Journal of Behavioral and Brain Science, 2013, 3, 131-136 Published Online February 2013 (
Amphetamine Conditioned Place Preference in Planarians
Robert B. Raffa1*, Sumira Shah2, Christopher S. Tallarida1,3, Scott M. Rawls3
1Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, USA
2Neuroscience Program, Temple University, Philadelphia, USA
3Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, USA
Email: *
Received October 6, 2012; revised November 7, 2012; accepted November 15, 2012
Meth- and other amphetamines currently present major drug-abuse concerns. However, the demonstration and study of
abuse-related behaviors expressed in animal models is expensive and time-consuming. We previously reported a novel
model of conditioned place preference (CPP), which is a standard tool in abuse research, in invertebrates (planarians).
In the present study, planarians were tested for light/dark preference, then exposed for 5 min to either d-amphetamine or
vehicle (water) in light and then re-tested for place preference (light vs dark). The planarians’ natural strong preference
for dark (15 of 16) was significantly altered by amphetamine experience, such that 12 of 16 preferred the unnatural, but
amphetamine-associated, light side. These results extend the demonstration of CPP to this in vertebrate species and pro-
vide further evidence in support of this model to testing/screening amphetamine-like and possibly other drugs of abuse.
Keywords: Amphetamine; Conditioned Place Preference; Drug Abuse; Planaria
1. Introduction
As a class, amphetamine psychostimulants have value in
a number of therapeutic applications (e.g., for narcolepsy
or ADHD (attention-deficit hyperactivity disorder) [1-3].
But they also have potential for abuse [4], with negative
health consequences [5]. An extensive body of evidence
suggests that the major rewarding/reinforcing effects of
psychostimulants such as the amphetamines is related to
their ability to inhib it the neuronal reup take of dop amine,
particularly in the mesocorticolimbic pathway [6-9], and
other neurotransmitters such as norepinephrine [10] and
the excitatory (glutamate) [6-9] and inhibitory (GABA,
-aminobutyric acid) [11] amino acids. In addition, there
is broad evidence of a functional interaction between the
dopamine and endogenous opioid systems, which might
play an important role in amphetamine abuse [12-25].
The conditioned place preference (CPP) paradigm is a
measure of incentive learning and an indicator of abuse
potential [26-30]. Amphetamine-induced CPP has been
demonstrated to occur in humans [31]. In animal models,
microinjections of amphetamine into nucleus accumbens
establishes a CPP, and the effect is attenuated by lesions
produced by 6-OHDA (6-hydroxydopamine) [29], or by
microinjections into the n. accumbens of
or reserpine [32], which suggests an involvement of the
mesolimbic dopamine pathway in this phenomenon. The
acquisition of amphetamine CPP is also attenu ated by the
selective antagonism of the dopamine D1 [33-34] and the
D2 [29,33] r eceptor or dual antagonism of bo th subtypes
[35]. This plus additional evidence suggests that both of
dopamine receptor types are involved when dopamine is
released by amphetamine during establishment of CPP
[36]. For example, null-mutant orphan G protein-coupled
receptor 37 (which colocalizes with the dopamine trans-
porter DAT) kno ckout mice (GPR37-KO ) do not respond
to the incentive properties in CPP tests [37].
Other neurotransmitters have been suggested to play a
role in CPP in addition to dopamine. For example: the
selective serotonin (5-HT, 5-hydroxytryptamine) 5-HT2C
receptor antagonist 6-Chloro-5-ethoxy-N-(pyridin-2-yl)
indline-1-carboxamide hydrochloride (CEPC) potentiates
low-dose amphetamine CPP [38]; amphetamine-induced
CPP is attenuated by selective antagonism of the growth
hormone secretagogue receptor 1A (GHS-R1A), which
suggests an involvement of the central ghrelin signaling
system [39]; the selective non-competitive antagonist of
the NMDA NR2B (N-methyl-D-aspartate 2B subunit) re-
ceptor, rhynchophylline, reverses the expression of am-
phetamine-induced CPP [40] and additional evidence
suggests that an activation of th e NMDA receptor and of
CaMKII (calcium/calmodulin-dependent protein kinase
II) activity are essential for amphetamine-induced CPP
[41]; intracerebroventricular administration of oxytocin
inhibits the acquisition and facilitates the extinction of
methamphetamine-induced CPP [42]; estradiol-treated
female rats have enhanced amphetamine-induced CPP
*Corresponding a uthor.
opyright © 2013 SciRes. JBBS
compared to vehicle-treated ovariectomized rats [43] (an
effect possibly related to the known estrogen enhance-
ment of dopamine-mediated behaviors; amphetamine-
induced CPP is blocked by an intra-hippocampal (CA3
region) infusion of an inhibitor of Trk (tyrosine kinase)
receptor [44]; intra-accumbens injection of a protein ki-
nase C inhibitor blocks amphetamine-induced CPP in
rats [45]; and both pre- and co-injections of diazepam
block the formation of amphetamine-induced CPP [46].
There is additiona l evidence, but it is beyond the scope of
the short overview presented here and the present report.
Planarians have the requisite endogenous neurotrans-
mitter systems relevant to a study amphetamine (ab) use
(for review see [47]), including dopamine, acetylcholine,
and opioids among others [48-55]. Planarians develop a
physical dependence to, and display abstinence-induced
and antagonist-precipitated withdrawal from, a diverse
list of drugs of abuse [56-61]. We recently reported the
development of nicotine- [62] and mephedrone- (“bath
sat”) induced [63] CPP in planarians.
2. Materials and Methods
2.1. Animals and Drugs
The planarians (Dugesia dorotocephala) were purchased
from Carolina Biological Supply (Burlington, NC). They
were acclimated to the laboratory temperature (21˚C) and
were tested within two days of receipt. d-Amphetamine
was obtained from the National Institute of Drug Abuse.
2.2. Behavioral Testing
The methodology was similar to that previously reported
by us [62,63]. Briefly, dark and light (ambient) sides
were created by covering half of the top, bottom, and
sides of a 60 mm diameter petri dish with black paper or
tape. Individual planarians were placed at the midline of
the dish. The time that the planarian spent in the non-
preferred side (light) over a 5-min interval was deter-
mined (the pre-pairing response). Planarians were then
conditioned with exposure to d-amphetamine (0.001, 0.1,
or 1 mM) for 30 min in the opposite non-preferred (light)
side. Immediately following conditioning, the planarian
was placed again at the midlin e of the petri dish (now half
light and half dark) containing vehicle and the amount of
time that the planarians spent in the non-preferred side
during the 5-min interval was measured.
3. Results
Untreated (drug-naïve) planarians spent 89% of the time
in the dark half of the test chamber (petri dish). The ef-
fect of 30-minute exposure to d-amphetamine on indi-
vidual planarian light/dark choice is shown in Figure 1.
The 0.001 mM dose reduced the preference to only about
Figure 1. Change in predominant preference for the dark of
drug-naïve planarians (Pre) to the dark after 30-min expo-
sure to d-amphetamine (Post) (0.001 mM, top graph; 0.1
mM, middle graph; 1 mM, bottom graph).
1/2. The doses of 0.1 and 1 mM reversed the natural pre-
ference for dark. Most of the planarians displayed a CPP
for the side in which they exposed to d-amphetamine, i.e.,
they spent more time in the light.
The effect of d-amphetamine exposure on reversal of
planarian light/dark preference choice was dose related.
d-Amphetamine (0.001, 0.1, and 1 mM) exposure during
conditioning produced dose-related increase in the time
planarians spent in the light (Figure 2). The data are
plotted as the mean ± s.e.m. of the percent of time that
planarians spen t in the light during th e 5-min observation
The effect of d-amphetamine exposure time on rever-
sal of planarian light/dark preference is shown in Figure 3.
Copyright © 2013 SciRes. JBBS
R. B. RAFFA ET AL. 133
0.001 0.01
Time in light (s) [max = 300]
0.1 1
ne (mM)
** **
Figure 2. Dose-related change in predominant preference
for the dark of planarians. N = 8 - 16 planarians per group.
**P < 0.01 (ANOVA df = 51, F = 11.2).
Time in light (s) [max = 300]
Amphetamine (0.1 mM)
exposure (min)
Figure 3. Change in the predominant preference for dark
after 30-min exposure to d-amphetamine (0.1 mM). N = 8 -
16 planarians per group. **P < 0.01 (ANOVA df = 51, F =
4. Discussion
Freely-moving planarians display a strong natural choice
for the dark, as in the presen t study of ~90% of the time.
We previously reported [64] that exposure of planarians
to cocaine reverses the strong preference that planarians
display for the dark in a simple choice paradigm. That is,
when cocaine-naïve planarians were allowed to choose,
they spent about 80 % of a 10-min test period in the dark,
similar to the present study. However, when exposed to
cocaine (8 × 10–5 M), they reversed their preference and
spent about 73% of the 10-min test period in visible light
(source maintained at a constant distance, 12.5 cm above
and perpendicular to the test apparatus). Other factors,
such as the ambient light conditions, test pH, directional
preference, local differences in test apparatus, etc. were
carefully controlled or randomized. The effect was not
simply secondary to an increase in spontaneous or drug-
induced locomo tor activity, since co caine only minimally
increases planarian locomoto r activity at the high est dose
tested [58]. It was also not due merely to a disruption of
sensory systems, since the behavior did not revert to a
random 50/50 split between light and dark. Hence, the
effect appeared to be directly related to cocaine.
Similarly, in the present study drug-naïve planarians
displayed a clear preference for light (about 90%), which
is consistent with our previous findings. Exposure of the
planarians to d-amphetamine (0.1 mM) for 15 minutes
reduced the dark-preference to only ~50% and exposure
to amphetamine for 30 minutes inverted the preference to
light––demonstrative of a conditioned place preference.
This is to our knowledge the first report of the develop-
ment of CPP to amphetamine in planarians. The demon-
stration of this phenomenon in planarians is important,
because planarians have proven to be a valuable model
system for studying drug action and abuse [47]. These
results can now form the basis for investigation of other
drugs of abuse and a more detailed investigation of the
biochemical processes involved.
5. Acknowledgements
The authors thank Timothy Shickley, Ph.D., for suggest-
ing Planaria as a model system. This work was sup-
ported by NIDA grants DA15378 and P30DA01342
(Ellen M. Unterwald, Ph.D., Temple University School
of Medicine, PI).
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