Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens.
Previously, we have reported that the orexigenic peptide ghrelin activates the cholinergic-dopaminergic reward link, involving nicotinic acetylcholine receptors (nAChR). The alpha(3)-alpha(7) and beta(2)-beta(4) subunits of the nAChR can be combined into pentameric nAChRs, with different functional roles. The present experiments show that the locomotor stimulatory effects of ghrelin, either into laterodorsal tegmental area (LDTg) or ventral tegmental area (VTA), are mediated via ventral tegmental nAChR, but neither the alpha(4)beta(2) (using dihydro-beta-erythroidine) nor the alpha(7) (using methyllycaconitine) subtypes appears to be involved. On the other hand, the alpha(3)beta(2), beta(3) and/or alpha(6) (using alpha-conotoxin MII) subtypes in the VTA mediate the stimulatory and DA-enhancing effects of ghrelin, a pattern that ghrelin shares with ethanol (n=5-8). Radioligand-binding experiments shown that ghrelin does not interfere directly with nAChRs (n=26). We therefore suggest that the alpha(3)beta(2), beta(3) and/or alpha(6) subtypes might be pharmacological targets for treatment of addictive behaviours including compulsive overeating and alcoholism.
Jerlhag
Elisabet
E
Section for Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at Göteborg University, SE-405 30 Göteborg, Sweden. elisabet.jerlhag@pharm.gu.se
Egecioglu
Emil
E
Dickson
Suzanne L
SL
Svensson
Lennart
L
Engel
Jörgen A
JA
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020916:Conotoxins / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D054439:Ghrelin / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D017551:Microdialysis / Q000379:methods; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D011978:Receptors, Nicotinic / Q000502:physiology*; D013997:Time Factors
D020916:Conotoxins; D054439:Ghrelin; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D004298:Dopamine