1. Academic Validation
  2. The nicotinic alpha 4 beta 2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices

The nicotinic alpha 4 beta 2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices

  • Neuropharmacology. 2003 Sep;45(3):334-44. doi: 10.1016/s0028-3908(03)00189-8.
Ying Chen 1 Thomas J W Sharples Keith G Phillips Giovanni Benedetti Lisa M Broad Ruud Zwart Emanuele Sher
Affiliations

Affiliation

  • 1 Lilly Research Centre, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Surrey GU20 6PH, Windlesham, UK. [email protected]
Abstract

The ability of alpha4beta2 nicotinic acetylcholine receptors to modulate dopaminergic (DA) cell activity in the ventral tegmental area (VTA) in rat midbrain slices was assessed using a selective alpha4beta2 receptor agonist, TC-2559 ((E)-N-methyl-4-[3-(5-ethoxypyridin)y1]-3-buten-1-amine). The selectivity of TC-2559 was characterized across 6 recombinant human nicotinic receptors (alpha4beta2, alpha2beta4, alpha4beta4, alpha3beta4, alpha3beta2 and alpha7) stably expressed in mammalian cell lines. Using a fluorescent imaging plate reader and fluo-3 to monitor changes in intracellular calcium, TC-2559 was found to be at least 69 fold more potent on alpha4beta2 than on other heteromeric subtypes, with an efficacy of 33%. No activity on the homomeric alpha7 subtype was detected. TC-2559 also showed selectivity for alpha4beta2 over the alpha4beta4 and alpha7 subtypes expressed in Xenopus oocytes. When bath applied to VTA slices, TC-2559 increased the firing of DA cells in a dose-dependent manner, in the same concentration range that activates alpha4beta2 receptors in recombinant cell lines or oocytes. The effect of TC-2559 was blocked by 2 microM dihydro-beta-erythroidine (an alpha4beta2-preferring antagonist), but not by 10 nM methyllycaconitine (an alpha7 antagonist). Glutamate receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione and D(-)-2-amino-5-phosphonopentanoic acid) did not reduce TC-2559-induced responses, suggesting that the increase in DA cell firing induced by TC-2559 is caused by direct postsynaptic depolarisation via the activation of alpha4beta2 receptors and not by enhancement of glutamate release.

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