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Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons.
J Physiol. 2009 Jan 15; 587(2):345-61.JP

Abstract

Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor-mediated current had faster activation and decay constant and IIID receptor-mediated current had larger current density. Pharmacologically, ID receptor-mediated current was sensitive to the alpha4beta2-nAChR agonist RJR-2403 and antagonist dihydro-beta-erythroidine (DHbetaE); IID receptor-mediated current was sensitive to the selective alpha7-nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor-mediated current was sensitive to the beta4-containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration-response relationships demonstrated that IID receptor-mediated current exhibited the highest EC(50) value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR-mediated currents are predominately mediated by activation of alpha4beta2-nAChR, alpha7-nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence.

Authors+Show Affiliations

Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013-4496, USA.No affiliation info availableNo affiliation info availableNo 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, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19047205

Citation

Yang, Kechun, et al. "Distinctive Nicotinic Acetylcholine Receptor Functional Phenotypes of Rat Ventral Tegmental Area Dopaminergic Neurons." The Journal of Physiology, vol. 587, no. 2, 2009, pp. 345-61.
Yang K, Hu J, Lucero L, et al. Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons. J Physiol (Lond). 2009;587(2):345-61.
Yang, K., Hu, J., Lucero, L., Liu, Q., Zheng, C., Zhen, X., Jin, G., Lukas, R. J., & Wu, J. (2009). Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons. The Journal of Physiology, 587(2), 345-61. https://doi.org/10.1113/jphysiol.2008.162743
Yang K, et al. Distinctive Nicotinic Acetylcholine Receptor Functional Phenotypes of Rat Ventral Tegmental Area Dopaminergic Neurons. J Physiol (Lond). 2009 Jan 15;587(2):345-61. PubMed PMID: 19047205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons. AU - Yang,Kechun, AU - Hu,Jun, AU - Lucero,Linda, AU - Liu,Qiang, AU - Zheng,Chao, AU - Zhen,Xuechu, AU - Jin,Guozhang, AU - Lukas,Ronald J, AU - Wu,Jie, Y1 - 2008/12/01/ PY - 2008/12/3/pubmed PY - 2009/3/10/medline PY - 2008/12/3/entrez SP - 345 EP - 61 JF - The Journal of physiology JO - J. Physiol. (Lond.) VL - 587 IS - 2 N2 - Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology. Kinetic analysis demonstrated that comparing to ID, IID receptor-mediated current had faster activation and decay constant and IIID receptor-mediated current had larger current density. Pharmacologically, ID receptor-mediated current was sensitive to the alpha4beta2-nAChR agonist RJR-2403 and antagonist dihydro-beta-erythroidine (DHbetaE); IID receptor-mediated current was sensitive to the selective alpha7-nAChR agonist choline and antagonist methyllycaconitine (MLA); while IIID receptor-mediated current was sensitive to the beta4-containing nAChR agonist cytisine and antagonist mecamylamine (MEC). The agonist concentration-response relationships demonstrated that IID receptor-mediated current exhibited the highest EC(50) value compared to ID and IIID receptors, suggesting a relatively low agonist affinity of type IID receptors. These results suggest that the type ID, IID and IIID nAChR-mediated currents are predominately mediated by activation of alpha4beta2-nAChR, alpha7-nAChR and a novel nAChR subtype(s), respectively. Collectively, these findings indicate that the VTA DAergic neurons express diversity and multiplicity of functional nAChR subtypes. Interestingly, each DAergic neuron predominantly expresses only one particularly functional nAChR subtype, which may have distinct but important roles in regulation of VTA DA neuronal function, DA transmission and nicotine dependence. SN - 1469-7793 UR - https://www.unboundmedicine.com/medline/citation/19047205/Distinctive_nicotinic_acetylcholine_receptor_functional_phenotypes_of_rat_ventral_tegmental_area_dopaminergic_neurons_ L2 - https://doi.org/10.1113/jphysiol.2008.162743 DB - PRIME DP - Unbound Medicine ER -