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Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis.
Neuropharmacology. 2007 Dec; 53(8):918-24.N

Abstract

Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the alpha7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague-Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the alpha7* nicotinic receptor methyllycaconitine (MLA; 1-4mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17959203

Citation

Linderholm, Klas R., et al. "Activation of Rat Ventral Tegmental Area Dopamine Neurons By Endogenous Kynurenic Acid: a Pharmacological Analysis." Neuropharmacology, vol. 53, no. 8, 2007, pp. 918-24.
Linderholm KR, Andersson A, Olsson S, et al. Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis. Neuropharmacology. 2007;53(8):918-24.
Linderholm, K. R., Andersson, A., Olsson, S., Olsson, E., Snodgrass, R., Engberg, G., & Erhardt, S. (2007). Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis. Neuropharmacology, 53(8), 918-24.
Linderholm KR, et al. Activation of Rat Ventral Tegmental Area Dopamine Neurons By Endogenous Kynurenic Acid: a Pharmacological Analysis. Neuropharmacology. 2007;53(8):918-24. PubMed PMID: 17959203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of rat ventral tegmental area dopamine neurons by endogenous kynurenic acid: a pharmacological analysis. AU - Linderholm,Klas R, AU - Andersson,Alexandra, AU - Olsson,Sara, AU - Olsson,Elin, AU - Snodgrass,Ralph, AU - Engberg,Göran, AU - Erhardt,Sophie, Y1 - 2007/09/20/ PY - 2007/07/12/received PY - 2007/08/24/revised PY - 2007/09/03/accepted PY - 2007/10/26/pubmed PY - 2008/3/22/medline PY - 2007/10/26/entrez SP - 918 EP - 24 JF - Neuropharmacology JO - Neuropharmacology VL - 53 IS - 8 N2 - Kynurenic acid (KYNA) is an endogenous NMDA receptor antagonist as well as a blocker of the alpha7* nicotinic receptor and mounting evidence suggests that the compound participates in the pathophysiology of schizophrenia. Previous studies have shown that elevated levels of endogenous KYNA are associated with an increased firing of midbrain dopamine (DA) neurons. In the present study, utilizing extracellular single unit cell recording techniques, the mechanism involved in this excitatory action of the compound was analyzed in male Sprague-Dawley rats. Administration of 4-chlorokynurenine (4-Cl-KYN; 25mg/kg, i.p.), which is converted to the selective NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), was found to increase firing rate and per cent burst firing activity of ventral tegmental area (VTA) DA neurons to the same magnitude as pretreatment of kynurenine (causing a 25-fold elevation in extracellular brain KYNA). Intravenous administration of the selective antagonist at the alpha7* nicotinic receptor methyllycaconitine (MLA; 1-4mg/kg) did not affect firing of VTA DA neurons, whereas intraperitoneal administration of this drug in a high dose (6mg/kg) was associated with a decreased firing rate and per cent burst firing activity. Administration of SDZ 220-581 (10mg/kg, i.v.), a competitive antagonist at the glutamate recognition-site of the NMDA receptor, was found to increase firing rate and per cent burst firing. Present results have potential implications for the treatment of schizophrenia, and indicate that the increased activity of VTA DA neurons following elevation of brain KYNA is mediated through glutamatergic rather than by nicotinergic mechanisms. SN - 0028-3908 UR - https://www.unboundmedicine.com/medline/citation/17959203/Activation_of_rat_ventral_tegmental_area_dopamine_neurons_by_endogenous_kynurenic_acid:_a_pharmacological_analysis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(07)00280-8 DB - PRIME DP - Unbound Medicine ER -