Examining the clinical efficacy of bupropion and nortriptyline as smoking cessation agents in a rodent model of nicotine withdrawal.
BACKGROUND
At present, there is a lack of an established animal model to demonstrate the clinical efficacy of smoking cessation agents in the laboratory. The aim of this study was to compare the effects of the antidepressants bupropion and nortriptyline, clinically proven smoking cessation aids, within a rodent model of a nicotine withdrawal based on somatic measures.


METHODS
Male hooded Lister rats were chronically exposed to nicotine (3.16 mg kg1 day1) for 7 days via SC implanted ALZET osmotic minipumps. Animals were acutely pre-treated with bupropion (10, 30 or 60 mg/kg, IP) or nortriptyline (1.5, 4.7 and 15 mg/kg, IP), and nicotine withdrawal was precipitated by mecamylamine (1 mg/kg).


RESULTS
Precipitation of nicotine withdrawal led to an increase in somatic signs including body shakes, chews, eye blinks, foot licks, head shakes and ptosis. Bupropion dose-dependently decreased the total abstinence scores and reduced the occurrence of some individual somatic signs. Pre-treatment with 60 mg/kg bupropion did not result in a significant increase in total abstinence scores or individual somatic signs scores after mecamylamine challenge, compared to the mecamylamine control group, suggesting nicotine withdrawal is fully attenuated at this dose. Similarly, the highest dose of nortriptyline reduced total abstinence scores and some individual somatic signs to the level of the mecamylamine control group. However, nortriptyline was only effective at alleviating somatic measures of withdrawal at doses which also suppressed locomotor activity.


CONCLUSIONS
In concurrence with clinical findings proposing alleviation of withdrawal states as a possible mechanism of bupropion and nortriptyline's smoking cessation action, both drugs were found to ameliorate somatic signs of nicotine withdrawal in rodents.
Wing
V C
VC
Psychobiology Research Laboratories, School of Neurology, Neurobiology and Psychiatry, University of Newcastle, Newcastle Upon Tyne, UK.
Shoaib
M
M
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016642:Bupropion / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008464:Mecamylamine; D009538:Nicotine / Q000009:adverse effects*; D009661:Nortriptyline / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D016540:Smoking Cessation; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000209:etiology; D014029:Tobacco Use Disorder / Q000188:drug therapy*
D000928:Antidepressive Agents; D016642:Bupropion; D008464:Mecamylamine; D009538:Nicotine; D009661:Nortriptyline
Psychopharmacology (Berl). 2002 Jul;162(2):156-67
12110993
Clin Ther. 2001 May;23(5):744-52
11394732
Pharmacol Biochem Behav. 1992 Nov;43(3):779-84
1448472
J Pharmacol Exp Ther. 2000 Mar;292(3):1053-64
10688623
Health Psychol. 1992;11(5):331-4
1425551
Nature. 1998 May 7;393(6680):76-9
9590692
Neuropharmacology. 1993 Oct;32(10):937-49
8295716
Psychopharmacology (Berl). 1997 Feb;129(4):348-56
9085404
J Psychiatry Neurosci. 1995 Jan;20(1):25-32
7865498
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD000031
17253443
Cell Mol Neurobiol. 1999 Aug;19(4):467-89
10379421
Addict Biol. 2005 Sep;10(3):219-31
16109583
Arch Gen Psychiatry. 1986 Mar;43(3):289-94
3954551
Ann Intern Med. 2001 Sep 18;135(6):423-33
11560455
Pharmacol Biochem Behav. 1981 Jun;14(6):823-6
7196048
J Clin Psychiatry. 1983 May;44(5 Pt 2):74-8
6406468
Clin Pharmacol Ther. 2001 Jun;69(6):438-44
11406741
Hosp Pract (1995). 1996 Oct 15;31(10):47-54, 57-9
8859207
Psychopharmacology (Berl). 2003 Jul;168(3):347-58
12698231
Brain Res. 1998 Jan 1;779(1-2):214-25
9473676
J Pharmacol Exp Ther. 1998 Mar;284(3):1015-25
9495862
Psychopharmacology (Berl). 2003 Aug;169(1):1-9
12811464
Psychiatry Res. 2004 Apr 30;130(3):269-81
15135160
Psychopharmacology (Berl). 1994 Jun;115(1-2):180-4
7862893
Nature. 1978 Nov 9;276(5684):186-8
216919
Br J Psychiatry. 1999 Feb;174:173-8
10211174
N Engl J Med. 1999 Mar 4;340(9):685-91
10053177
Prim Care. 1999 Sep;26(3):653-69
10436292
Psychopharmacology (Berl). 2006 Mar;184(3-4):494-503
16163521
Arch Gen Psychiatry. 1998 Aug;55(8):683-90
9707377
Eur J Pharmacol. 2002 Jul 19;448(2-3):185-91
12144940
Arch Intern Med. 1998 Oct 12;158(18):2035-9
9778204
Proc Natl Acad Sci U S A. 1990 Oct;87(19):7522-6
1977162
Am Fam Physician. 2005 Jan 1;71(1):67-8
15663027
J Affect Disord. 1998 Dec;51(3):237-54
10333980
Psychopharmacology (Berl). 2000 Jan;148(1):33-40
10663415
Psychopharmacology (Berl). 1976 Oct 20;50(1):35-9
827760
Pharmacol Biochem Behav. 2001 Dec;70(4):551-9
11796153
J Clin Psychiatry. 1998;59 Suppl 4:66-72
9554323
J Clin Psychiatry. 1995 Sep;56(9):395-401
7665537
Psychopharmacology (Berl). 2003 Feb;165(4):405-12
12451438
N Engl J Med. 1997 Oct 23;337(17):1195-202
9337378
Arch Gen Psychiatry. 1991 Jan;48(1):52-9
1984762
Naunyn Schmiedebergs Arch Pharmacol. 1994 May;349(5):443-6
8065457
Synapse. 2003 Oct;50(1):20-8
12872290
J Pharmacol Exp Ther. 2000 Oct;295(1):321-7
10991997
Psychopharmacology (Berl). 1992;107(2-3):285-9
1615127
Neuropsychopharmacology. 1999 Oct;21(4):560-74
10481840
Psychopharmacology (Berl). 1999 Aug;145(4):370-7
10460313
Am J Psychiatry. 2004 Nov;161(11):2100-7
15514412