Left Panel. The two highest nicotine doses (0.8 & 2.0 mg/kg) produced a CTA on the test session (* = Vehicle vs. 0.8 mg/kg; # = Vehicle vs. 2.0 mg/kg).

Right Panel. Group differences in water consumption were not detected.

Because bupropion has been found to be a nicotinic receptor antagonist

(Fryer et al. 1999; Miller et al. 2002; Slemmer et al. 2000), it was predicted

that bupropion would dose-dependently attenuate the acquisition and

expression of a nicotine CTA.

Anthony S. Rauhut Anthony S. Rauhut 1,2 1,2 andand Stacey K. MardekianStacey K. Mardekian22, Department of Psychology, Department of Psychology11 and Neuroscience Program and Neuroscience Program22, Dickinson College, Carlisle, PA, Dickinson College, Carlisle, PA

ReferencesReferences

DiscussionDiscussionAbstractAbstract

The atypical antidepressant, bupropion, has been shown to be an efficacious

smoking-cessation agent. Its therapeutic mechanism of action, however, is

unknown. In vitro research has shown that bupropion non-competitively

inhibits several nicotinic receptor subtypes (α3β2, α3β4, α4β2 and α7) and

competitively inhibits the α3β2 nicotinic receptor subtype. Using an in vivo

preparation, the present experiments determined the effects of bupropion on

the acquisition (Experiment 2) or expression (Experiment 3) of nicotine

conditioned taste aversion (CTA) in mice. A preliminary experiment

(Experiment 1) examined several nicotine doses to determine an effective

nicotine dose to produce a CTA in CD-1 mice. In Experiment 1, mice (n = 7-

8/dose) were administered vehicle or nicotine (0.2, 0.4, 0.8, or 2.0 mg/kg)

following a 60-minute (min) period of drinking saccharin (0.15%) on 4

alternating drug sessions. On the 4 intervening, nondrug sessions, mice

were permitted to drink water for a 60-min period. The test session occurred

48 hours (h) after the last drug session. In Experiments 2 and 3, mice (n =

6-8/group) were administered vehicle or bupropion (1, 5, 10 or 20 mg/kg) 5

min prior to the nicotine treatment during the drug sessions of Experiment 2

or 5 min prior to the test session of Experiment 3. Consumption data were

subjected to analyses of variance followed by post hoc contrasts involving

Tukey’s HSD tests. The two highest nicotine doses (0.8 and 2.0 mg/kg)

produced reliable CTAs. Furthermore, the lowest bupropion dose (1 mg/kg)

failed to alter acquisition of nicotine CTA whereas the moderate (5 mg/kg)

and high (10 and 20 mg/kg) bupropion doses attenuated and blocked

acquisition of nicotine CTA, respectively. No bupropion dose altered

expression of nicotine CTA. Thus, bupropion dose-dependently and

specifically altered the acquisition of nicotine CTA, suggesting that nicotinic

receptor activation is involved in the acquisition, but not the expression, of

nicotine CTA.

Experiment 1 found that nicotine dose-dependently produced a CTA in CD-1

mice. These results are consistent with other reports that have shown that

nicotine produces a CTA in other mouse strains (Risinger & Boyce, 2002).

Experiment 2 found that bupropion dose-dependently blocked the acquisition of

a nicotine CTA. That is, the lowest bupropion dose (1 mg/kg) failed to alter the

CTA, whereas the moderate bupropion dose (5 mg/kg) attenuated and the high

bupropion doses (10 and 20 mg/kg) blocked the acquisition of the nicotine CTA.

These results suggest that bupropion blocks the aversive properties of nicotine,

consistent with its biochemical effect as a nicotinic receptor antagonist (Fryer &

Lucas,1999; Miller et al. 2002; Slemmer et al. 2000).

The results of Experiment 2 are inconsistent with a previous study that showed

that bupropion fails to alter a nicotine CTA (Shoaib et al. 2003). Most likely, the

discrepancy between the Shoaib et al. (2003) study and the present report is

due to differences in the injection interval between bupropion and nicotine, as

the injection interval has been found to be an important variable in determining

a nicotinic receptor antagonist’s effect on nicotine CTA. For example, it has

been shown that the classic competitive nicotinic receptor antagonist, dihydro-

ß-erythroidine, administered 30 min in advance of nicotine fails to alter a

nicotine CTA; however, co-administration of dihydro-ß-erythroidine with nicotine

effectively attenuates the acquisition of a nicotine CTA (Shoaib et al. 2000).

Experiment 3 found that bupropion did not alter expression of nicotine CTA,

suggesting that expression of nicotine CTA is mediated by a neurotransmitter

system other than the cholinergic system.

HypothesisHypothesis

IntroductionIntroduction

The atypical antidepressant, bupropion, has been shown to be an

efficacious smoking-cessation agent (Hurt et al. 1997; Jorenby et al. 1999).

The biochemical mechanisms by which bupropion helps people quit

smoking are unknown.

Recently, several in vitro and in vivo studies have shown that bupropion is

a nicotinic receptor antagonist (Fryer & Lucas, 1999; Miller et al. 2002;

Slemmer et al. 2000).

However, studies examining the effects of bupropion on nicotine

conditioned taste aversion (CTA) have produced mixed results, with

bupropion either facilitating (Dwoskin et al., 2006) or having no effect

(Shoaib et al., 2003).

PurposePurpose Thus, the present experiment determined the ability of bupropion to

attenuate the aversive properties of nicotine as assessed using the CTA

paradigm. The effects of bupropion on both the acquisition and expression

of nicotine CTA were evaluated.

MethodsMethods

Experiment 1

ResultsResults

This research was supported by a grant from the

USPHS (DA019866) awarded to A. S. Rauhut.

Bupropion Blocks Acquisition, but not Expression, of Nicotine Conditioned Taste Aversion in CD-1 MiceBupropion Blocks Acquisition, but not Expression, of Nicotine Conditioned Taste Aversion in CD-1 Mice

Acclimation7 Days

Pretest1 Session

20 min access to saccharin (15%) in the absence of any injections

Conditioning8 Sessions—Alternating Drug and Nondrug Sessions (counterbalanced)

Drug Sessions: 1 h access to saccharin followed immediately by an injection (sc) of vehicle or nicotine (0.2, 0.4, 0.8, or 2.0 mg/kg)

Nondrug Sessions: 1 h access to tap water in the absence of any injections

Experiments 2 & 3

Conditioning8 Sessions—Alternating Drug and Nondrug Sessions (counterbalanced)

Drug Sessions:

Exp 2: 1 h access to saccharin followed immediately by an injection (sc) of vehicle or bupropion (1, 5, 10, or 20 mg/kg), followed 5 min later by an injection (sc) of vehicle or nicotine (0.8 mg/kg)

Exp 3: 1 h access to saccharin followed immediately by an injection (sc) of vehicle or nicotine (0.8 mg/kg)

Nondrug Sessions: 1 h access to tap water in the absence of any injections

Experiment 1

Experiment 2

AcknowledgementsAcknowledgements

24 h

24 h

24 h

24 h

24 h

24 h

Test1 Session

1 h access to saccharin in the absence of any injections

Pretest1 Session

20 min access to saccharin (15%) in the absence of any injections

Test1 Session

Exp 2: 1 h access to saccharin in the absence of any injections

Exp 3: Injection (sc) of vehicle or bupropion (1, 5, 10, or 20 mg/kg) 5 min prior to a 1 h access period to saccharin

1. Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT. (2006) Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 12(3-4):178-207.

2. Fryer JD and Lukas RJ (1999) Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine and ibogaine. Journal of Pharmacology and Experimental Therapeutics 288:88-92.

3. Hurt R, Sachs D, Glover P, Sullivan C, Croghan I, Sullivan P (1997) A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine 337:1195-1202.

4. Jorenby DE, Leischow S, Nides M, Rennard S, Johnston J, Hughes A, Smith S, Muramoto M, Daughton D, Doan K, Fiore M, Baker T (1999) A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. New England Journal of Medicine 340:685-691.

5. Miller DK, Sumithran SP, Dwoskin LP (2002) Bupropion inhibits nicotine-evoked [3H] overflow from rat straital slices preloaded with [3H] dopamine and from rat hippocampal slices preloaded with [3H] norepinephrine. Journal of Pharmacology and Experimental Therapeutics 302:1113-1122.

6. Risinger FO and Boyce JM (2002) Conditioning tastant and the acquisition of conditioned taste avoidance to drugs of abuse in DBA/2J mice. Psychopharmacology 160:225-232.

7. Shoaib M, Sidhpura N, Shafait S (2003) Investigating the actions of bupropion on dependence-related effects of nicotine in rats. Psychopharmacology 165:405-412.

8. Shoaib M, Zubaran C, Stolerman IP (2000) Antagonism of stimulus properties of nicotine by dihydro-ß-erythroidine (DHßE) in rats. Psychopharmacology 149:140-146.

9. Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. Journal of Pharmacology and Experimental Therapeutics 295:321-327.

Left Panel. Bupropion dose-dependently blocked acquisition of nicotine CTA. The lowest bupropion dose (1 mg/kg) failed to alter the acquisition of the nicotine CTA whereas the moderate (5 mg/kg) and high (10 and 20 mg/kg) bupropion doses attenuated and blocked the acquisition of the nicotine CTA, respectively, on several sessions. (* = Vehicle + Nicotine vs. 10 Bup + Nicotine; # = Vehicle + Nicotine vs. 20 Bup + Nicotine).

Right Panel. Group differences were not detected in mice pretreated with any bupropion dose followed by vehicle compared to the Vehicle + Vehicle control mice.

Acclimation7 Days

Experiment 3

Left Panel. All nicotine-conditioned mice, regardless as to the bupropion dose, (except the Nicotine +10 Bupropion mice) drank significantly less than control mice (* = comparison to Vehicle + Vehicle control mice), suggesting that bupropion did not attenuate the expression of nicotine CTA. The Nicotine + 20 Bupropion mice drank significantly less than the Nicotine + Vehicle mice (# = comparison to Nicotine + Vehicle mice). However, the Vehicle + 20 Bupropion mice drank significantly less than the Vehicle + Vehicle control mice, suggesting that the potentiation observed in the Nicotine + 20 Bupropion mice was an artifact of a bupropion induced disruption of drinking.

Right Panel. Group differences in weight were not detected on the test session.

1 2 3 4 Pretest Test 0

1

2

3

4

5

6

7

8

9

10

Vehicle + Nicotine

1 Bup + Nicotine

5 Bup + Nicotine

10 Bup + Nicotine

20 Bup + Nicotine

Pretreatments

* # * #

Drug Session

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char

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(ml)

1 2 3 4 Pretest Test 0

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Vehicle + Vehicle1 Bup + Vehicle5 Bup + Vehicle

10 Bup + Vehicle

20 Bup + Vehicle

Pretreatments

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(ml)

Vehicle 1 5 10 200

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VehicleNicotine

Nicotine Pretreatment

** **#*

Test

Bupropion Pretreatment(mg/kg)

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Vehicle 1 5 10 200

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Nicotine PretreatmentTest

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Wei

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1 2 3 4 Pretest Test 0

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2

3

4

5

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Vehicle0.2 mg/kg

0.4 mg/kg

0.8 mg/kg

2.0 mg/kg

Nicotine Dose

*#

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Sac

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sum

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1 2 3 4 Test 0

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0.2 mg/kgVehicle

2.0 mg/kg

0.4 mg/kg0.8 mg/kg

Nondrug Session

Wat

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(ml)