Opinion
What’s conditioned in conditioned
place preference?
Joseph P. Huston1, Maria A. de Souza Silva1, Bianca Topic1, and Christian P. Müller2
1
Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, 40204 Düsseldorf, Germany
2
Section of Addiction Medicine, Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-
Nuremberg, 91054 Erlangen, Germany
Conditioned place preference (CPP) is a learned behavior
shown in many vertebrates, including humans. CPP
occurs when a subject comes to prefer one place more
than others because the preferred location has been
paired previously with rewarding events. The CPP para-
digm is widely used to explore the reinforcing effects of
natural and pharmacological stimuli, including drugs of
addiction. There is a general assumption that an ac-
quired place preference is based on classical condition-
ing derived ‘incentive motivation’. However, this may be
an oversimplification of the multiple learning processes
involved. We argue that although CPP may appear as an
incentive-driven behavior related to secondary reinfor-
cers, it may also be a result of operant conditioning of
behavior prevailing at the conditioning site, as well as a
result of conditioned treatment effects. Here, we outline
alternative explanations for an observed CPP, which may
fundamentally affect the interpretation of results with
this paradigm in its use as a screening tool for rewarding
properties of treatments.
Humans and most animal species prefer certain places
over others. Although place preferences may be solely due
to sensory characteristics of particular places, they may
also be acquired as a consequence of events which are
associated with those places. These events can shape the
preferred dwelling and local behavior for the future, which
is considered to be a result of learning and memory and
observed as conditioned place preference (CPP). CPP can
be easily induced under controlled experimental conditions
in many species, such as flies [1], rodents [2,3], primates
[4,5], and humans [6] (Box 1).
The CPP method has assumed considerable importance
and is now routinely used in the neurosciences, genetics,
and pharmacology to explore the reinforcing effects of
natural and pharmacological stimuli [3]. A major advan-
tage of the method is that it can identify reinforcing as well
as aversive effects of a treatment in the same procedure
[7,8]. It also plays an important role in the study of addic-
tive and potentially addictive drugs [9–15]. In that, phar-
macological (e.g., receptor agonist/antagonist) or genetic
(e.g., receptor knock out) brain manipulations are tested
for how they affect CPP as an addiction-related behavior
Corresponding author: Huston, J.P. (huston@uni-duesseldorf.de).
Keywords: conditioned place preference; reinforcement; reward; incentive; classical
conditioning; operant conditioning; conditioned drug effects.
162 0165-6147/$ – see front matter ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2013.01.004 Trends in Pharmacological Sciences, March 2013, Vol. 34, No. 3
[16–19]. Although the theoretical underpinnings of CPP
are complex, there is a general assumption that it is based
on classical conditioning-derived ‘incentive motivation’
[20,21]. However, this may be an oversimplification of
the multiple learning processes involved, which may bias
and misdirect the interpretation of experimental results
with this paradigm. Here, we address the question of what
is actually conditioned in the CPP procedure and what
learning processes may occur.
An important impetus to experimental use of CPP was
the discovery of rewarding effects of brain stimulation by
Olds and Milner [22], who observed that rats returned to
the site of a chamber where they had received electrical
brain stimulation. Subsequently, CPP was observed with
various other rewarding agents and it became a screening
tool for new drugs with an unknown reward potential
[23,24]. For example, CPP is one way to investigate the
reinforcing effects and addiction potential early in devel-
opment of new drug therapies. Whereas CPP methods are
undoubtedly simpler to employ than drug self-administra-
tion techniques [23], it is certainly not simpler to interpret
results derived there from. Distinct learning processes are
involved in the establishment of a CPP. In addition, CPP
retrieval depends on yet other mechanisms. A CPP can be
induced by various pathways but also altered in multiple
ways [25,26]. Understanding and experimental character-
ization of the reinforcer-specific mechanisms is, thus, piv-
otal for an advanced interpretation of CPP results.
What is conditioned during CPP learning?
There are at least three major processes by which to
account for why an animal spends more time in a place
in which it received a reinforcer. Whichever of these three
processes is operative will determine the interpretation of
the result of the place-preference experiment.
Incentive-driven behavior
The most commonly assumed explanation invokes the seek-
ing out of a place or stimulus complex which had been paired
with the reinforcer. The underlying learning process for
incentive-driven behavior is assumed to be based on Pav-
lovian conditioning [27]. Thereby, the reinforcer can be a
drug treatment or a conventional ‘reward’, such as food, that
the animal ‘likes’ or ‘wants’ [28]. In this paradigm, the
reinforcer, an unconditioned stimulus (UCS), has some
effects on the organism which elicits an unconditioned
Opinion
Box 1. How CPP is measured
In principle, CPP involves the association of a treatment with a
particular section of an arena. A ‘rewarding/reinforcing’ effect is
considered to be manifested by a relative increase in time spent in
the area that had been paired with the treatment. CPP in rodents
and primates is usually tested in test boxes which contain at least
two different compartments, which differ sufficiently [14,57,58] or
in test environments with distinct subareas [13,59]. Thereby,
proximal intra-maze cues appear to be of greater importance for
compartment distinction than distal spatial cues [60]. The CPP
procedure involves three phases that can be varied in the number
of trials [21,60]. During a baseline phase, the animal is allowed to
explore all areas of the maze without restrictions to habituate to
the environment and to provide a baseline for sojourn times in the
single compartments. Thereby, no gross spontaneous preference
for one of the compartments should emerge. In the conditioning
phase, the treatment (e.g., a drug with rewarding properties) is
paired with the conditioning compartment. Although drugs are
administered before the animal is placed in the compartment,
natural reinforcers, such as food or sexual encounter, are
presented in the compartment. Thereafter, the animals are
returned to their home cages. A pseudo-conditioning session is
usually administered, whereby the animal receives a sham
treatment (e.g., a vehicle injection) and is placed in the alternative
compartment of the maze. This is done to avoid a novelty based
preference and to control for the emotional effects of the (mostly
aversive) drug application procedure. Conditioning and pseudo-
conditioning are repeated several times [40]. Drug-induced CPP is
usually tested after a vehicle injection, but may be enhanced after
a drug injection [23]. The main readout in the paradigm is the time
that is spent in the conditioning compartment during test minus
baseline. If the difference is positive, a CPP and ‘reinforcing action’ of
the treatment is inferred. If the difference is negative, a conditioned
place avoidance and aversive action of the treatment is concluded.
response (UCR). This is associated with the stimulus
properties of the place, which become conditioned stimuli
(CS). Consequently, the CS assume ‘incentive value’ of their
own, which leads the organism to ‘seek’ these out, or to
‘prefer’ them [20,21,29–31]. According to this view, the
expression of a CPP reflects a Pavlovian conditioned ap-
proach response similar to sign-tracking behavior, that is,
the animal is attracted to the CS [32]. An additional contri-
bution is assumed by conditioned reinforcement or reward.
This is the learning about the relationship between the
rewarding effects of a stimulus and the cues in the paired
compartment. Both processes were dissociated at anatomi-
cal level. Whereas the Pavlovian conditioned approach
depends on amygdala and nucleus accumbens, conditioned
reinforcement appears to rely on the hippocampus [26].
Although such an analysis has considerable face validity
it should be remembered that it is a theoretical accounting
and not to be confused as fact. The notion of ‘conditioned
incentive’ as developed by Bolles [30] and Bindra [29] has
much appeal as an explanatory concept, but it may only
partially provide a valid account for the CPP phenomenon
(Figure 1).
Operant conditioning of behavior prevailing at the
conditioning site
Less obvious is the theoretical possibility that CPP occurs as
a consequence of reinforced behavior. A reinforcer acts to
increase the probability of recurrence of those behaviors
that precede or coincide with the onset of a rewarding event.
Both natural stimuli and drugs can influence behaviors that
are spontaneously shown in the test environment. Although
Trends in Pharmacological Sciences March 2013, Vol. 34, No. 3
drugs are administered before CPP conditioning, their be-
havioral effects are usually expressed and perceived during
and after place conditioning. These behaviors can be single
limb movements or complex chains of behavior. In another
context, this was shown as ‘superstitious behavior’ and
demonstrated by Skinner and others in pigeons [32,33].
Superstitious behavior occurs upon inadvertent reinforce-
ment of spontaneously shown behaviors, which then in-
crease in frequency. During CPP conditioning, a behavior
or chain of behavior can hypothetically be enhanced in its
frequency and linked to a particular place by a reinforcing
agent. When the animal confronts this place again, it is
likely to re-engage in whatever behavior was reinforced in
that context including those behaviors that produce contact
with the place [34]. Thus, the behavior is under control of the
discriminative stimuli (SD) that prevailed during presenta-
tion of the reinforcer (Figure 1). Consequently, engaging in
such reinforced behavior will increase the probability that
the animal will remain in the vicinity of the SD (i.e., in the
compartment in which it received the reinforcer).
Conditioned treatment effects
As a third theoretical alternative, pharmacologically in-
duced CPP may be a consequence of conditioned treatment
effects. A stimulus paired with a drug-induced behavior
can serve to elicit behavior very similar to that induced by
the drug itself [35–37]. Conditioned drug effects may occur
independently of a drug–CPP [38]. Their potential contri-
bution to CPP is particularly obvious in the case of psy-
chostimulant drugs, the behavioral effects of which are
well known to be conditionable to environmental cues
which have been paired with their action [35,36,39]. As
in case 2 above for operantly conditioned behavior, condi-
tioned treatment effects may increase the probability that
the animal will remain in the vicinity of the stimuli asso-
ciated with the acute treatment effects which may finally
contribute to CPP sojourn time (Box 1). Note that the
resulting place preference in this case may be totally
independent of any ‘reinforcing’ consequences of the treat-
ment, and the term ‘place preference’ would be a misnomer,
because the animal’s conditioned response may simply
prevent it from leaving this particular environment
(Figure 1). Such an account may explain the difficulty
and lack of a CPP dose–response function for the powerful
pharmacological reinforcer, cocaine [40–42]. Cocaine-in-
duced hyperactivity can readily be conditioned to an
UCS [35,36,39]. The CS may then elicit conditioned hyper-
activity during testing. This activity may actually increase
the probability that the animal will leave the conditioning
compartment in the test and, thus, mask possible reinfor-
cing (case 2) and incentive (case 1) processes. The same
reinforcer may also lead to conditioned treatment effects
that may be incompatible with leaving the treatment
compartment (e.g., vocalization [34,43]). A single condi-
tioned drug effect may or may not imply that a drug has
reward or reinforcing value, in spite of an apparent CPP.
And in some cases, the conditioned drug effect may simply
mask the reinforcing properties of the drug.
Hypothetically, all three processes could operate con-
currently in a CPP paradigm and, thus, contribute addi-
tively or counteract one another. These factors must be
163
 Opinion Trends in Pharmacological Sciences March 2013, Vol. 34, No. 3

Baseline Condioning Test

(a) Incenve-driven behavior

UCS*+ UCS*- CS+* CS*-

(b) Operant condioned behavior

SD*+ SD*- SD+* SD*-

R R

(c) Condioned drug effects

Observed:
place preference
UCS*+ UCS*- CS+* CS*-

UCR CR

TRENDS in Pharmacological Sciences

Figure 1. Different learning processes may lead to conditioned place preference (CPP) after drug or natural reinforcers. (a) CPP may occur as incentive-driven behavior. As a
result of conditioning, neutral, unconditioned stimuli (UCS) work as proximal/intra-maze (UCS+) and distal/extra-maze (UCS*+) cues that become associated with the
positive drug effects (orange). Thereby, they become conditioned stimuli (CS+/CS*+) which may elicit incentive motivation to ‘seek them out’ during the test. The UCS–/
UCS*– become associated with sham (vehicle) treatment to become a CS–/CS*– and do not elicit an incentive motivation during the test. (b) Animals may show
spontaneous behaviors (R) in the maze which can be reinforced by operant conditioning. Thereby, proximal and distal discriminative stimuli (SD+/SD*+) become associated
with R by the reinforcer. During the test, SD+/SD*+ may induce R, which prevents the animal from leaving the conditioning compartment. The SD–/SD*– will be associated
with sham treatment and do not elicit specific behavioral responses during the test. (c) Drugs and natural reinforcer may induce an acute unconditioned behavioral
response (UCR). This can be conditioned to a UCS+/UCS*+. They become a CS+/CS*+ and may elicit a conditioned response (CR) similar to the UCR during the test.
Thereby, the CR occurs in the conditioning compartment and prevents the animal from leaving this compartment.

considered when interpreting the outcome of any CPP
experiment. Possible interactions between brain manipu-
lations and all three processes should be considered.
Dissociating mechanisms at experimental level
Assuming that all three processes are active in the CPP,
and let us say that one wishes to test the influence of a
brain manipulation on CPP, it might be possible to segre-
gate the contribution of the three processes to the main
CPP readout, the sojourn time, by small manipulations
during testing and behavioral fine analysis. The contribu-
tion of incentive processes to CPP can be assessed by
manipulating the perception of the CS+, for example, by
using clear versus opaque walls between compartments
during testing [26]. With clear walls, the CS+ is visible also
from the sham-conditioned compartment and may induce
approach behavior into the conditioned compartment.
With opaque walls and the CS+ only being visible inside
the conditioned compartment, it may not induce condi-
tioned approach behavior from the other compartment.
A higher sojourn time during a CPP test in the ‘clear’
versus the ‘opaque’ condition can provide an index for
incentive learning as an acting mechanism [26]. Alterna-
tive measures, such as the time per stay in the conditioned
compartment may also be considered [25], but interpreta-
164
tion can be limited when conditioned drug effects on loco-
motor activity occur.
Testing the contribution of operant behavior may re-
quire a more careful monitoring of spontaneous behaviors
and their frequency in the CPP compartments. One may
need to score these behaviors during baseline and the
conditioning sessions. An increase in frequency of these
behaviors during conditioning trials can show whether a
reinforcer (e.g., a drug) acts on these spontaneous beha-
viors. Accordingly, this action should result in distinct
effects during conditioning, but not during pseudo-condi-
tioning sessions (Box 1). Finally, a comparison of behav-
ioral frequency/time in the conditioning compartment
between baseline and test may then show the degree of
operant conditioning and reveal how much of CPP sojourn
time can be explained by these behaviors. To segregate
operant conditioned behaviors from conditioned drug
effects, the scoring may need to be done retrospectively,
that is, behaviors/sequences occurring during the test in
the conditioning compartment may need to be identified
and subsequently scored and compared during baseline.
Although conditioned behaviors should be the same be-
tween all animals (e.g., hyperlocomotion [35,36,39], instru-
mental and superstitious behavioral sequences may be
highly specific for individual animals [32].
Opinion
The contribution of conditioned drug effects may be
tested by measuring the acute drug effects on behavior
during conditioning trials (e.g., on locomotor activity [37]),
and then assess them again during the test trial, separate-
ly for conditioning and pseudo-conditioning compartments.
An increase in behavioral frequency/time between baseline
and test (and between treatment groups) provides an
indicator for conditioned drug effects.
Depending on the species tested and the reinforcer
used, a fine analysis of CPP behavior may be able to tell
more about the specific effects of central nervous system
(CNS) manipulations. Different anatomical lesions may
block, for example, a morphine-induced CPP to the same
degree by either inhibiting conditioned approach
responses or behavior in the conditioning compartment
[26]. It may also help to reveal why certain reinforcers,
such as cocaine, work in a CPP paradigm only in some but
not all individuals [34]. Applying an analysis of all three
mechanisms may, thus, be able to tell an experimenter by
which way a CPP was blocked.
Other mechanisms affecting CPP
Memory
Whether or not any of the three possible effects of the
treatment will be manifested in the test trial will depend
on whether the animal remembers/retrieves the respective
associations [26,44]. A drug may be reinforcing and at the
same time establish a state–state dependent learning
[45,46]. This may diminish the probability of recalling
associations when animals are tested in a drug-free state
[23,47]. Furthermore, should an additional treatment ef-
fect on the CPP be the object of interest (e.g., a genetic
manipulation), such a treatment can potentially influence
establishment of the three processes above, but also the
memory/retrieval for any of these. A further complication
arises when one considers that a treatment may influence
not only the memory retrieval but also the cue processing
and associative process themselves for either of these three
[48,49].
Release-reward
Simply releasing an unhandled animal into a chamber
might have rewarding effects on its own, given that han-
dling by a human experimenter is usually an aversive
experience for the animal. This may be influenced by
further pharmacological treatment and eventually influ-
ence behavior attributed to properties of the treatment.
Extinction
Another serious problem pertains to the testing trial in the
CPP. Every test trial is essentially an extinction trial with
unique behavioral responses [45]. These can include ex-
tinction-induced aggression, ‘frustration’, and less obvious,
extinction-induced ‘despair’. Extinction-induced behaviors
may also induce search behavior [50] and escape from the
previously rewarded chamber [51,52]. This will reduce the
probability that the animal spends time in the treatment
compartment. A similar problem exists with spatial learn-
ing in the Morris water maze [52–56] where the ‘probe’ trial
may indicate not simply recall of the conditioned place, but
resistance to extinction and its emotional concomitants.
Trends in Pharmacological Sciences March 2013, Vol. 34, No. 3
Concluding remarks
In this opinion article, we discuss the alternative explana-
tions for an observed CPP and advocate the view that
although remaining a valuable instrument to assess the
potential of a stimulus or drug treatment to serve as a
reward, the interpretation given to concomitant changes in
genetics, epigenetics, neuropharmacology, and neuroanat-
omy must take into account processes besides classical
conditioning based incentives that can contribute to results
of CPP experiments. Accumulating evidence shows that
there are multiple processes working in parallel which
determine the establishment and retrieval of a CPP. It
is suggested that by relatively modest expansions in the
test design and a fine analysis of behavior during CPP
establishment and testing, advanced use of the technique
can be made which may then yield valuable information on
the nature of the reward learning and retrieval processes
involved. Because not all processes apply to the same
extent for all natural or pharmacological reinforcers alike,
the interplay between the described, but so far only sepa-
rately investigated processes needs to be characterized
simultaneously. For each reinforcer, appropriate instru-
mental and conditioned behaviors shown in a CPP setting
need to be identified so that interpretation may no longer
rely on sojourn times only. Based on that, the interpreta-
tion of manipulations will advance and help to understand
the often complex effects of genetic or pharmacological
interventions on parallel acting brain systems that control
reward learning.
Acknowledgments
This work was supported by Deutsche Forschungsgemeinschaft grants
DE 792/2-4, Hu 306/27-2, as well as NEURON-ERANET DISCover
(BMBF 01EW1003), and funds of the Friedrich–Alexander-University
Erlangen–Nuremberg.
References
1 Kaun, K.R. et al. (2011) A Drosophila model for alcohol reward. Nat.
Neurosci. 14, 612–619
2 Cunningham, C.L. et al. (2006) Drug-induced conditioned place
preference and aversion in mice. Nat. Protoc. 1, 1662–1670
3 Tzschentke, T.M. (2007) Measuring reward with the conditioned place
preference (CPP) paradigm: update of the last decade. Addict. Biol. 12,
227–462
4 Barros, M. et al. (2013) Decreased methylation of the NK3 receptor coding
gene (TACR3) after cocaine-induced place preference in marmoset
monkeys. Addict. Biol. http://dx.doi.org/10.1111/j.1369-1600.2011.00409
5 Wang, J. et al. (2011) Effect of morphine on conditioned place
preference in rhesus monkeys. Addict. Biol. 17, 539–546
6 Childs, E. and de Wit, H. (2009) Amphetamine-induced place
preference in humans. Biol. Psychiatry 65, 900–904
7 Lammel, S. et al. (2012) Input-specific control of reward and aversion in
the ventral tegmental area. Nature 491, 212–217
8 Lemos, J.C. et al. (2012) Severe stress switches CRF action in the
nucleus accumbens from appetitive to aversive. Nature 490, 402–406
9 Bilbao, A. et al. (2008) Loss of the Ca2+/calmodulin-dependent protein
kinase type IV in dopaminoceptive neurons enhances behavioral effects
of cocaine. Proc. Natl. Acad. Sci. U.S.A. 105, 17549–17554
10 Deng, J.V. et al. (2010) MeCP2 in the nucleus accumbens contributes to
neural and behavioral responses to psychostimulants. Nat. Neurosci.
13, 1128–1136
11 Jocham, G. et al. (2007) Neurokinin 3 receptor activation potentiates the
psychomotor and nucleus accumbens dopamine response to cocaine, but
not its place conditioning effects. Eur. J. Neurosci. 25, 2457–2472
12 LaPlant, Q. et al. (2010) Dnmt3a regulates emotional behavior and
spine plasticity in the nucleus accumbens. Nat. Neurosci. 13,
1137–1143
165
Opinion
13 Pum, M.E. et al. (2008) Role of medial prefrontal, entorhinal, and
occipital 5-HT in cocaine-induced place preference and
hyperlocomotion: evidence for multiple dissociations.
Psychopharmacology (Berl.) 201, 391–403
14 Solinas, M. et al. (2008) Reversal of cocaine addiction by environmental
enrichment. Proc. Natl. Acad. Sci. U.S.A. 105, 17145–17150
15 Szumlinski, K.K. et al. (2005) Homer2 is necessary for EtOH-induced
neuroplasticity. J. Neurosci. 25, 7054–7061
16 McBride, W.J. et al. (1999) Localization of brain reinforcement
mechanisms: intracranial self-administration and intracranial place-
conditioning studies. Behav. Brain Res. 101, 129–152
17 Müller, C.P. et al. (2007) Serotonin and psychostimulant addiction:
focus on 5-HT1A-receptors. Prog. Neurobiol. 81, 133–178
18 Olmstead, M.C. (2006) Animal models of drug addiction: Where do we
go from here? Q. J. Exp. Psychol. (Colchester) 59, 625–653
19 Sanchis-Segura, C. and Spanagel, R. (2006) Behavioural assessment of
drug reinforcement and addictive features in rodents: an overview.
Addict. Biol. 11, 2–38
20 Bardo, M.T. and Bevins, R.A. (2000) Conditioned place preference:
what does it add to our preclinical understanding of drug reward?
Psychopharmacology (Berl.) 153, 31–43
21 Prus, A.J. et al. (2009) Conditioned place preference. In Methods of
Behavior Analysis in Neuroscience (Buccafusco, J.J., ed.), CRC Press
22 Olds, J. and Milner, P. (1954) Positive reinforcement produced by
electrical stimulation of septal area and other regions of rat brain.
J. Comp. Physiol. Psychol. 47, 419–427
23 Bozarth, M.A. (1987) Conditioned place preference: a parametric
analysis using systemic heroin injections. In Methods of Assessing
the Reinforcing Properties of Abused Drugs (Bozarth, M.A., ed.), pp.
241–273, Springer
24 Katz, R.J. and Gormezano, G. (1979) A rapid and inexpensive
technique for assessing the reinforcing effects of opiate drugs.
Pharmacol. Biochem. Behav. 11, 231–233
25 Bardo, M.T. et al. (1984) Conditioned place preference with morphine:
the effect of extinction training on the reinforcing CR. Pharmacol.
Biochem. Behav. 21, 545–549
26 White, N.M. et al. (2005) Learning the morphine conditioned cue
preference: cue configuration determines effects of lesions.
Pharmacol. Biochem. Behav. 81, 786–796
27 Rescorla, R.A. and Wagner, A.R. (1972) A theory of Pavlovian
conditioning: variations in the effectiveness of reinforcement and
nonreinforcement. In Classical Conditioning II: Current Research
and Theory (Black, A.H. and Prokasy, W.F., eds), pp. 64–99,
Appleton-Century-Crofts
28 Berridge, K.C. (2007) The debate over dopamine’s role in reward: the
case for incentive salience. Psychopharmacology (Berl.) 191, 391–431
29 Bindra, D. (1974) A motivational view of learning, performance, and
behavior modification. Psychol. Rev. 81, 199–213
30 Bolles, R.C. (1972) Reinforcement, expectancy, and learning. Psychol.
Rev. 79, 394–409
31 Spiteri, T. et al. (2000) What is learned during place preference
conditioning? A comparison of food- and morphine-induced reward.
Psychobiology 28, 367–382
32 Skinner, B.F. (1948) ‘Superstition’ in pigeons. J. Exp. Psychol. 38,
168–172
33 Staddon, J.E.R. et al. (1971) The ‘‘superstition’’ experiment: a
reexamination of its implications for the principles of adaptive
behavior. Psychol. Rev. 78, 3–43
34 Meyer, P.J. et al. (2012) A cocaine cue is more preferred and evokes
more frequency-modulated 50-kHz ultrasonic vocalizations in rats
prone to attribute incentive salience to a food cue.
Psychopharmacology (Berl.) 219, 999–1009
35 Carey, R.J. and Damianopoulos, E.N. (1992) Opponent-process theory
and drug conditioning: an assessment for conditioned stimulant-
induced movement. Behav. Brain Res. 51, 139–147
36 Carey, R.J. and Gui, J. (1998) Cocaine conditioning and cocaine
sensitization: What is the relationship? Behav. Brain Res. 92, 67–76
166
Trends in Pharmacological Sciences March 2013, Vol. 34, No. 3
37 Cunningham, C.L. and Noble, D. (1992) Conditioned activation
induced by ethanol: role in sensitization and conditioned place
preference. Pharmacol. Biochem. Behav. 43, 307–313
38 Reicher, M.A. and Holman, E.W. (1977) Location preference and flavor
aversion reinforced by amphetamine in rats. Anim. Learn. Mem. 5,
343–346
39 Carey, R.J. et al. (2005) Evidence for Pavlovian conditioning of cocaine-
induced responses linked to emotional behavioral effects. Pharmacol.
Biochem. Behav. 80, 123–134
40 Bardo, M.T. et al. (1995) Conditioned place preference using opiate and
stimulant drugs: a meta-analysis. Neurosci. Biobehav. Rev. 19, 39–51
41 Durazzo, T.C. et al. (1994) Cocaine-induced conditioned place approach
in rats: the role of dose and route of administration. Pharmacol.
Biochem. Behav. 49, 1001–1005
42 Shimosato, K. and Watanabe, S. (2003) Concurrent evaluation of
locomotor response to novelty and propensity toward cocaine
conditioned place preference in mice. J. Neurosci. Methods 128,
103–110
43 Ma, S.T. et al. (2010) Repeated intravenous cocaine experience:
development and escalation of pre-drug anticipatory 50-kHz
ultrasonic vocalizations in rats. Behav. Brain Res. 212, 109–114
44 White, N.M. and Milner, P.M. (1992) The psychobiology of reinforcers.
Annu. Rev. Psychol. 43, 443–471
45 Bouton, M.E. and Moody, E.W. (2004) Memory processes in classical
conditioning. Neurosci. Biobehav. Rev. 28, 663–674
46 Overton, D.A. (1978) Basic mechanisms of state-dependent learning.
Psychopharmacol. Bull. 14, 67–68
47 Dockstader, C.L. and van der Kooy, D. (2001) Mouse strain differences
in opiate reward learning are explained by differences in anxiety, not
reward or learning. J. Neurosci. 21, 9077–9081
48 Carey, R.J. et al. (2008) Cocaine effects on behavioral responding to a
novel object placed in a familiar environment. Pharmacol. Biochem.
Behav. 88, 265–271
49 Pum, M.E. et al. (2011) The effects of cocaine on light-induced activity.
Brain Res. Bull. 84, 229–234
50 Pecoraro, N.C. et al. (1999) Incentive downshifts evoke search
repertoires in rats. J. Exp. Psychol. Anim. Behav. Process 25, 153–167
51 Komorowski, M. et al. (2012) Distance from source of reward as a marker
for extinction-induced ‘‘despair’’: modulation by the antidepressants
clomipramine and citalopram. Neuroscience 223, 152–162
52 Huston, J.P. et al. (2009) Toward an animal model of extinction-
induced despair: focus on aging and physiological indices. J. Neural
Transm. 116, 1029–1036
53 Schulz, D. et al. (2007) ‘‘Despair’’ induced by extinction trials in the
water maze: relationship with measures of anxiety in aged and adult
rats. Neurobiol. Learn. Mem. 87, 309–323
54 Schulz, D. et al. (2007) Extinction-induced ‘‘despair’’ in the water maze,
exploratory behavior and fear: effects of chronic antidepressant
treatment. Neurobiol. Learn. Mem. 87, 624–634
55 Huston, J.P. et al. Animal models of extinction-induced depression: loss
of reward and its consequences. Neurosci. Biobehav. Rev. (in press)
56 Topic, B. et al. (2008) Extinction-induced ‘‘despair’’ in aged and adult
rats: links to neurotrophins in frontal cortex and hippocampus.
Neurobiol. Learn. Mem. 90, 519–526
57 Mueller, D. and Stewart, J. (2000) Cocaine-induced conditioned place
preference: reinstatement by priming injections of cocaine after
extinction. Behav. Brain Res. 115, 39–47
58 Rotter, A. et al. (2012) Glucocorticoid receptor antagonism blocks
ethanol-induced place preference learning in mice and attenuates
dopamine D2 receptor adaptation in the frontal cortex. Brain Res.
Bull. 88, 519–524
59 Hasenöhrl, R.U. et al. (1989) Conditioned place preference in the corral:
a procedure for measuring reinforcing properties of drugs. J. Neurosci.
Methods 30, 141–146
60 Cunningham, C.L. et al. (2006) Spatial location is critical for
conditioning place preference with visual but not tactile stimuli.
Behav. Neurosci. 120, 1115–1132