TC-2559 excites dopaminergic neurones in the ventral tegmental area by stimulating alpha4beta2-like nicotinic acetylcholine receptors in anaesthetised rats.
1. The in vivo effects of a selective partial agonist for neuronal nicotinic acetylcholine receptor (nAChRs) alpha4beta2 subtype, TC-2559, characterised recently in in vitro preparations, have been profiled. The brain bioavailability of TC-2559 and its effects on the spontaneous firing and bursting properties of the dopaminergic (DAergic) neurones recorded extracellularly in the ventral tegmental area (VTA) were studied following systemic administration in anaesthetised rats. 2. Cumulative doses of TC-2559 (0.021-1.36 mg kg(-1), i.v.) increased both the firing and bursting activities of VTA DA neurones. The effect of bolus doses of TC-2559 of 0.66 or 1.32 mg kg(-1), i.v., was approximately equivalent to that of 0.0665 mg kg(-1), i.v. nicotine. 3. The excitation evoked by both nicotine and TC-2559 was fully reversed by DHbetaE (0.39-0.77 mg kg(-1), i.v.), an alpha4beta2-subtype-preferring nicotinic antagonist, and application of nicotine after DHbetaE failed to evoke any excitation. MLA (0.23 mg kg(-1), i.v.), an alpha7 selective antagonist, failed to alter TC-2559-evoked excitation and bursting activities, and a novel alpha7 agonist (PSAB-OFP; 0.23 mg kg(-1), i.v.) was also without effect. 4. The present results indicated that TC-2559 fully mimics nicotine by increasing both the excitability and bursting behaviour of VTA DA neurones, effects that are predominantly due to activation of alpha4beta2-like nAChRs. 5. TC-2559 has been demonstrated to be a useful in vivo pharmacological tool for studying the alpha4beta2 subtype of nicotinic receptor.
Wang
Yun
Y
Lilly Research Centre, Eli Lilly & Co. Ltd, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH. y2003wang@yahoo.co.uk
Sherwood
John L
JL
Miles
Colin P
CP
Whiffin
Gary
G
Lodge
David
D
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D008024:Ligands; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D018491:Dopamine Agonists; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C419442:TC 2559; D009538:Nicotine; D001058:Apomorphine; D004298:Dopamine