Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats.
Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABA(B) receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABA(B) receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABA(B) receptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABA(B) receptor agonists. Thus, GABA(B) receptor agonists and antagonists, and GABA(B) receptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABA(B) receptor agonist CGP44532, the GABA(B) receptor antagonist CGP56433A, and the GABA(B) receptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14days. ICSS thresholds were assessed 6h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30min prior to ICSS testing. Both GABA(B) receptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABA(B) receptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABA(B) receptors.
Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA 92093-0603, USA.
Styliani
S
Vlachou
Neil E
NE
Paterson
Sebastien
S
Guery
Klemens
K
Kaupmann
Wolfgang
W
Froestl
Deboshri
D
Banerjee
M G
MG
Finn
Athina
A
Markou
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D003863:Depression / Q000139:chemically induced* / Q000378:metabolism; D004357:Drug Synergism; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D010721:Phosphinic Acids / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism*; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
C112036:3-amino-2-(S)-hydroxypropyl-methyl-phosphinic acid; D001565:Benzoates; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D010721:Phosphinic Acids; D011743:Pyrimidines; D018080:Receptors, GABA-B; C105509:(3-(1-((3-(cyclohexylmethyl)hydroxyphosphinyl)-2-hydroxypropyl)amino)ethyl)benzoic acid; D005680:gamma-Aminobutyric Acid; D009538:Nicotine; C030986:pyrimidine
Bioorg Med Chem Lett. 2007 Nov 15;17(22):6206-11
17884493
Neuropharmacology. 2005 Jun;48(7):956-64
15857622
Arch Gen Psychiatry. 2004 Jul;61(7):705-13
15237082
Biol Psychiatry. 2006 Feb 1;59(3):284-6
16139814
Psychopharmacology (Berl). 2003 Jul;168(3):347-58
12698231
Trends Pharmacol Sci. 1999 Mar;20(3):87-9
10203861
J Pharmacol Exp Ther. 2008 Jul;326(1):306-14
18445779
Behav Pharmacol. 2010 Jul;21(4):359-68
20571366
Eur J Pharmacol. 1997 Jun 25;329(2-3):223-9
9226416
Behav Pharmacol. 2009 Mar;20(2):146-54
19300238
Psychopharmacology (Berl). 2004 Mar;172(2):179-86
14610636
Behav Brain Res. 2010 Mar 17;208(1):258-64
20006648
Drugs. 2008;68(8):1067-88
18484799
Pharmacol Biochem Behav. 2001 Dec;70(4):531-49
11796152
Brain Res. 1996 Feb 19;709(2):215-20
8833757
J Biol Chem. 1999 Mar 19;274(12):7607-10
10075644
Mol Pharmacol. 2006 Dec;70(6):2027-36
16966477
Drugs Today (Barc). 2005 Nov;41(11):755-66
16395415
Behav Neural Biol. 1993 Jul;60(1):62-8
8216160
Trends Pharmacol Sci. 2005 Jan;26(1):36-43
15629203
Neuropharmacology. 1999 Nov;38(11):1797-804
10587095
Pharmacol Rep. 2007 Nov-Dec;59(6):645-55
18195453
Science. 1999 Jan 1;283(5398):74-7
9872744
Brain Res. 1996 Nov 25;741(1-2):240-5
9001728
J Comp Neurol. 1999 Sep 13;412(1):1-16
10440706
Adv Pharmacol. 2010;58:315-71
20655488
Eur J Pharmacol. 1999 Sep 17;381(1):1-7
10528127
Brain Res. 1997 Aug 22;766(1-2):101-6
9359592
Psychopharmacology (Berl). 1998 Jun;137(4):369-73
9676897
Neuron. 2002 Mar 14;33(6):905-19
11906697
Pharmacol Biochem Behav. 2008 Sep;90(3):409-15
18466962
Psychopharmacology (Berl). 1993;111(2):134-8
7870943
Neuropsychopharmacology. 2004 Jun;29(6):1050-62
15039762
Pharmacol Biochem Behav. 2009 Jan;91(3):409-16
18789350
Proc Natl Acad Sci U S A. 1988 Jul;85(14):5274-8
2899326
Psychopharmacology (Berl). 2003 Jul;168(3):280-92
12712232
Nature. 1997 Mar 20;386(6622):239-46
9069281
Mol Pharmacol. 2001 Nov;60(5):963-71
11641424
Neuropharmacology. 2008 Jun;54(8):1223-32
18452957
Biochem Pharmacol. 2004 Oct 15;68(8):1479-87
15451390
Eur J Neurosci. 2007 May;25(10):3099-108
17561823
Nature. 2010 May 13;465(7295):231-5
20400944
Pharmacol Rev. 2002 Jun;54(2):247-64
12037141
Nature. 1998 Dec 17;396(6712):683-7
9872317
J Biol Chem. 2004 Jul 9;279(28):29085-91
15126507
Behav Brain Res. 2007 Jul 19;181(1):158-62
17498817
Alcohol Alcohol. 2002 Sep-Oct;37(5):495-8
12217945
Br J Pharmacol. 2006 Nov;149(5):581-90
16921399
Neuropeptides. 2008 Jun;42(3):215-27
18468678
J Neurosci. 2003 Apr 15;23(8):3498-505
12716959
Adv Pharmacol. 2010;58:427-51
20655491
Nature. 1998 Dec 17;396(6712):674-9
9872315
Drug Discov Today. 2003 Nov 15;8(22):1025-34
14690633
J Biol Chem. 2010 Jul 2;285(27):20625-33
20406808
Pharmacol Ther. 2006 Jun;110(3):533-43
16644017
Neuroreport. 2005 Feb 28;16(3):307-10
15706241
CNS Neurol Disord Drug Targets. 2007 Apr;6(2):127-40
17430150
J ECT. 2008 Sep;24(3):224-8
18562944
Eur J Pharmacol. 2008 Dec 3;599(1-3):58-64
18848829
Fed Proc. 1979 Oct;38(11):2473-6
488370
J Pharmacol Exp Ther. 2003 Sep;306(3):1068-76
12805481
Psychopharmacology (Berl). 2005 May;179(3):688-99
15668819
Nature. 1998 Dec 17;396(6712):679-82
9872316
Eur Neuropsychopharmacol. 2010 Oct;20(10):731-46
20627663
Neurosci Biobehav Rev. 2005;29(4-5):675-706
15893821
Psychopharmacology (Berl). 2004 Nov;176(2):166-74
15064920
Psychopharmacology (Berl). 2000 Apr;149(2):107-14
10805604
Neuropharmacology. 2001 Apr;40(5):676-85
11311895
Neuron. 2006 May 18;50(4):589-601
16701209
Nature. 1998 May 7;393(6680):76-9
9590692
J Med Chem. 1995 Aug 18;38(17):3297-312
7650684
Brain Res. 1996 Jul 29;728(2):225-30
8864486
Neuropsychopharmacology. 2001 Jul;25(1):55-71
11377919
Psychopharmacology (Berl). 2008 Jun;198(3):351-62
18438738
Physiol Behav. 1992 Jan;51(1):111-9
1741436
Nicotine Tob Res. 2007 Mar;9(3):329-39
17365765
J Pharmacol Exp Ther. 2005 Jan;312(1):290-6
15333677
Psychopharmacology (Berl). 2007 Mar;190(4):541-53
17171558
J Pharmacol Exp Ther. 2003 Oct;307(1):322-30
12954816