Article date: February 2006
By: Yun Wang, John L Sherwood, Colin P Miles, Gary Whiffin, David Lodge in Volume 147, Issue 4, pages 379-390
The in vivo effects of a selective partial agonist for neuronal nicotinic acetylcholine receptor (nAChRs) α4β2 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.
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.
The excitation evoked by both nicotine and TC‐2559 was fully reversed by DHβE (0.39–0.77 mg kg−1, i.v.), an α4β2‐subtype‐preferring nicotinic antagonist, and application of nicotine after DHβE failed to evoke any excitation. MLA (0.23 mg kg−1, i.v.), an α7 selective antagonist, failed to alter TC‐2559‐evoked excitation and bursting activities, and a novel α7 agonist (PSAB‐OFP; 0.23 mg kg−1, i.v.) was also without effect.
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 α4β2‐like nAChRs.
TC‐2559 has been demonstrated to be a useful in vivo pharmacological tool for studying the α4β2 subtype of nicotinic receptor.
The in vivo effects of a selective partial agonist for neuronal nicotinic acetylcholine receptor (nAChRs) α4β2 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.
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.
The excitation evoked by both nicotine and TC‐2559 was fully reversed by DHβE (0.39–0.77 mg kg−1, i.v.), an α4β2‐subtype‐preferring nicotinic antagonist, and application of nicotine after DHβE failed to evoke any excitation. MLA (0.23 mg kg−1, i.v.), an α7 selective antagonist, failed to alter TC‐2559‐evoked excitation and bursting activities, and a novel α7 agonist (PSAB‐OFP; 0.23 mg kg−1, i.v.) was also without effect.
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 α4β2‐like nAChRs.
TC‐2559 has been demonstrated to be a useful in vivo pharmacological tool for studying the α4β2 subtype of nicotinic receptor.
British Journal of Pharmacology (2006) 147, 379–390. doi:10.1038/sj.bjp.0706621
DOI: 10.1038/sj.bjp.0706621
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