman,
Neural plasticity to stress and antidepressant treatment.
1999,
Pubmed Eisenach,
Intrathecal amitriptyline acts as an N-methyl-D-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats.
1995,
Pubmed Engelhart,
Comparison of drug concentrations in postmortem cerebrospinal fluid and blood specimens.
2007,
Pubmed Fonnum,
Glutamate: a neurotransmitter in mammalian brain.
1984,
Pubmed Glotzbach,
Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats.
1982,
Pubmed Gołembiowska,
Involvement of adenosine in the effect of antidepressants on glutamate and aspartate release in the rat prefrontal cortex.
2001,
Pubmed Hasuo,
Activation of presynaptic 5-hydroxytryptamine 2A receptors facilitates excitatory synaptic transmission via protein kinase C in the dorsolateral septal nucleus.
2002,
Pubmed Huang,
Critical role of serine 465 in isoflurane-induced increase of cell-surface redistribution and activity of glutamate transporter type 3.
2006,
Pubmed Huang,
Isoflurane induces a protein kinase C alpha-dependent increase in cell-surface protein level and activity of glutamate transporter type 3.
2005,
Pubmed Kanai,
Primary structure and functional characterization of a high-affinity glutamate transporter.
1992,
Pubmed
,
Xenbase Kanai,
A new family of neurotransmitter transporters: the high-affinity glutamate transporters.
1993,
Pubmed Kim,
Effects of ethanol on the rat glutamate excitatory amino acid transporter type 3 expressed in Xenopus oocytes: role of protein kinase C and phosphatidylinositol 3-kinase.
2003,
Pubmed
,
Xenbase McCaslin,
Amitriptyline prevents N-methyl-D-aspartate (NMDA)-induced toxicity, does not prevent NMDA-induced elevations of extracellular glutamate, but augments kainate-induced elevations of glutamate.
1992,
Pubmed McQuay,
A systematic review of antidepressants in neuropathic pain.
1996,
Pubmed Palucha,
The involvement of glutamate in the pathophysiology of depression.
2005,
Pubmed Paul,
Glutamate and depression: clinical and preclinical studies.
2003,
Pubmed Pittenger,
The NMDA receptor as a therapeutic target in major depressive disorder.
2007,
Pubmed Rothstein,
Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate.
1996,
Pubmed Rothstein,
Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis.
1992,
Pubmed Tai,
Amitriptyline preserves morphine's antinociceptive effect by regulating the glutamate transporter GLAST and GLT-1 trafficking and excitatory amino acids concentration in morphine-tolerant rats.
2007,
Pubmed Torp,
Differential distribution of the glutamate transporters GLT1 and rEAAC1 in rat cerebral cortex and thalamus: an in situ hybridization analysis.
1997,
Pubmed
