Role of the subunit composition of central nicotinic acetylcholine receptors for the stimulatory and dopamine-enhancing effects of ethanol.
OBJECTIVE
The stimulatory, rewarding, and dopamine (DA)-enhancing effects of ethanol may involve central nicotinic acetylcholine receptors (nAChR), especially those located in the ventral tegmental area (VTA). Identifying the subunit composition that mediates these effects of ethanol would increase the understanding of the neurochemical basis underlying the addictive properties of ethanol. In the present series of experiments, the role of the alpha(3)beta(2)(*) and/or beta(3)(*) and/or alpha(6)(*) subunits of the nAChR for the stimulatory and DA-enhancing effects of ethanol was investigated by using alpha-conotoxin MII (alphaCtxMII), selective to the alpha(3)beta(2)(*) and/or beta(3)(*) and/or the alpha(6)(*) subunits of the nAChR, and the alpha-conotoxin PIA-analogue (alphaCtxPIA-analogue), suggested to be selective to the alpha(6)(*) subunits.


METHODS
alphaCtxMII and the alphaCtxPIA-analogue were synthesized using a modified literature procedure. The purity and identity of the peptides were confirmed with HPLC and FAB-MS analyses, respectively. Locomotor activity and in vivo microdialysis in freely moving mice were used.


RESULTS
alphaCtxMII and the alphaCtxPIA-analogue were synthesized in good yields (>95%; >90%). In addition, we found that synthesized alphaCtxMII antagonized ethanol-induced locomotor stimulation, which confirms our previous results with the commercially available alphaCtxMII. Furthermore, the synthesized alphaCtxPIA-analogue, assumably also selective for alpha(6)(*) subunits of the nAChR, did neither antagonize the stimulatory nor the accumbal DA-enhancing effects of ethanol.


CONCLUSIONS
These results indicate that alphaCtxMII- but not alphaCtxPIA-analogue-sensitive receptors, i.e. the alpha(3)beta(2)(*) and/or beta(3)(*) rather than the alpha(6)(*) subunits of the nAChR, appear to be of greater importance for these effects of ethanol and that these subunits could constitute neurochemical targets for developing new drugs for the treatment of alcohol dependence.
Jerlhag
Elisabet
E
Institute of Physiology and Pharmacology, Department of Pharmacology, Göteborg University, Box 431, SE 405 30 Göteborg, Sweden. jorgen.engel@pharm.gu.se
Grøtli
Morten
M
Luthman
Kristina
K
Svensson
Lennart
L
Engel
Jörgen A
JA
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020916:Conotoxins / Q000138:chemical synthesis / Q000494:pharmacology*; D004298:Dopamine / Q000096:biosynthesis*; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D011978:Receptors, Nicotinic / Q000502:physiology*; D012201:Reward
D020916:Conotoxins; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D000431:Ethanol; D004298:Dopamine