Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues.
BACKGROUND
Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse.


OBJECTIVE
We investigated the possible involvement of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) in the conditioned reinforcing properties of ethanol-associated stimuli in the rat.


METHODS
First, using in vivo microdialysis, we analyzed the effect of VTA perfusion of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha4beta2* nAChR antagonist dihydro-beta-erythroidine (DHbetaE) on the nucleus accumbens (nAc) dopaminergic response to the presentation of an ethanol-associated conditioned stimulus (CS). Second, rats were trained to associate a tone+light CS with the presentation of 10% ethanol and were subsequently tested on the acquisition of a new instrumental response with conditioned reinforcement (CR) after local VTA infusion of MEC, DHbetaE, or alpha-Conotoxin MII (alpha-CtxMII, a selective alpha3beta2* and alpha6* nAChR antagonist).


RESULTS
The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DHbetaE. Systemic administration of MEC or local VTA infusion of MEC or alpha-CtxMII selectively blocked ethanol-associated CR, whereas systemic DHbetaE had no effect.


CONCLUSIONS
We hypothesize a novel mechanism by which alcohol-associated cues promote drug-seeking behavior via activation of dopamine-stimulating alpha-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse.
Löf
Elin
E
Inst. Neuroscience and Physiology, Sect. Psychiatry and Neurochemistry, Sahlgrenska Academy, Göteborg University and Beroendekliniken, Sahlgrenska University Hospital, Gothenburg, Sweden. elin.lof@neuro.gu.se
Olausson
Peter
P
deBejczy
Andrea
A
Stomberg
Rosita
R
McIntosh
J Michael
JM
Taylor
Jane R
JR
Söderpalm
Bo
B
D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D020916:Conotoxins / Q000494:pharmacology; D003463:Cues; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017551:Microdialysis; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D020916:Conotoxins; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; D004079:Dihydro-beta-Erythroidine; D000431:Ethanol; D008464:Mecamylamine; D004298:Dopamine
Addiction. 1999 Mar;94(3):327-40
10605857
Alcohol Clin Exp Res. 2002 Mar;26(3):318-25
11923583
J Neurochem. 1988 Apr;50(4):1243-7
3346676
Eur J Pharmacol. 1997 Sep 10;334(2-3):149-56
9369343
Synapse. 2000 Oct;38(1):1-9
10941135
Prog Neurobiol. 2004 Dec;74(6):363-96
15649582
J Neurosci. 2003 Feb 1;23(3):742-7
12574402
Alcohol Clin Exp Res. 2004 Apr;28(4):550-7
15100605
J Neurosci. 2004 Nov 24;24(47):10726-30
15564590
Psychopharmacology (Berl). 1999 Feb;142(1):31-40
10102780
J Neurosci. 2005 May 11;25(19):4725-32
15888648
Eur J Pharmacol. 1993 Sep 28;242(2):151-63
8253112
Alcohol Clin Exp Res. 2003 Oct;27(10):1573-82
14574227
Alcohol Alcohol. 2006 Sep-Oct;41(5):486-93
16799162
J Neurophysiol. 1998 Jul;80(1):1-27
9658025
J Neurochem. 1985 Aug;45(2):427-33
4009168
Neuropharmacology. 2000 Oct;39(13):2570-90
11044728
Eur J Neurosci. 2004 Mar;19(6):1661-7
15066162
Psychopharmacology (Berl). 1986;90(3):390-7
3097729
Eur J Pharmacol. 1998 Oct 9;358(3):189-96
9822883
Eur J Pharmacol. 2003 Apr 25;467(1-3):85-93
12706460
J Comp Neurol. 2006 Feb 20;494(6):863-75
16385486
J Neurosci. 1999 Dec 1;19(23):10502-11
10575046
Brain Res Brain Res Rev. 2001 Oct;36(2-3):129-38
11690609
Neuroscience. 2007 Feb 23;144(4):1209-18
17184925
J Abnorm Psychol. 1988 May;97(2):133-52
3290304
J Biol Chem. 1996 Mar 29;271(13):7522-8
8631783
Alcohol Clin Exp Res. 2000 Feb;24(2):155-63
10698366
J Neurosci. 1998 Dec 15;18(24):10663-71
9852601
Trends Neurosci. 1999 Nov;22(11):521-7
10529820
J Neurosci. 1995 Sep;15(9):5859-69
7666171
J Neurosci. 2004 Mar 24;24(12):2923-33
15044531
J Pharmacol Exp Ther. 1993 Oct;267(1):250-8
8229752
J Pharmacol Exp Ther. 2002 Mar;300(3):882-9
11861794
J Comp Neurol. 1999 Jul 26;410(2):197-210
10414527
J Neural Transm (Vienna). 2001;108(7):887-94
11515754
Neuroscience. 1994 Sep;62(1):51-64
7816212
Neuroscience. 2002;111(2):351-62
11983320
Psychopharmacology (Berl). 2004 Sep;175(3):296-302
15127179
Psychopharmacology (Berl). 1997 Feb;129(4):390-7
9085409
J Neurosci. 2000 Nov 1;20(21):8122-30
11050134
Psychopharmacology (Berl). 1984;84(3):405-12
6440188
Behav Neurosci. 2000 Apr;114(2):285-94
10832790
Psychopharmacology (Berl). 2004 Apr;173(1-2):98-104
14727001
Psychopharmacology (Berl). 1995 Jan;117(1):67-73
7724704
Alcohol Clin Exp Res. 1999 Nov;23(11):1751-60
10591591
Drug Alcohol Depend. 1998 Jan 1;49(2):95-104
9543646
Alcohol. 2004 Oct-Nov;34(2-3):239-50
15902919
Neuroreport. 1998 Sep 14;9(13):3097-101
9804323
J Neurosci. 1996 Apr 15;16(8):2605-11
8786436
Psychopharmacology (Berl). 2004 Jan;171(2):173-8
13680077
Neuropsychopharmacology. 2001 May;24(5):576-89
11282258
J Neurochem. 2005 Jun;93(6):1469-81
15935063
Alcohol. 2002 Nov;28(3):157-67
12551757
Neuron. 2006 Jun 15;50(6):911-21
16772172
Psychopharmacology (Berl). 2006 Mar;184(3-4):328-38
16133126
Psychopharmacology (Berl). 1993;110(3):355-64
7831431
Neuropsychopharmacology. 1999 Mar;20(3):297-307
10063490
Psychopharmacology (Berl). 1994 Aug;115(4):516-28
7871097
Eur J Pharmacol. 1993 Nov 9;249(2):207-13
8287902
Br J Pharmacol. 2000 Jul;130(5):1147-55
10882401
J Pharmacol Exp Ther. 1983 Sep;226(3):817-25
6887012
Behav Pharmacol. 1996 Nov;7(7):669-674
11224464
Brain Res Brain Res Rev. 1993 Sep-Dec;18(3):247-91
8401595
Brain Res Bull. 1992 Aug;29(2):173-8
1525672
Trends Pharmacol Sci. 1997 Feb;18(2):54-9
9090311