Varenicline effects on cocaine self administration and reinstatement behavior

ArticleinBehavioural pharmacology 21(2):96-103 · March 2010with29 Reads
Impact Factor: 2.15 · DOI: 10.1097/FBP.0b013e328336e9c5 · Source: PubMed
Abstract

This study tested the effects of the nicotine addiction treatment varenicline on cocaine self administration (SA) and reinstatement. In one SA experiment, rats were trained to self-administer cocaine (0.75 mg/kg/infusion). Thereafter, daily SA sessions continued as before except that every fourth session was preceded by a presession injection of varenicline (0.0, 0.3, 1.0 and 2.0 mg/kg, SC, 50-min presession). In three reinstatement experiments, animals were exposed sequentially to SA training, extinction training, and several reinstatement test sessions. In two of the reinstatement experiments, cocaine-seeking was reinstated by presentation of cocaine-predictive cues at the onset of the test session (cue reinstatement). In a third reinstatement experiment, cocaine-seeking was reinstated by a presession injection of cocaine (drug reinstatement). Each reinstatement session was preceded by an injection of either vehicle or varenicline (dose range of 0.1-2.0 mg/kg). The SA and reinstatement experiments showed that low-dose varenicline decreases reinstatement behavior, without significantly affecting cocaine SA. In contrast, high-dose varenicline increases reinstatement of cocaine-directed behavior and decreases cocaine SA. A control study showed that sucrose-directed behavior is unaltered by varenicline. On the basis of these findings, low-varenicline doses might decrease relapse in cocaine-addicted individuals, but high doses of varenicline might have the opposite effect.

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Available from: Karine Guillem
96 Original article
Varenicline effects on cocaine self administration
and reinstatement behavior
Karine Guillem
a
and Laura L. Peoples
b
This study tested the effects of the nicotine addiction
treatment varenicline on cocaine self administration (SA)
and reinstatement. In one SA experiment, rats were trained
to self-administer cocaine (0.75 mg/kg/infusion).
Thereafter, daily SA sessions continued as before except
that every fourth session was preceded by a presession
injection of varenicline (0.0, 0.3, 1.0 and 2.0 mg/kg, SC,
50-min presession). In three reinstatement experiments,
animals were exposed sequentially to SA training,
extinction training, and several reinstatement test sessions.
In two of the reinstatement experiments, cocaine-seeking
was reinstated by presentation of cocaine-predictive cues
at the onset of the test session (cue reinstatement). In a
third reinstatement experiment, cocaine-seeking was
reinstated by a presession injection of cocaine (drug
reinstatement). Each reinstatement session was preceded
by an injection of either vehicle or varenicline (dose range
of 0.1–2.0 mg/kg). The SA and reinstatement experiments
showed that low-dose varenicline decreases reinstatement
behavior, without significantly affecting cocaine SA.
In contrast, high-dose varenicline increases reinstatement
of cocaine-directed behavior and decreases coc aine SA.
A control study showed that sucrose-directed behavior
is unaltered by varenicline. On the basis of these findings,
low-varenicline doses might decrease relapse in cocaine-
addicted individuals, but high doses of varenicline might
have the opposite effect. Behavioural Pharmacology
21:96–103
c
2010 Wolters Kluwer Health | Lippincott
Williams & Wilkins.
Behavioural Pharmacology 2010, 21:96–103
Keywords: acetylcholine, addiction, cocaine, dopamine, ethanol, nicotine,
reinstatement, relapse, self administration, varenicline
a
Department of Integrative Neurophysiology, CNCR, VU University, Amsterdam,
The Netherlands and
b
Department of Psychiatry, University of Pennsylvania
Medical School, Philadelphia, Pennsylvania, USA
Correspondence to Dr Laura L. Peoples, PhD, Department of Psychiatry,
University of Pennsylvania School of Medicine, 125 S 31st Street, Philadelphia,
PA 19106, USA
E-mail: lpeoples@mail.med.upenn.edu
Received 6 October 2009 Accepted as revised 21 December 2009
Introduction
Cocaine addiction is a chronic relapse disorder for which
there is currently no effective treatment. Clinical studies
suggest that relapse can be induced by a number of
factors, including exposure to either cocaine-predictive
stimuli or a dopamine (DA) agonist drug (Jaffe et al.,
1989; O’Brien et al., 1990; Ehrman et al., 1992; Reid et al.,
1998; Volkow et al., 1999). As in humans, drug-associated
cues, cocaine and other DA agonist drugs precipitate
cocaine-directed behavior in animals (De Wit and
Stewart, 1981; Wise et al., 1990; Schenk and Partridge,
1999). Pharmacological treatments that decrease cue-
activated and drug-activated cocaine-directed behavior of
animals are considered candidate relapse prevention
medications for cocaine-addicted individuals.
In animals, DA neuron activity contributes to both cue
and drug-evoked cocaine-directed behavior (Spealman
et al., 1999; Ikemoto and Wise, 2004; Bossert et al., 2005).
Recent findings show that the increase in DA activity is
mediated in part by an increase in acetylcholine (ACh)
actions at ventral tegmentum (VTA) nicotinic alpha4be-
ta2 (a4b2) receptors (You et al., 2008). Disruption of these
nicotinic receptor actions is thus a potential target for
relapse prevention medications. Consonant with this possi-
bility, the nicotine-receptor antagonist mecamylamine de-
creases cocaine craving in individuals addicted to both
cocaine and nicotine (Reid et al., 1999).
One drug that could be useful in disrupting effects of
conditioned ACh-induced activation of nicotine recep-
tors is varenicline. The drug, which is a new nicotine
addiction treatment (Gonzales et al., 2006; Rollema et al.,
2007), is a partial agonist at a4b2 receptors. Owing to the
high affinity and low efficacy of varenicline for the a4b2
receptor, the drug is expected to weakly stimulate a4b2
receptors and to concomitant ly block access of more
efficacious, full agonists to the receptor. (Coe et al., 2005;
Rollema et al., 2007). These partial agonist actions are
expected to limit ACh-induced increases in DA neuron
firing. Given evidence for a role of ACh-induced activa-
tion of nicotinic receptors in evoking cocaine seeking in
animals (Wise et al., 1990; Schenk and Partridge, 1999,
You et al., 2008) and cocaine craving in humans (Reid
et al., 1998, 1999), we hypothesized that varenicline
might decrease cue-evoked and drug-evoked cocaine-
directed behavior.
To evaluate the varenicline hypothesis, we tested for an
effect of varenicline on cue-induced and cocaine-induced
reinstatemen t of previously extinguished cocaine-directed
behavior (also referred to herein as cocaine seeking) in
rats. We additionally characterized the effect of vareni-
cline on cocaine-reinforced operant behavior (i.e. cocaine
self administration), as the effect of varenicline on the
behavior is relevant to the potential therapeutic utility of
varenicline. In total, the present experiments show that
0955-8810
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2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e328336e9c5
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Page 1
low doses of varenicline do not affect cocaine SA but
high doses decrease it. Though low varenicline doses
have the predicted effect of decreasing cue-evoked and
drug-evoked cocaine seeking, high-dose varenicline has
the opposite effect. The data have implications for treat-
ment of cocaine addiction. The results are also rele-
vant to varenicline treatment of other drug addict ions.
Methods
Subjects
Male Long–Evans rats were used in all experiments.
Protocols were in accordance with the Guide for the Care
and Use of Laboratory Animals published by the US
Public Health Service and approved by the Animal Care
and Use Committee of the University of Pennsylvania.
Surgery and postoperative maintenance
Animals were deeply anesthetized with ketamine
(30 mg/kg intraperitoneal) and xylazine (5 mg/kg intra-
peritoneal) and then implanted with an indwelling
catheter (Silastic tubing: inner diameter = 0.012 inches,
outer diameter = 0.025 inches; Dow Corning Corpora-
tion, Midlan d, Michigan, USA) in the external jugular
vein, as described earlier (Guillem et al., 2005). The
catheter was secured to the vein with surgical silk sutures
and passed subcutaneously to the top of the back where it
exited into a connector (modified 22 gauge cannula).
After surgery, animals were flushed daily with 0.2 ml of
an ampicillin solution (0.1 g/ml) containing heparin
(300 IU/ml) to maintain patency. Animals had free access
to water but were restricted to 15–20 g of food each day
to maintain body weight at approximately 370 g.
Apparatus
All training and testing sessions were conducted in
operant chambers placed in sound-attenuating cubicles.
The operant chambers were equipped with a retractable
response lever. There was also a cue light, which was
located above the lever and a speaker at the top of the
chamber. The operant chambers, as well as the co mputer
hardware and software used to control events in the
chambers were purchased from Med Associates Inc.
Cocaine self administration sessions and training
Experimental sessions started at the beginning of the
dark cycle on the sixth day postsurgery. All animals were
trained to self-administer cocaine (0.75 mg/kg/infusion)
under a fixed ratio 1 (FR1) schedule of reinforcement
during daily 2-h sessions . Each cocaine infusion was
paired with a 7-s illumination of the cue light and a 7-s
activation of an auditory tone. A 20-s timeout period
followed each reinforced lever press, during which
responding was reco rded but not reinforced. In all experi-
ments, SA training continued 21 days, until the average
group response rate varied less than 10% for three
consecutive sessions.
Experiment 1: effect of varenicline pretreatment
on cocaine self administration and cue-induced
reinstatement
Cocaine self administration
Eight rats were trained to self-administer cocaine (see
above). Thereafter, daily train ing sessions continued as
before except that every fourth session was preceded by
an injection of varenicline (0.0, 0.3, 1.0 and 2.0 mg/kg,
free base, subcutaneous). The tes t doses of varenicline
overlapped with the range of doses tested in studies of
nicotine and ethanol SA (Rollema et al., 2007; Steensland
et al., 2007). Injec tions were administered 50 min before
the start of a session. Each animal was exposed to each of
the varenicline doses. The order in which the varenicline
doses were tested was counterbalanced across animals,
according to a within-subject Latin-square design.
Cue-induced reinstatement
A separate group of animals (n = 8) were trained to self-
administer cocaine and then exposed to daily 2-h extinc-
tion sessions. During these sessions, the operant response
lever was available but lever presses were not followed by
either cocaine or the conditioned cues that were normally
paired with cocaine delivery during daily SA sessions.
Extinction training continued for 14 days, until the
average group response rate varied less than 10% for three
consecutive sessions.
Following extinction training, animals were exposed to
cue reinstatement sessions. Between each cue reinstate-
ment session rats underwent 3 days of extinction training.
Each reinstatement session began with a single presenta-
tion of the light plus tone cue that was normally paired
with cocaine infusion during SA sessions. The light
plus tone cue was not presented at any other time during
the 2-h cue reinstatement session. During the first two
reinstatement sessions, animals were exposed to 0.0 and
2.0 mg/kg varenicline. The drug doses were administered
according to a Latin-square design in two separate reinstate-
ment sessions. On the basis of the outcome of these
sessions, three additional cue reinstatement sessions were
conducted to first characterize the effect of two additio-
nal varenicline doses (i.e. 0.1 and 0.3 mg/kg), and to then
retest the effect of 2.0 mg/kg varenicline.
Experiment 2: effect of low-dose varenicline
on reinstatement behavior
Experiment 2 included three new animal groups. In one
group, we again tested the effect of the low varenicline
doses on cue-induced reinstatement of cocaine seeking.
In a second group of animals, we examined the effect
of the same varenicline doses on cocaine-induced rein-
statement of cocaine seeking. Finally, in a third animal
group, we tested the effect of low-dose varenicline on
cue-induced reinstatement of sucrose-directed operant
behavior. The cocaine groups were exposed to the
same SA and extinction training procedures used in
Varenicline and cocaine Guillem and Peoples 97
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 2
Experiment 1. Cue reinstatemen t sessions were also
conducted as in Experiment 1. The drug reinstatement
sessions were similar to the cue reinstatement sessions,
except that in the drug sessions animals were exposed
to cocaine (i.e. 10 mg/kg intraperitoneal, 15 min before
the session start), rather than to the cocaine-predictive
light plus tone cue. The sucrose group was trained to
self-administer sucrose on an FR1 schedule of reinforce-
ment. Sucrose SA sessions were conducted in an iden-
tical manner to the cocaine SA sessions except for the
following: (i) each reinforced lever press was followed by
delivery of sucrose solution into a drinking well (0.2 ml of
32% sucrose over 10 s) inste ad of a cocaine infusion and
(ii) the number of sucrose infusions was matched to the
daily number of cocaine infusions earned by the cocaine
group. After 21 days of sucrose self-administration train-
ing, the sucrose group was exposed to 14 days of extinc-
tion training. Extinction training was followed by cue
reinstatement test sessions. At the beginning of each of
these cue reinstatement sessions, the tone plus light
cue typically paired with delivery of the sucrose reinforcer
was presented at the onset of the session. The cue
reinstatement procedures applied to the sucrose group
were otherwise comparable to those applied to the cocaine
groups. The varenicline test doses were the same for all
three groups of animals. Varenicline exposure was counter-
balanced across animals according to a Latin-square
design.
Results
Experiment 1: effect of varenicline on cocaine self
administration and cue reinstatement of cocaine
seeking
Cocaine self administration
Animals included in the cocaine SA experiment acquired
and maintained stable cocaine SA (Fig. 1a). The SA beha-
vior of this group of animals was comparable to that
exhibited by other groups of animals included in experi-
ments 1 and 2 (not shown).
Once stable SA behavior was established, we tested the
effect of varenicline (Fig. 1b). A repeated-measures
analysis of variance (ANOVA) with dose as a factor (0.0,
0.3, 1.0 and 2.0 mg/kg, free base, subcutaneous) showed
a significant effect of dose [F(3,21) = 14.78; P < 0.001]
on average total number of cocaine infusions. Post-hoc
analyses showed that both 1.0 and 2.0 mg/kg vareni-
cline significantly decreased cocaine intake compared
with vehicle (Newman–Keuls: 0.0 vs. 1.0 mg/kg vareni-
cline, P < 0.01; 0.0 vs. 2.0 mg/kg varenicline, P < 0.01).
A plot of self-infusion rate as a function of 10-min inter-
vals during the varenicline test sessions (Fig. 2) showed
that varenicline did not have an immediate effect on the
rate of cocaine intake. However, at most session time-
points Z 30 min, the co caine infusion rate was decreased
during the 1.0 and 2.0 mg/kg varenicline sessions relative
to the 0.0 mg/kg varenicline session. A repeated-measures
ANOVA with dose (0.0, 0.3, 1.0 and 2.0 mg/kg) and time
(10-min intervals) as factors showed a significant effect
of time [F(11,77) = 27.38; P < 0.001] on average number
of cocaine infusions per 10-min, as well as a signi-
ficant interaction between dose and time [F(33,23) = 1.68;
P < 0.05]. Post-hoc analyses showed that the cocaine
infusion rate was significantly lower during the 2.0 mg/kg
varenicline session than during the 0.0 mg/kg varenicline
session, at the 50-min time-point and all time-points
Z 80 min (P < 0.05). The cocaine infusion rate during
the 1.0 mg/kg varenicline test session was reduced
relative to the 0.0 mg/kg varenicline session at all session
time-points Z 80 min.
Fig. 1
35
30
25
20
15
10
0123456789101112131415161718192021
∗∗
∗∗
(a)
(b)
Average number of cocaine infusions
Self-administration sessions (2h/day)
Varenicline doses (mg/kg)
30
25
20
15
10
5
0
0 0.3 1 2
Reinforced responses
Effects of varenicline on cocaine self administration in Experiment 1.
(a) Acquisition and maintenance of stable cocaine self administration.
Average number of cocaine infusions per session is plotted as a
function of session number. (b) Varenicline-induced decreases in
cocaine self administration. Average number of cocaine infusions is
plotted as a function of varenicline dose. ** a significant difference
compared with 0.0 mg/kg varenicline with P < 0.01.
98 Behavioural Pharmacology 2010, Vol 21 No 2
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 3
Cue reinstatement
Following cocaine SA training and subsequent extinction
training (Fig. 3a), animals were exposed to two cue
reinstatement test sessions. Before the start of each session,
animals were pretreated with either 0.0 or 2.0 mg/kg vareni-
cline. Exposure to the cocaine-associated cues reinstated
cocaine seeking during both test sessions (Fig. 3b). A
repeated-measures ANOVA with varenicline dose as a
factor showed a significant effect of varenicline dose
[F(1,7) = 8.87; P < 0.05] on average number of responses
during the 2-h cue reinstatement sessions. In contrast, to
the predicted effect, the operant response rate during
cue reinstatement was increased at the 2.0 mg/kg vareni-
cline dose relative to the response rate at the 0.0 mg/kg
varenicline dose (Fig. 2b).
Given the unexpected outcome of the 2.0 mg/kg test
session, three additio nal cue reinstatement sessions were
conducted. The first two sessions were used to test the
effects of two lower varenicline doses (0.1, 0.3 mg/kg).
The third session was used to retest the effect of the
2.0 mg/kg dose (Fig. 3b). A repeated-measures ANOVA
with varenicline dose (0.0, 0.1, 0.3 mg/kg and the second
2.0 mg/kg test session) as a factor showed a significant
effect of dose [F(3,21) = 22.88; P < 0.001] on average
number of operant responses. Post-hoc analyses sh owed
that 0.1 and 0.3 mg/kg varenicline decreased average
number of responses (Newman–Keuls: 0.0 vs. 0.1 mg/kg
varenicline, P < 0.01; 0.0 vs. 0.3 mg/kg varenicline,
P < 0.05). The 2.0 mg/kg varenicline dose significantly
increased average number of operant responses (0.0 vs.
2.0 mg/kg varenicline, P < 0.05). The increas ed operant
responding during the second 2.0 mg/kg varenicline test
session replicated the result of the original 2.0 mg/kg
varenicline test and showed that the reduced operant
response rates during the 0.01 and 0.3 mg/kg varenicline
test sessions were not attributable to repeated exposure
to the cue reinsta tement procedure.
Experiment 2: effect of low-dose varenicline on
reinstatement of cocaine-directed and sucrose-directed
behavior
Cocaine seeking
In Experiment 2, we retested the effect of low-dose
varenicline (i.e. 0.0, 0.1 and 0.3 mg/kg) on cue-induced
Fig. 2
5
4
3
2
1
0
0204060
Time (min)
80 100 120
Number of infusions
0
0.3
1
2
Effect of varenicline on the pattern of operant behavior during cocaine
self administration sessions. Number of responses per 10-min interval
is plotted as a function of session time. Data are shown for all
varenicline test doses.
Fig. 3
Average number of responses
∗∗
(b)
Varenicline doses (mg/kg)
100
80
60
40
20
0
100
80
60
40
20
0
0
0.30.1 22
35
40
30
25
20
15
10
5
0
(a)
01234567891011121314
Self-administration sessions (2h/day)
Reinforced responses
Extinction behavior and effects of varenicline during the cue-induced
reinstatement sessions of Experiment 1. (a) Extinction of cocaine-
directed operant behavior. Average number of presses is plotted as a
function of the extinction session number. (b) Effects of varenicline on
cue-induced reinstatement. Average number of presses is plotted as a
function of varenicline dose. The left panel of the graph corresponds to
the initial 0.0 and 2.0 mg/kg varenicline tests and the right panel shows
data collected during the subsequent evaluation of the 0.1 and
0.3 mg/kg varenicline sessions, as well as the retest of the 2.0 mg/kg
varenicline dose. * and ** a significant difference compared with
0.0 mg/kg varenicline with P < 0.05 and P < 0.01 respectively.
Varenicline and cocaine Guillem and Peoples 99
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 4
reinstatement and additionally tested the effect of the
same varenicline doses on cocaine-induced reinstatement
of cocaine seeking. For the cue reinstatement sessions, a
repeated-measures ANOVA showed a significant effect of
varenicline dose [F(2,14) = 25.08; P < 0.001] on operant
responding (Fig. 4a). Post-hoc analyses showed that 0.1
and 0.3 mg/kg varenicline decreased average number of
responses relative to the 0.0 mg/kg dose (Newman–Keuls:
0.0 vs. 0.1 mg/kg varenicline, P < 0.001; 0.0 vs. 0.3 mg/kg
varenicline, P < 0.001). Moreover, 0.3 mg/kg varenicline
induced a more pronounced decrease in responding
than did 0.1 mg/kg varenicline (P <0.05). For the drug-
reinstatement experiment, a repeated-measures ANOVA
revealed a significant effect of varenicline dose on ave-
rage number of responses during drug reinstatement
[F(2,14) = 13.48; P < 0.001] (Fig. 4b). Post-hoc analyses
showed that each of the 0.1 and 0.3 mg/kg varenicline
doses decreased average number of responses relative
to 0.0 mg/kg varenicline (Newman–Keuls: 0.0 vs. 0.1
mg/kg varenicline, P < 0.01; 0.0 vs. 0.3 mg/kg varenicline,
P < 0.001).
Sucrose seeking
To test for a general effect of low-dose varenicline
on reinstatement of operant responding we tested the
effect of varenicline (i.e. 0.0, 0.1 and 0.3 mg/kg) on
cue reinstatement of sucrose-directed operant behavior
(Fig. 4c). Animals were first trained to self-administer
sucrose (oral) and then subjected to the same extinc-
tion and cue reinstatement procedures as were the cocaine-
trained animals. A repeated-measures ANOVA showed that
there was no significant effect of varenicline dose on the
average number of operant responses during cue reinstate-
ment of sucrose seeking [F(2,14) = 1.75; NS].
Discussion
Major findings
Low varenicline doses (i.e. 0.1 and 0.3 mg/kg) decrease
cue and drug-induced reinstatement of cocaine seeking,
without affecting cocaine SA. In contrast, high-dose
varenicline (2.0 mg/kg) increases cue reinstatement and
decreases cocaine SA.
Varenicline effect on reinstatement of cocaine-directed
behavior
A specific effect on cocaine-directed behavior
One interpretation of the varenicline effects on reinstate-
ment of cocaine seeking is that varenicline has general
effects on operant responding. Available data are not
consistent with this interpretation. The present experi-
ment showed that varenicline doses that significantly
decrease cue and drug reinstatement of cocaine seeking
have no effect on cue reinstatement of sucrose-directed
behavior. In addition, the varenicline dose that increased
cue reinstatement of cocaine seeking in the present
experiment has no effect on rates of food-maintained
behavior (Rollema et al., 2007; Steensland et al., 2007;
LeSage et al., 2009) . An alternative interpretation of the
varenicline effects on reinstatement is that the drug acts
selectively on mechanisms that mediate reinstatement
of cocaine-directed behavior. More specifically, it is reason-
able to infer that low-dose varenicline disrupts mechan-
isms that mediate reinstatement of cocaine seeking and
that high-dose varenicline has the opposite effect.
Possible mechanisms
The present reinstatement studies were motivated by
the hypothesis that the partial antagonist a4b2 vareni-
cline actions are sufficient to block the ACh a4b2 recep-
tor mechanisms that contribute to the onset of cocaine
Fig. 4
(a)
Average number of responses
Varenicline doses (mg/kg)
∗∗∗
∗∗∗
+
60
50
40
30
20
10
0
0 0.1
0.3
∗∗
∗∗∗
80
70
60
50
40
30
20
10
0
0 0.1
0.3
(b)
35
30
25
20
15
10
5
0
0 0.1 0.3
(c)
Low-dose varenicline effects on cue-induced and cocaine-induced reinstatement of cocaine seeking and cue-induced sucrose-directed behavior. (a–
c) Varenicline effect on cue-induced reinstatement of cocaine seeking (a), cocaine-induced reinstatement of cocaine seeking (b), and cue-induced
reinstatement of sucrose seeking (c). In each graph average number of presses is plotted as a function of varenicline dose. ** and *** a significant
difference when compared with 0.0 mg/kg varenicline with P < 0.01 and P < 0.001, respectively. + a significant difference between 0.1 and 0.3
varenicline, P < 0.05.
100 Behavioural Pharmacology 2010, Vol 21 No 2
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 5
seeking; moreover, the partial a4b2 agonist actions of the
drug are too weak to have any significant positive effect
on those same mechanisms. Based on this hypothesis we
predicted that varenicline would decrease both cue and
cocaine reinstatement of cocaine seeking. The present
findings are not wholly consistent with this prediction,
or the underlying hypothesis: low varenicline doses did
decrease reinstatement but a high dose increased it.
One potential explanation of the unpredicted findings is
that varenicline-induced stimulation of DA neuron firing
is dose dependent. Moreover, the increased DA neuron
activity induced by higher doses of varenicline is sufficient
to evoke cocaine-directed behavior, despite partial vareni-
cline-induced blockade of ACh effects on DA neuron
activity. This interpretation though plausible is not consis-
tent with available microdialysis data, which show that the
low and high doses of varenicline similarly increase DA
in a major VTA DA target area, the nucleus accumbens
(Rollema et al., 2007). The dose-dependent effects of
varenicline might thus be mediated by an alternative
mechanism. There are a number of possibilities. For exam-
ple , low and high doses of varenicline potentially induce
different ratios of activation versus desensitization of the
a4b2 receptors (c.f. W ooltorton et al., 2003; Giniatullin et al.,
2005). In addition, varenicline is a low affinity, full agonist
for a7anda3b4 nicotine receptors. It is therefore possible
that high but not low doses of varenicline significantly
stimulate a7anda3b4-mediated mechanisms. Such differ-
ential effects of low versus high doses of varenicline could
contribute to qualitatively different effects of the vareni-
cline doses on reinstatement of cocaine seeking.
Varenicline as a potential relapse prevention
medication for cocaine addiction
The high-dose varenicline effect on reinstatement raises
concerns about the utility of varenicline as a cocaine
addiction treatment. Nevertheless, the low-dose effects of
varenicline in decreasing reinstatement are fairly robust.
Additional investigation of the effects could be useful in
identifying potential therapeutic targets for prevention of
cocaine-addiction relapse. A number of preclinical issues
that will be of interest in future studies of the low-dose
varenicline effects, in addition to the specific underlying
pharmacological mechanism of action, include the follow-
ing: (i) whether the acute effects of varenicline observed
in this study generalize to chronic varenicline exposure,
which is more consistent with the treatment regimen used
in humans (Gonzales et al., 2006; Patterson et al., 2009) and
(ii) whether the effect of varenicline generalizes to animals
that have a history of abstinence without extinction
exposure (cf. Fuchs et al. , 2006), which is potentially more
consistent with human abstinence experience.
Varenicline effects on cocaine self administration
High-dose varenicline (i.e. 1.0 and 2.0 mg/kg) decreased
the average cocaine intake during 2-h SA sessions. A
decrease in average cocaine intake during a session
can reflect either an agonist or an antagonist interacti on.
The pattern of change in response rates across an SA
session can be helpful in differentiating between these
two possibilities. Specifically, a moderate antagonism of a
reliably self-administered dose of cocaine, such as the
0.75 mg/kg cocaine dose used in this study, is expected
to induce a compensatory increase in the rate of cocaine
self administration. An insurmountable antagonism is
expected to engender an extinction-like pattern of
operant responding, with animals showing an initial
increase in response rates followed by a near or complete
cessation of responding. In contrast, agonist administra-
tion is expected to eng ender a stable, but reduced rate of
cocaine SA (De Wit and Wise, 1977; Yokel, 1987a;
You et al., 2008). In this study, high-dose varenicline did
not significantly affect response rate during the first half
of the 2-h cocaine SA session but caused a significant
stable decrease in cocaine intake in the second half of the
session. Though the delayed onset of the varenicline
effect is unusual, the pattern of change in cocaine SA
during high-dose varenicline exposure is most consistent
with that associated with an agonist effect. One alter-
native interpretation is that high-dose varenicline
increases an aversive effect of high cocaine levels,
which would be expected to suppress the rate of cocaine
intake (Groves RaS, 1973). Additional studies (e.g.
progressive ratio and cocaine dose response studies) are
needed to clarify interpretation of the varenicline effects
on cocaine SA (Yokel, 1987b; Richardso n and Roberts,
1996).
Understanding the source of the delayed onset of
the varenicline effect on cocaine SA could be important
to a full understanding of mechanisms that mediate the
varenicline effect. One could hypothesize that the delayed
onset reflects a pharmacokinetic mechanism, such as
absorption of varenicline or the accumulation of an active
metabolite. Available pharmacokinetic data are not suffi-
cient to completely exclude these mechanisms. Howeve r,
the active metabolite interpretation seems unlikely given
that greater than 80% of varenicline is excreted as the
parent compound (Obach et al.,2006).Thedelayedonset
of the varenicline effect on cocaine SA could alternatively
reflect a pharmacological mechanism. For example, there is
evidence of changes in VTA neurochemical levels during
the first hour of cocaine self administration that are distinct
relative to the subsequent hours of the session, including
changes in VTA ACh and glutamate levels. There is also
evidence of a time-dependent change in the relative contri-
bution of conditioned mechanisms versus cocaine-induced
mechanisms in mediating the neurochemical changes that
occur during an SA session (You et al., 2007, 2008). The
neurochemical and mechanistic changes that occur over
thecourseofacocaineSAsessionmightinteractwith
the pharmacological effects of varenicline and determine
the time-dependent effect of varenicline on cocaine SA.
Varenicline and cocaine Guillem and Peoples 101
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 6
The doses of varenicline that decreased cocaine SA in this
study were observed in previous experiments to decrease
nicotine and ethanol SA (Rollema et al., 2007; Steensland
et al., 2007). One interpretation of the varenicline effects
on nicotine and ethanol SA is that varenicline blocks the
reinforcing effects of nicotine and ethanol through an
antagonist mechanism. Clinical studies have shown that
varenicline decreases the subjective effects of nicotine
(McKee et al., 2009; Patterson et al., 2009), which is
potentially consistent with an antagonist interpretation
of the varenicline effects on nicotine and ethanol SA in
animals. However, subjective and reinforcing effects of
drugs are not necessarily mediated by the same mechan-
isms. Moreover, in light of the high-dose varenicline
effects of the present study, a plausible alternative inter-
pretation of the nicotine and ethanol SA data is that the
varenicline effects reflect an agonist rather than an anta-
gonist mechanism. Further experiments are required to
clearly differentiate an agonist versus an antagonist action
of varenicline on nicotine, ethanol and cocaine SA (for
relevant findings and discussion see Refs Steensland et al.,
2007; LeSage et al., 2009). In addition, the effects of
varenicline on the reinforcing effects of cocaine, nicotine
and ethanol could be different, given the different actions
of the drugs at nicotinic receptors, and the relative
importance of the receptors in mediating the reinforcing
properties of the drugs (Picciotto et al., 1998; Picciotto and
Corrigall, 2002; Davis and de Fiebre, 2006; Steensland
et al., 2007; You et al., 2008).
Conclusions and future research directions
On the basis of the present findings one might expect
that low doses of varenicline will decrease the risk of
cue-induced and DA agonist-induced relapse in cocaine-
addicted individual s. Higher doses of varenicline might
increase the risk of relapse. Varenicline might decrease
cocaine intake during periods of drug self administra-
tion, but only at the higher doses of varenicline, which
based on the present findings are expected to increase
relapse risk. Given the present findings it could be inter-
esting to further explore the effects of low-dose vareni-
cline in relapse models. Varenicline is a clinically available
treatment for nicotine addiction and has been proposed
as a possible alcohol addiction treatment (Steensland
et al., 2007; McKee et al., 2009). The effect of varenicline
on reinstatement of nicotine-directed and ethanol-directed
behavior has not yet been tested. Addressing this issue is
relevant to use of varenicline as a treatment for smoking
and alcoholism, particularly in cases where nicotine and
ethanol addiction occur comorbidly with cocaine addiction
(Wiseman and McMillan, 1998; Wiseman et al., 2005;
Gossop et al., 2006).
Acknowledgements
This study was supported by NIDA Grants DA05186 and
DA026942. Varenicline tartrate was kindly donated by
Pfizer Inc. The authors thank Drs AR Childress and
CP O’Brien for conversations which pr ompted the
experiments. The authors also thank Dr DCS Roberts
for a helpful discussion about the findings of the
cocaine self-administration experiment. Dr RS Obach
provided information on varenicline pharmacokinetics.
The authors especially thank Dr Hans Rollema for
numerous discussions related to varenicline.
References
Bossert JM, Ghitza U E, Lu L, Epstein DH, Shaham Y (2005). Neurobiology of
relapse to heroin and cocaine seeking: an update and clinical implications.
Eur J Pharmacol 526:36–50.
Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, et al. (2005).
Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking
cessation. J Med Chem 48:3474–3477.
Davis TJ, de Fiebre CM (2006). Alcohol’s actions on neuronal nicotinic
acetylcholine receptors. Alcohol Res Health 29:179–185.
De Wit H, Stewart J (1981). Reinstatement of cocaine-reinforced responding in
the rat. Psychopharmacology (Berl) 75:134–143.
De Wit H, Wise RA (1977). Blockade of cocaine reinforcement in rats with the
dopamine receptor blocker pimozide, but not with the noradrenergic blockers
phentolamine or phenoxybenzamine. Can J Psychol 31:195–203.
Ehrman RN, Robbins SJ, Childress AR, O’Brien CP (1992). Conditioned
responses to cocaine-related stimuli in cocaine abuse patients. Psycho-
pharmacology (Berl) 107:523–529.
Fuchs RA, Branham RK, See RE (2006). Different neural substrates mediate
cocaine seeking after abstinence versus extinction training: a critical role for
the dorsolateral caudate-putamen. J Neurosci 26:3584–3588.
Giniatullin R, Nistri A, Yakel JL (2005). Desensitization of nicotinic ACh receptors:
shaping cholinergic signaling. Trends Neurosci 28:371–378.
Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, et al. (2006).
Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist,
vs. sustained-release bupropion and placebo for smoking cessation: a
randomized controlled trial. JAMA 296:47–55.
Gossop M, Manning V, Ridge G (20 06). Concurrent use of alcohol and cocaine:
differences in patterns of use and problems among users of crack cocaine
and cocaine powder. Alcohol Alcohol 41:121–125.
Groves RaS CR (1973). Suppression of cocaine self-administration by extinction
and punishment. Pharmacol Biochem Behav 2:199–208.
Guillem K, Vouillac C, Azar MR, Parsons LH, Koob GF, Cador M, Stinus L (2005).
Monoamine oxidase inhibition dramatically increases the motivation to self-
administer nicotine in rats. J Neurosci 25:8593–8600.
Ikemoto S, Wise RA (2004). Mapping of chemical trigger zones for reward.
Neuropharmacology 47 (Suppl 1):190–201.
Jaffe JH, Cascella NG, Kumor KM, Sherer MA (1989). Cocaine-induced cocaine
craving. Psychopharmacology (Berl) 97:59–64.
LeSage MG, Shelley D, Ross JT, Carroll FI, Corrigall WA (2009). Effects of
the nicotinic receptor partial agonists varenicline and cytisine on the
discriminative stimulus effects of nicotine in rats. Pharmacol Biochem Behav
91:461–467.
McKee SA, Harrison EL, O’Malley S S, Krishnan-Sarin S, Shi J, Tetrault JM, et al.
(2009). Varenicline reduces alcohol self-administr ation in heavy-drinking
smokers. Biol Psychiatry 66:185–190.
O’Brien CP, Childress AR, McLellan T, Ehrman R (1990). Integrating systemic
cue exposure with standard treatment in recovering drug dependent patients.
Addict Behav 15:355–365.
Obach RS, Reed-Hagen AE, Krueger SS, Obach BJ, O’Connell TN, Zandi KS,
et al. (2006). Metabolism and disposition of varenicline, a selective
alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro. Drug
Metab Dispos 34:121–130.
Patterson F, Jepson C, Strasser AA, Loughead J, Perkins KA, Gur RC, et al.
(2009). Varenicline improves mood and cognition during smoking abstinence.
Biol Psychiatry 65:144–149.
Picciotto MR, Corrigall WA (2002). Neuronal systems underlying behaviors
related to nicotine addiction: neural circuits and molecular genetics.
J Neurosci 22:3338–3341.
Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, et al.(1998).
Acetylcholine receptors containing the beta2 subunit are involved in the
reinforcing properties of nicotine. Nature 391:173–177.
102 Behavioural Pharmacology 2010, Vol 21 No 2
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Page 7
Reid MS, Mickalian JD, Delucchi KL, Hall SM, Berger SP (1998). An acute dose
of nicotine enhances cue-induced cocaine craving. Drug Alcohol Depend
49:95–104.
Reid MS, Mickalian JD, Delucchi KL, Berger SP (1999). A nicotine antagonist,
mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent
subjects. Neuropsychopharmacology 20:297–307.
Richardson NR, Roberts DC (1996). Progressive ratio schedules in drug self-
administration studies in rats: a method to evaluate reinforcing efficacy.
J Neurosci Methods 66:1–11.
Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, et al. (2007).
Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor
partial agonist varenicline, an effective smoking cessation aid. Neuropharma-
cology 52:985–994.
Rollema H, Hajos M, Seymour PA, Kozak R, Majchrzak MJ, Guanowsky V, et al.
(2009). Preclinical pharmacol ogy of the alpha4beta2nAChR partial agonist
varenicline related to effects on reward, mood and cognition. Biochem
Pharmacol 78:813–824.
Schenk S, Partridge B (1999). Cocaine-seeking produced by experimenter-
administered drug injections: dose-effect relationships in rats. Psycho-
pharmacology (Berl) 147:285–290.
Spealman RD, Barrett-Larimore RL, Rowlett JK , Platt DM, Khroyan TV (1999).
Pharmacological and environmental determinants of relapse to cocaine-
seeking behavior. Pharmacol Biochem Behav 64:327–336.
Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE (2007). Varenicline,
an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively
decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A
104:12518–12523.
Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Angrist B, Gatley SJ, et al.
(1999). Association of methylphenidate-induced craving with changes in
right striato-orbitofrontal metabolism in cocaine abusers: implications in
addiction. Am J Psychiatry 156:19–26.
Wise RA, Murray A, Bozarth MA (1990). Bromocriptine self-administration and
bromocriptine-reinstatement of cocaine-trained and heroin-trained lever
pressing in rats. Psychopharmacology (Berl) 100:355–360.
Wiseman EJ, McMillan DE (1998). Rationale for cigarette smoking and for
mentholation preference in cocaine- and nicotine-dependent outpatients.
Compr Psychiatry 39:358–363.
Wiseman EJ, Williams DK, McMillan DE (2005). Effectiveness of payment for
reduced carbon monoxide levels and noncontingent payments on smoking
behaviors in cocaine-abusing outpatients wearing nicotine or placebo
patches. Exp Clin Psychopharmacol 13:102–110.
Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA (2003). Differential
desensitization and distribution of nicotinic acetylcholine receptor subtypes
in midbrain dopamine areas. J Neurosci 23:3176–3185.
Yokel R (1987a). Intravenous self-administration: response rates, the effects of
pharmacological challenges, and drug preferences. In: Bozarth MA, editor.
Methods of assessing the reinforcing properties of abused drugs. New York:
Springer-Verlag; pp. 1–34.
Yokel RA (1987b). Intravenous self-dministration: responses rates, the effects of
pharmacological challenges, and drug preferences. In: Bozarth MA, editor.
Methods of Assesing the Reinforcing Properties of Abused Drugs. New York:
Springer-Verlag; pp. 1–34.
You ZB, Wang B, Zitzman D, Azari S, Wise RA (2007). A role for conditioned
ventral tegmental glutamate release in cocaine seeking. J Neurosci
27:10546–10555.
You ZB, Wang B, Zitzman D, Wise RA (2008). Acetylcholine release in the
mesocorticolimbic dopamine system during cocaine seeking: conditioned
and unconditioned contributions to reward and motivation. J Neurosci
28:9021–9029.
Varenicline and cocaine Guillem and Peoples 103
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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    • "With regard to other psychostimulants, a number of nACR antagonists were found to decrease cocaine self-administration, prevent cue-induced craving for cocaine, and to decrease cocaine effects in a place preference paradigm or reduce cocaine-induced behavioral sensitization (Levin et al., 2000; Zachariou et al., 2001; Champtiaux et al., 2006; Hansen and Mark, 2007) suggesting a direct involvement of nAChRs in cocaine-taking and -seeking behavior. In addition, recent studies indicate that varenicline reduces cocaine-induced reward in rodents and humans (Guillem and Peoples, 2010; Plebani et al., 2012). In contrast, varenicline was found ineffective in reducing cocaine self-administration in a primate model (Gould et al., 2011), indicating mixed effects across models which may be due to species' differences . "
    [Show abstract] [Hide abstract] ABSTRACT: Alcohol and drug dependence are serious public health problems worldwide. The prevalence of alcohol and drug dependence in the United States and other parts of the world is significant. Given the limitations in the efficacy of current pharmacotherapies to treat these disorders, research in developing alternative pharmacotherapies continues. Preclinical and clinical evidence thus far has indicated that brain nicotinic acetylcholine receptors (nAChRs) are important pharmacological targets for the development of medications to treat alcohol and drug dependence. The nAChRs are a super family of ligand gated ion channels, and are expressed throughout the brain with twelve neuronal nAChR subunits (α2–α10 and β2–β4) identified. Here, we review preclinical and clinical evidence involving a number of nAChR ligands that target different nAChR subtypes in alcohol and nicotine addiction. The important ligands include cytisine, lobeline, mecamylamine, varenicline, sazetidine A and others that target α4β2∗ nAChR subtypes as small molecule modulators of the brain nicotinic cholinergic system are also discussed. Taken together, both preclinical and clinical data exist that support nAChR–based ligands as promising therapeutic agents for the treatment of alcohol and drug dependence.
    Full-text · Article · Jan 2015 · Frontiers in Neuroscience
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    • "Interestingly, Wouda et al. (2011) found that varenicline effectively attenuated the cue-induced reinstatement of alcohol-seeking behaviour. Together with another report (Guillem and Peoples, 2010), in which varenicline at lower doses reduced the cue-induced reinstatement of cocaine-seeking, these results suggests a role for α4β2 nAChRs in the motivational effects of cues conditioned to alcohol and cocaine but not nicotine. Elucidating such a significant difference between nicotine and other drugs of abuse and the involvement of associative learning and memory processes warrants future studies. "
    [Show abstract] [Hide abstract] ABSTRACT: Exposure to environmental stimuli conditioned to nicotine consumption critically contributes to the high relapse rates of tobacco smoking. Our previous work demonstrated that non-selective blockade of nicotinic acetylcholine receptors (nAChRs) reversed the cue-induced reinstatement of nicotine seeking, indicating a role for cholinergic neurotransmission in the mediation of the conditioned incentive properties of nicotine cues. The present study further examined the relative roles of the two major nAChR subtypes, α4β2 and α7, in the cue-induced reinstatement of nicotine seeking. Male Sprague-Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion, free base) on a fixed-ratio 5 schedule of reinforcement. A nicotine-conditioned cue was established by associating a sensory stimulus with each nicotine infusion. After nicotine-maintained responding was extinguished by withholding the nicotine infusion and its paired cue, reinstatement test sessions were conducted with re-presentation of the cue but without the availability of nicotine. Thirty minutes before the tests, the rats were administered the α4β2-selective antagonist dihydro-β-erythroidine (DHβE) and α7-selective antagonist methyllycaconitine (MLA). Pretreatment with MLA, but not DHβE, significantly reduced the magnitude of the cue-induced reinstatement of responses on the active, previously nicotine-reinforced lever. In different sets of rats, MLA altered neither nicotine self-administration nor cue-induced reinstatement of food seeking. These results demonstrate that activation of α7 nAChRs participates in the mediation of the conditioned incentive properties of nicotine cues and suggest that α7 nAChRs may be a promising target for the development of medications for the prevention of cue-induced smoking relapse.
    Preview · Article · Aug 2013 · The International Journal of Neuropsychopharmacology
    0Comments 7Citations
    • "Varenicline's effects on cocaine self-administration and reinstatement were studied on rats. Low doses of varenicline diminished cocaine reinstatement, while high doses increased it, but decreased self-administration [89]. Varenicline has also been shown to work against alcohol dependence in mice: in doses similar to those used to reduce nicotine reward, varenicline reduced ethanol but not sucrose seeking on a self-administration drinking paradigm. "
    [Show abstract] [Hide abstract] ABSTRACT: To thrive in any given environment, mobile creatures must be able to learn from the outcomes of both successful and disappointing events. To learn from success, the brain relies on signals originating in the ventral tegmental area and substantia nigra that result in increased release of dopamine in the striatum. Recently, it was shown that to learn from disappointment the brain relies on signals originating in the lateral habenula, which indirectly inhibit dopaminergic activity. The habenula is a small brain region that has been shown in mice to be critical for the appearance of nicotine withdrawal symptoms. The nicotinic acetylcholine receptor subunits expressed in the medial habenula are necessary to observe withdrawal symptoms in mice, and blocking nicotinic activity in the medial habenula only is sufficient to precipitate withdrawal in dependent mice. In addition, recent genome wide association studies have shown that in humans, genetic variants in the same nicotinic receptor subunits are at least partially responsible for the genetic predisposition to become a smoker. The habenula is linked not only to nicotine, but also to the effects of several other drugs. We postulate that the continuous use of drugs of abuse results in habenular hyperactivity as a compensatory mechanism for artificially elevated dopamine release. Drug withdrawal would then result in non-compensated habenular hyperactivity, and could be thought of as a state of continuous disappointment (or a negative emotional state), driving repeated drug use. We believe that drugs that alter habenular activity may be effective therapies against tobacco smoke and drug addiction in general.
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