Review article 363
The role of the aversive effects of drugs in
self-administration: assessing the balance of reward
and aversion in drug-taking behavior
Andrey Verendeev and Anthony L. Riley
Since the first experimental demonstration that a drug of
abuse supports instrumental behavior, drugs have been
discussed in the context of their rewarding effects, which
are assumed to drive and maintain drug-taking behavior.
Indeed, drug reward has been fundamental in the
formulation of most models of drug use, abuse, and
addiction. Over the last several decades, however, drugs
of abuse have been increasingly recognized as complex
pharmacological compounds producing multiple stimulus
effects, not all of which are rewarding. The aversive effects
of such drugs, for example, have been described by a
number of researchers working in the field, although few
attempts have been made to investigate the role of these
aversive effects in drug taking. The present paper offers
a historical perspective on the view that drugs of abuse are
complex pharmacological compounds with multiple
stimulus effects. In doing so, we argue that the discussion
of drug reward only may be insufficient in accounting for
drug taking and we present evidence for the theoretical
position that both the rewarding and the aversive effects
of drugs should be taken into consideration in ongoing
attempts to model drug-taking behavior. The present
review summarizes several decades of research
characterizing the aversive effects of major drugs of abuse,
as well as more recent studies seeking to assess directly
the role of drug aversion in drug taking. Behavioural
c 2013 Wolters Kluwer Health |
Pharmacology 24:363–374 Lippincott Williams & Wilkins.
Drugs as rewarding stimuli
of a desire to re-experience the drug-induced euphoria
associated with initial drug taking, a desire that results
from neuroplastic changes that accompany chronic drug
taking. The physical dependence model stresses the role
of withdrawal relief associated with drug taking in
dependent individuals. The incentive-sensitization model argues that chronic drug taking is a function of the
psychological process of incentive salience wherein
certain internal and external stimuli associated with the
drug use become extremely salient, resulting in an
increased desire for the drug. Finally, the opponentprocess model assumes that chronic drug taking is
associated with the lowering of a hedonic set point and
is maintained by removal of the consequent dysphoria
produced by the absence of the drug. For all models, it is
clear that reward plays important roles in the initiation
and maintenance of drug taking and is instrumental in
the transition from use to abuse.
Drug addiction is a developing disorder that is characterized by a progression from initial experimentation and
nonproblem use to loss of control over the amount,
frequency, and/or duration of drug intake. This escalation
from controlled to compulsive use is believed to be
mediated by specific drug-induced neurobiological
changes that mark the shift to pathophysiology that
underlies compulsive drug seeking (reviewed in Koob and
Le Moal, 2006). Moreover, this transition to chronic use is
likely to be modulated by a host of genetic and
environmental factors that contribute toward the vulnerability to drug dependence.
In a recent discussion of human drug taking, Meyer and
Quenzer (2005) describe four basic models (positive
reinforcement, physical dependence, incentive sensitization, and opponent process) that address the transition
from drug use to drug abuse. For all four models, drug
taking is initiated and temporarily maintained by the
drug’s positively rewarding effects, although other
sources of reward (e.g. anxiety reduction) may also be
involved. With long-term maintenance and escalation,
however, the models assume different processes. For the
positive reinforcement model, drug use is a function of
the previous history of reinforcement of drug-taking
behavior, which presumably is driven by the development
c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
0955-8810 Behavioural Pharmacology 2013, 24:363–374
Keywords: addiction, conditioned place preference, conditioned taste
aversion, drug aversion, drug reward, self-administration
Psychopharmacology Laboratory, Department of Psychology, American
University, Washington, District of Columbia, USA
Correspondence to Andrey Verendeev, PhD, Psychopharmacology Laboratory,
Department of Psychology, American University, 4400 Massachusetts Ave NW,
Washington, DC 20016, USA
E-mail: andrey.verendeev@gmail.com
Received 3 March 2013 Accepted as revised 31 May 2013
Given the importance of the rewarding effects of drugs, it
is not surprising that these effects have been well
characterized in terms of their behavioral, neuroanatomical, and neurochemical effects (Koob and Le Moal, 2006).
Great advances have been made in our understanding of
such effects and their relationship with drug vulnerability,
abuse, and addiction. Although this relationship is more
complicated than initially assumed (Wise and Bozarth,
DOI: 10.1097/FBP.0b013e32836413d5
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
364 Behavioural Pharmacology 2013, Vol 24 No 5&6
1987), characterization of the mechanisms that mediate
reward has been fundamental in our understanding
of drug use and abuse.
It should be noted, however, that drugs of abuse are
complex pharmacological compounds with multiple
stimulus effects, not all of which are rewarding (Wise
et al., 1976; Stolerman, 1992; Koob and Le Moal, 2006;
Verendeev and Riley, 2012). For example, the aversive
effects of drugs of abuse have also been increasingly
recognized (Goudie, 1979; Gaiardi et al., 1991; Riley,
2011; Verendeev and Riley, 2012). These aversive effects
have been well described for all major classes of drugs of
abuse (Verendeev and Riley, 2012) and have been found
to occur independent of the drugs’ rewarding effects
(Cunningham et al., 2009; Verendeev and Riley, 2011,
2012). Despite being well described, however, the nature
of these aversive effects remains to be determined (see
below; Verendeev and Riley, 2012).
It has been suggested by several authors that drug taking
may be a function of the relative balance between drug
reward and aversion (Stolerman and D’Mello, 1981;
Gaiardi et al., 1991; Riley and Simpson, 2001; Riley,
2011; for a discussion of the interaction of drug reward
and aversion in the repeated use of plant-derived drugs,
see Hagen et al., 2009). If so, the discussion of drug use
and abuse necessitates the examination of both of these
drug effects, their interaction, and the different factors
impacting them. In the present paper, we present
evidence in support of the inclusion of the aversive
effects of drugs in discussions of drug use and abuse. In so
doing, we summarize several decades of research
characterizing the aversive effects of drugs of abuse, as
well as more recent studies seeking to assess directly the
role of drug aversion in drug taking.
Aversive effects of drugs of abuse
Garcia et al. (1955), in a paper published in Science,
reported that rats avoid consumption of a preferred
saccharin solution if its initial consumption was followed
by exposure to ionizing radiation. This required only one
pairing of the taste and radiation exposure, was dose
dependent (i.e. higher levels of gamma radiation resulted
in greater suppression of intake), and appeared to be
quite robust (i.e. rats persisted in taste avoidance for at
least 30 days despite continuous exposure to both water
and the saccharin solution). Termed a conditioned taste
aversion (CTA), this phenomenon was interpreted in
classical conditioning terms; specifically, the taste (CS)
was paired with the radiation-induced nausea (US),
resulting in a conditioned avoidance (CR) of the taste
on a subsequent exposure. According to early interpretations, CTA was a specialized form of learning that allowed
organisms to quickly recognize and reliably avoid
potentially poisonous substances (see Freeman and Riley,
2009 and Verendeev and Riley, 2012 for a review of the
history of CTA as well as discussion of the unique nature
of this phenomenon).
Shortly after CTA was described in irradiated animals,
a number of reports showed similar effects using other
treatments, both pharmacological (e.g. well-known poisons and toxins; Garcia and Ervin, 1968; Freeman and
Riley, 2009) and nonpharmacological (e.g. full body
rotation; Braun and McIntosh, 1973). Quite surprisingly,
a number of drugs of abuse, known for their rewarding
effects, were also found to support CTA learning. For
example, Goudie et al. (1978) administered rats a novel
saccharin solution to drink, followed by an injection of
a drug vehicle or one of four doses of cocaine (5, 10, 20,
or 36 mg/kg intraperitoneally). This taste–drug pairing
was repeated for several trials, after which the subjects
were presented with the saccharin on a taste-avoidance
test. Cocaine induced avoidance of saccharin in a dosedependent manner (cf. Garcia et al., 1955), with the
lowest dose (5 mg/kg) being ineffective in producing an
avoidance and the largest dose producing the greatest
suppression of saccharin consumption. Moreover, suppression was greater after several conditioning trials than
after a single pairing (at least for the two largest doses
tested; see Fig. 1).
Although cocaine was one of the first drugs for which
CTAs were characterized (see also Ferrari et al., 1991;
Glowa et al., 1994), the list of drugs that can support
taste-avoidance learning includes all major drugs of abuse:
amphetamine (Cappell and LeBlanc, 1971; Carey and
Goodall, 1974; Booth et al., 1977; Verendeev and Riley,
2011), morphine (White et al., 1977; Riley et al.,
1978; Bechara and van der Kooy, 1985; Verendeev and
Riley, 2011), heroin (Grigson et al., 2000; Davis et al.,
2009), nicotine (Etscorn, 1980; Kumar et al., 1983;
Iwamoto and Williamson, 1984; Etscorn et al., 1986;
Pescatore et al., 2005; Rinker et al., 2008), ethanol
(Cappell et al., 1973; Cunningham, 1979; Roma et al.,
2006), caffeine (White and Mason, 1985; Steigerwald
et al., 1988; Brockwell et al., 1991; Vishwanath et al., 2011),
tetrahydrocannabinol (Corcoran et al., 1974; Kay, 1975;
Fischer and Vail, 1980; Parker and Gillies, 1995), MDMA
(Lin et al., 1994; Albaugh et al., 2011), and various
hallucinogens (Cappell and LeBlanc, 1971; De Beun
et al., 1993; Parker, 1993, 1996) (for a bibliography of
psychoactive substances that can support taste avoidance
learning, see http://www.ctalearning.com).
Factors affecting the aversive effects of drugs
The ability of drugs of abuse to support CTA learning
suggested that drugs had some intrinsic aversive properties. It is important to note, however, that these
properties were not fixed, but were a function of a
number of experimental and subject variables. For
example, as discussed above, Goudie et al. (1978)
reported that the magnitude of suppression of intake of
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Balance of reward and aversion Verendeev and Riley 365
Fig. 1
16
Saline
14
5
Mean intake(g)
12
10
10
8
of different factors. Although aversions can be impacted
by a wide variety of factors, it is important to note that
the vast majority of drugs induce aversions across a wide
variety of parametric conditions in almost all organisms
tested (including humans; see Garb and Stunkard,
1974; Klosterhalfen and Klosterhalfen, 1985; Logue,
1985; Garcia and Riley, 1998; Freeman and Riley, 2009;
see also Reilly and Schachtman, 2009).
Reward and aversion: independent effects
20
6
36
4
2
Water 1
day 5
2
3
4
Trial
Mean (±SEM) saccharin consumption over three saccharin–cocaine
pairings and the final taste avoidance test (trial 4) of rats injected with
one of the four doses of cocaine (5, 10, 20, or 36 mg/kg) or a drug
vehicle (saline control). Adapted with permission from Fig. 1 of Goudie
et al. (1978).
a flavored solution paired with cocaine injections was
dependent on both the dose (higher doses resulted in
greater suppression) and the number of conditioning
trials (more flavor–drug pairings resulted in greater
suppression; although see Siegel et al., 1995). Route of
administration was also important. For example, Riley
et al. (1978) found moderate, albeit significant, suppression following intraperitoneal morphine. Later studies
found that morphine administered subcutaneously resulted in a much more robust suppression (see, for
example, Lancellotti et al., 2001; Verendeev and Riley,
2011; see also Ferrari et al., 1991 for a direct comparison
between intraperitoneal and subcutaneous cocaine to
produce CTA).
Other factors reported to influence the ability of drugs to
produce aversive effects were age, sex, drug history, and
strain. For example, adolescent rats appear less sensitive
to the aversive effects of drugs compared with adult
rats (reviewed in Schramm-Sapyta et al., 2009). Male rats
appear more responsive to the aversive effects of drugs
than female rats, as evidenced by their ability to acquire
CTAs faster (Chambers et al., 1981; Sherrill et al., 2011a).
Drug history weakens the ability of drugs of abuse to
produce CTA, which implies that previous drug exposure
attenuates the aversive effects of drugs (reviewed
in Riley and Simpson, 2001). Finally, the ability of drugs
to produce CTA differs across different strains of rats and
mice (Cunningham et al., 2009; Riley et al., 2009). All
these reports suggested that the aversive effects of drugs
of abuse are not static, but can be influenced by a number
The finding that drugs that were reliably self-administered by animals and able to produce place preferences
(see Tzschentke 2007), also supported CTA learning
presented a conundrum (Gamzu, 1977; White et al.,
1977; Goudie, 1979; Hunt and Amit, 1987). How could
drugs that are rewarding in both rats and humans also
produce avoidance of taste stimuli with which they were
paired? One simple solution for this dilemma was to argue
that any specific drug may have both rewarding and
aversive effects, but that these effects are dependent on
the specific parameters under which they are examined.
Indeed, Cappell and LeBlanc (1971), in a study assessing
the ability of amphetamine to induce CTA, did just this
and pointed to the ‘gross and obvious’ (p. 355)
differences between the experimental procedures measuring drug reward and aversion that could potentially
explain the apparent paradox.
However, this argument met with some criticism when it
was reported that a drug could produce both rewarding
and aversive effects under the same experimental
conditions. For example, Wise et al. (1976) presented
rats with a novel saccharin solution to drink and allowed
them to self-administer 0.5 mg/kg apomorphine for a
single session. They found that individual rats both selfadministered intravenous apomorphine and subsequently
avoided the saccharin solution. Moreover, there was
a strong relationship between the two: individual rats
that self-administered the most apomorphine showed
the greatest avoidance of saccharin intake. The authors
were led to conclude that drugs of abuse exert multiple
stimulus effects, both positive and negative. They noted:
‘These data, then, demonstrate for the first time that the
same drug injection can be both positive reinforcing and
aversive. The demonstration of both properties in the
same animals, in the same test session, rules out
arguments that differences in paradigms can account for
the fact that in one paradigm a drug seems aversive while
in the other paradigm the same drug seems reinforcing.
Thus it must be concluded that injections of abused
drugs do not represent simple positive pharmacological
stimuli; rather, drug injections must be viewed as
compound stimuli with both positive and negative
elements’ (Wise et al., 1976, p. 1274).
In a related study, White et al. (1977) trained rats to run
down a straight alley for food available in a goal box.
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366 Behavioural Pharmacology 2013, Vol 24 No 5&6
Immediately after consumption, rats were injected with
one of the two doses of morphine sulfate (9 or 15 mg/kg)
and returned to the empty goal box for 50 min. Over
trials, rats increased their running speed to reach the goal
box, but decreased the amount of food consumed. Similar
to Wise et al. (1976), this study showed that a drug of
abuse produced both rewarding and aversive effects in
the same animal and by the same drug injection, as
indicated by the increase in running speed and decrease
in food consumption, respectively (see also Reicher and
Holman, 1977; Sherman et al., 1980; for more recent
reports, see Ettenberg and Geist, 1991, 1993; Simpson
and Riley, 2005; Verendeev and Riley, 2011). Although
both effects are produced, their temporal nature is
unknown. Indeed, from work with ethanol and cocaine,
the specific timing of these two responses differs,
suggesting that they are drug specific (see, for
example, Cunningham et al., 1997; Ettenberg et al., 1999).
Nature of drug aversion
The ability of drugs of abuse to produce drug reward and
drug aversion under the same conditions suggested to
some investigators a functional relationship between the
two. According to these authors (Hunt and Amit,
1987; Grigson, 1997), the ability of drugs of abuse to
produce drug aversion depended on their ability to
produce drug reward. That is, rather than being
dichotomous, which might suggest some differences in
the underlying mechanisms, the aversive effects of drugs
of abuse were interpreted in the context of their
rewarding effects. In this context, two possible mechanisms for drug aversion have been suggested: drug novelty
(Hunt and Amit, 1987) and reward comparison (Grigson,
1997; see Verendeev and Riley, 2012, for a full discussion
of these and other interpretations).
According to the drug novelty hypothesis of Hunt and
Amit (1987), the rewarding effects of drug administration
provide a novel discriminative state for the animal, which,
although positively reinforcing under most conditions
(i.e. self-administration and place preference conditioning), may have aversive effects when paired with a novel
taste solution. These authors acknowledge the regulated
homeostatic state of the animal and argue that disruption
of homeostasis (by a drug’s rewarding effects) serves as a
negative punishing effect within the CTA procedure. The
rewarding and suppressing effects of drugs, therefore, are
not dichotomous but share a common discriminative
profile, and their ability to serve as either positively
reinforcing or negatively punishing depends on the
conditions of the experimental manipulation.
The second hypothesis, according to which drugs of
abuse suppress taste consumption because of their
rewarding effects, has been proposed more recently
by Grigson (1997) and is known as reward comparison
(see Flaherty, 1996). According to the reward comparison
hypothesis, when presented with two rewarding stimuli
(e.g. a taste and a drug), ‘[r]ats decrease intake of a
gustatory CS y because the rewarding properties of the
gustatory stimulus pale in comparison to those of the
impending drug of abuse’ (Grigson, 1997, p.134). In other
words, CTA is not a measure of drug aversion, but instead
a measure of drug reward.
Although interesting, these two hypotheses are not well
supported by evidence. If, according to these positions,
drug reward and drug aversion are not separate but
dependent on each other (as drug aversion is a function
of drug reward for both of the above-mentioned positions),
the ability of a drug to produce reward and the ability of the
drug to produce aversion should covary. Moreover, manipulations should affect the two in a similar and a consistent
manner. For example, Hunt and Amit (1987) argued that
pharmacological manipulations that block the rewarding
effects of drugs also attenuate their suppressing effects
(see also Sklar and Amit, 1977). Although there is some
evidence to support this position (e.g. pimozide, a
dopamine receptor antagonist, has been shown to attenuate
amphetamine and cocaine self-administration as well as
amphetamine-induced and cocaine-induced CTAs), several
other studies show that some pharmacological manipulations affect a drug’s rewarding and aversive effects
differentially. Further, Simpson and Riley (2005) examined
the effects of morphine pre-exposure on morphine-induced
place preference and taste avoidance in the same subjects.
They found that pre-exposure to morphine enhanced place
preference but attenuated taste avoidance, a result
incompatible with the position that drug reward and
aversion are mediated by the same mechanism. Similar
dissociations of drug reward and drug aversion have been
found in other studies that examined this phenomenon in
the same subjects (Martin et al., 1988; Gaiardi et al., 1991)
or in separate groups of subjects (LeBlanc and Cappell,
1974; Cappell et al., 1975; Dacanay and Riley, 1982; Domjan
and Siegel, 1983; Riley et al., 1984; Harris and Aston-Jones,
2003; He et al., 2004; Manzanedo et al., 2005).
In addition to pre-exposure and pharmacological treatments, the rewarding and aversive effects of drugs can be
dissociated using a number of other manipulations. For
example, adolescent rats are more sensitive to the
rewarding effects, but less sensitive to the aversive
effects of drugs than adult rats (see above; see
also Schramm-Sapyta et al., 2009 for a review). Lesion
data also show that drug reward and aversion are
anatomically dissociable. Sellings et al. (2008), for
instance, found that 6-OHDA lesions of the nucleus
accumbens medial shell, but not core, attenuated
nicotine-induced place preference, whereas lesions of
the nucleus accumbens core, but not the medial shell,
blocked nicotine-induced taste avoidance (see Verendeev
and Riley, 2012 for a review of the role of reward in the
mediation of taste avoidance).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Balance of reward and aversion Verendeev and Riley 367
First, we found that individual subjects differed considerably in their sensitivity to the rewarding and aversive
effects of both morphine and amphetamine. Individual
subjects were sensitive to the rewarding effects of drugs
but not to their aversive effects and vice versa, or,
individual subjects were sensitive to both or neither of
these effects. Second, we found no relationship between
the ability of either drug to produce a place preference
and its ability to produce a taste avoidance (see Fig. 2).
Specifically, animals were divided into high and low
responders for all conditions and the relationships
between the change in saccharin consumption and
change in time spent on the DPS were analyzed. We
found only one significant relationship between the two
in any of the conditions: animals administered 5 mg/kg
amphetamine that showed the strongest aversions were
less likely to show an increase (or showed an actual
decrease) in the time spent on the DPS (a relationship
opposite to what would be expected if a drug’s aversive
effects depended on its rewarding effects). Apart from
this single significant relationship out of 16 possible,
it seems to be the case that the ability of a drug to
produce drug aversion is not dependent on the drug’s
ability to produce drug reward.
If taste avoidance produced by drugs of abuse is not
mediated by their rewarding effects, what then is the
nature of the drugs’ aversive effects? Several hypotheses
have been put forward, but none has proved conclusive
(see Verendeev and Riley, 2012 for a full discussion of
these positions as well as their criticisms). One recent
account of a drug’s aversive effects was summarized
recently by Parker et al. (2009). Termed the ‘conditioned
fear’ hypothesis, this position argues that drugs upset the
tight homeostatic state of the animal, resulting in
conditioned fear of the drug-associated internal state
(for a summary, see Verendeev and Riley, 2012). Although
Fig. 2
r = 0.031; P = 0.897
300
Change in time spent on the DPS (s)
In a recent test of the relationship between drug reward
and drug aversion, we (Verendeev and Riley, 2011)
examined the relationship between the ability of two
different classes of drugs (an opiate and a psychostimulant) to produce drug reward and drug aversion in the
same animal. Using the combined CTA/conditioned place
preference (CPP) procedure (cf. Simpson and Riley,
2005), we assessed the relationship between morphineinduced and amphetamine-induced place preference and
taste avoidance in individual subjects at two different
doses (5 and 10 mg/kg morphine and 3 and 5 mg/kg
amphetamine). Specifically, rats were given a novel
saccharin solution to drink, injected with a drug, and
placed in the CPP apparatus. We then examined the
change from baseline in saccharin consumption (decrease
from baseline in saccharin consumption indicated avoidance) and change from baseline in the time spent on the
drug-paired side (DPS) of the CPP apparatus (increase in
the time spent of the DPS indicated preference).
200
100
0
−100
−15
−10
0
−5
Change in saccharin consumption (ml)
5
Lack of relationship between the rewarding and aversive effects of
morphine. Correlational analysis of the relationship between change in
the time spent on the drug-paired side (DPS) and change in saccharin
consumption for animals injected subcutaneously with 5 mg/kg
morphine. Visual analysis shows considerable individual variability in
sensitivity to both the rewarding and the aversive effects of morphine.
Included in the graph are Pearson’s r, the P value, and the line of best fit
for the given relationship. See also Verendeev and Riley (2012).
supported by a number of observations, it is yet to be
determined what exactly is disrupted by the drug
injection, which may be drug specific (e.g. psychostimulant anxiogenesis vs. alcohol toxicity).
It is important to note, in this context of the nature of the
aversive effects of drugs, that the suppression of intake
induced by such effects does not necessarily support the
position that an aversion is produced to the drug-associated
taste. In fact, it has been suggested that the term ‘taste
aversion’ may inaccurately describe the ability of drugs of
abuse to produce suppression of consumption of taste
stimuli. Comparing the ability of emetic agents and
rewarding drugs to produce conditioned aversive responses
to a taste CS, Parker and colleagues found that drugs of
abuse, unlike classical toxins, do not produce conditioned
aversive reactions, although both produce conditioned
suppression of a taste CS at comparable magnitude (Parker,
1995). This led her to conclude that the term ‘conditioned
taste aversion’ was inappropriately applied to describe druginduced suppression and that the term ‘conditioned taste
avoidance’ should be used instead (see Verendeev and
Riley, 2012, for a more detailed discussion of this).
Impact of drug aversion on drug taking
Irrespective of the exact nature of the aversive effects of
drugs, on which there is no current consensus, it is clear
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
368 Behavioural Pharmacology 2013, Vol 24 No 5&6
that the positive rewarding and negative aversive effects
of drugs are independent processes. If drugs of abuse
produce both rewarding and aversive effects, it follows
that to better understand drug vulnerability in both rats
and humans, it is necessary to understand both effects
and the interplay between them. Indeed, it has been
suggested by several authors that drug taking may be a
function of the relative balance between drug reward and
aversion (Stolerman and D’Mello, 1981; Gaiardi et al.,
1991; Riley and Simpson, 2001; see also Riley et al., 2009),
with the drug’s aversive effects serving as a limiting factor
in drug taking. If so, successful modeling of drug-taking
behavior (both problem and nonproblem use) should take
into account the relative input of both rewarding and
aversive effects of drugs as well as different factors that
affect these two properties.
If drug use is a function of the balance between drug
reward and drug aversion, one would expect that knowing
the relative strength of these two effects would enable
direct predictions of drug intake. Although it is often not
feasible to know the relative contributions of a drug’s
rewarding and aversive effects to the overall drug
experience, which may vary from one individual to
another (see Verendeev and Riley, 2011), it is nonetheless
possible to examine the role of drug reward and drug
aversion in drug taking. One way to do this is by studying
the effects of different manipulations that differentially
impact a drug’s rewarding and aversive effects and subsequently examine these manipulations in relation to drug selfadministration. Here, we will focus on two examples of such
an approach: drug history and genetic models.
Drug history
Drug history has been examined in animal models in the
context of US pre-exposure. In a standard procedure,
animals are administered a drug (US) before conditioning: in other words, the animal is no longer drug-naive
when its rewarding and aversive effects are subsequently
examined. The effects of drug history within US preexposure are a function of the number of pre-exposure
sessions, the dose of the drug used during drug preexposure, and the interval between drug pre-exposure
and subsequent conditioning (Riley and Simpson, 2001).
The effects of previous drug experience are then
examined in comparison with animals that receive no
such experience with the drug (i.e. drug-naive). Using
the CPP design as a measure of drug reward and the CTA
design as a measure of drug aversion, such drug
experience (i.e. US pre-exposure) impacts the rewarding
and aversive effects of drugs differentially. We will
consider the effects of drug history on drug reward first.
In an attempt to examine whether previous drug exposure
produces tolerance or sensitization to the rewarding effects
of drugs, Lett (1989) administered repeated injections of
amphetamine, morphine, or cocaine to rats before place
preference conditioning with these drugs. The following
parameters were varied for pre-exposure (dose and the
number of pre-exposure sessions) and CPP conditioning
(dose and the number of conditioning trials), respectively:
amphetamine – 1.5 mg/kg (six injections) and 1.5 mg/kg
(three trials); morphine – 5 mg/kg (five injections) and
5 mg/kg (one trial); and cocaine – 20 mg/kg (10 injections)
and 2.5 mg/kg (three trials). Lett (1989) reported that
whereas animals treated with either amphetamine or
cocaine during conditioning showed place preferences for
the DPS of the CPP apparatus, animals with previous
amphetamine or cocaine experience, respectively, showed
significantly enhanced place preferences compared with
animals with no drug pre-exposure (see Fig. 3). Rats with
no morphine pre-exposure showed no significant place
preference, a finding that was attributed to the use of
a single drug–place pairing. Interestingly, animals that
received previous morphine exposure did show a significant
place preference, which suggested that the rewarding
effects of morphine were also enhanced by drug preexposure under this condition as well (see Fig. 3). Subsequent research with these compounds confirmed that
drug history enhances the rewarding effects of amphetamine (Nocjar and Panksepp, 2002), morphine (Gaiardi
et al., 1991; Shippenberg et al., 1996; Simpson and Riley,
2005), and cocaine (Shippenberg and Heidbreder, 1995),
as well as other drugs of abuse (Shoaib et al., 1994).
Interestingly, similar enhancing effects of drug preexposure on the rewarding effects of drugs were found
when different drugs were used for pre-exposure and
conditioning. For example, in addition to examining
within-drug effects, Lett (1989) examined the effects of
morphine pre-exposure on amphetamine and cocaine place
preferences as well as the effects of amphetamine
on morphine-induced CPP. Morphine (5 mg/kg) was
found to enhance the rewarding effects of both amphetamine (1.5 mg/kg) and cocaine (2.5 mg/kg), and amphetamine (1.5 mg/kg) was found to enhance the rewarding
effects of morphine (1 mg/kg), as evidenced by significant
increases in the percent time spent on the DPS in
drug-experienced versus drug-naive animals (Lett, 1989).
Although some subsequent research has extended these
findings to other drug interactions (Hutchison and Riley,
2012), other studies have failed to do so (Le Pen et al.,
1998; Busse et al., 2005).
Although US pre-exposure has been found to enhance the
rewarding effects of drugs (at least when examined
within the same drug), its effects on the aversive effects
of drugs are opposite, that is, such pre-exposure
attenuates the ability of drugs to produce taste avoidance.
The attenuating effects of US pre-exposure on the ability
of drugs of abuse to condition CTAs have been well
documented (see Riley and Simpson, 2001 for a review;
see also Hall, 2009). For example, Riley and Diamond
(1998) examined the effects of previous cocaine exposure
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Balance of reward and aversion Verendeev and Riley 369
Fig. 3
Fig. 4
Drug history
Time spent on the DPS (%)
A
60
∗
C
M
∗
20
∗
40
20
0
Saccharin consumption (ml)
No drug history
on cocaine-induced CTAs. Animals were administered
cocaine (32 mg/kg) injections every fourth day for a total
of five injections before conditioning with cocaine (at the
same dose). The authors reported that in drug-naive
animals, cocaine produced a robust suppression of intake of
the drug-paired solution; however, cocaine did not exert an
effect in the cocaine pre-exposed animals (see Fig. 4).
Similar effects of US pre-exposure on the aversive effects of
drugs (i.e. attenuation) have been reported for other drugs
examined under similar conditions (see Riley and Simpson,
2001 for a comprehensive review). The ability of exposure
to one drug in attenuating CTAs induced by another has
also been examined extensively within the US preexposure literature (Cappell et al., 1975; Goudie and
Thornton, 1975; Vogel and Nathan, 1976; Gamzu,
1977; Brown et al., 1979; Switzman et al., 1981; Ton and
Amit, 1983; Bienkowski et al., 1998; Hutchison et al.,
2010; Rinker et al., 2011). Unlike CPP, where the results are
mixed, the attenuating effects of cross-drug pre-exposure
seem to be more robust within the CTA preparation.
It is important to note here that the effects of drug
history on the rewarding and aversive effects of drugs can
be subject to a number of different manipulations and are
likely dependent on a number of different factors. Earlier,
we mentioned that the aversive effects of drugs are not
fixed and can be influenced by different experimental
and subject variables. It is likely that these same variables
can also influence the effects of drug history on drug
reward and drug aversion; some effects of this kind have
been reported (see Riley and Simpson, 2001; Tzschentke,
2007 for a more detailed discussion).
WC
CW
WW
15
10
5
0
1
Sensitization of the rewarding effects of drugs by drug history.
Conditioned place preference was measured by %time spent on the
drug-paired side (DPS) in subjects receiving amphetamine (A),
morphine (M), or cocaine (C) with no history (open bars) and a previous
history (dark bars). *Significant differences between the subjects with
or without drug history. See text for further details. Reproduced with
permission from Table 3 of Lett (1989).
CC
2
3
Trials
4
5
Attenuation of the aversive effects of cocaine by cocaine history. Mean
(±SEM) saccharin consumption by groups receiving saccharin–cocaine
(groups CC and WC) or saccharin–water (groups CW and WW)
pairings during taste avoidance conditioning. The first letter in the group
designation refers to the drug received during pre-exposure, that is,
cocaine (C) or water (W); the second letter refers to the drug received
during conditioning, that is, C or W. See Riley and Diamond (1998) for
more detail. Adapted with permission from Fig. 1 of Riley and Diamond
(1998).
Another important caveat to mention is that most studies
that examined the effects of drug pre-exposure on
subsequent place preference or taste avoidance conditioning did so in separate animals and across different
studies. To evaluate the effects of drug history on drug
reward and drug aversion more directly, these assessments should be performed in the same animals and
under the same parametric conditions. Recently, Simpson
and Riley (2005) examined the effects of morphine preexposure on morphine-induced place preference and
taste avoidance in the same subjects. Rats were first
administered subcutaneous injections of 5 mg/kg morphine every other day for a total of five injections. They
were then trained in a combined CTA/CPP procedure
(see above), wherein a single injection of morphine (1 or
5 mg/kg) was administered to condition both a place
preference and a taste avoidance. Both preferences and
aversions were conditioned and, similar to what has been
reported in between-subject analyses, pre-exposure to
morphine enhanced place preference and attenuated
taste avoidance within the same subjects.
If drug history enhances the rewarding effects of a drug
and attenuates its aversive effects, the resulting overall
drug experience should be shifted toward a relative
increase in its perceived rewarding effects. On the basis
of the view that drug taking is a function of the balance
between drug reward and drug aversion, we might expect
that previous drug history will result in increased drug
taking. Several lines of evidence support this position. For
example, Rodd-Henricks et al. (2002) examined the effect
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
370 Behavioural Pharmacology
2013, Vol 24 No 5&6
of ethanol exposure early in life on ethanol selfadministration in adulthood and found that drug history
increased drug taking later in life. Specifically, adolescent
rats were either allowed free access to a 15% ethanol
solution for 30 days or received no such exposure. In
adulthood, drug-experienced and drug-naive rats were
allowed to self-administer 15% ethanol in a choice
(ethanol vs. water) procedure. Following acquisition, rats
were also compared in extinction as well as reacquisition
of responding for ethanol. Compared with drug-naive
animals, rats with a previous history of ethanol exposure
acquired self-administration faster. Moreover, drug-experienced rats showed a greater resistance to extinction
(i.e. higher rates of responding when ethanol was no
longer available) as well as greater responding for ethanol
during reacquisition. These findings are consistent with
the above-mentioned view that drug history alters the
balance between drug reward and drug aversion in such a
way as to make drug taking more probable (i.e. enhanced
rewarding effects, attenuated aversive effects). Similar
results have been reported with ethanol (Siciliano and
Smith, 2001; Pascual et al., 2009; Sherrill et al., 2011b).
Genetic models
Another way to study the role of drug reward and drug
aversion in drug taking is to examine these effects in
selectively bred mouse and rat lines (Crabbe, 2002) as
well as inbred strains of these species (see Riley et al.,
2009). Selectively bred lines share the common phenotype of interest (such as sensitivity to either rewarding or
aversive effects of a drug or high or low propensity for
drug self-administration) by virtue of selective breeding
over a number of generations. Inbred strains, however, are
more genetically homogeneous as a result of successive
uninterrupted full-sibling matings (Beck et al., 2000).
Multiple selectively bred lines and inbred strains of mice
and rats are available, and these have been indispensable
in studies of drug use and abuse.
The use of these genetic models in relation to the relative
roles of drug reward and aversion in drug intake has usually
focused on examination of the relative sensitivity of the
selected line or inbred strain to either the rewarding or
aversive effects in relation to drug taking. In other words,
if two particular lines or strains have been described in
terms of their sensitivity to the rewarding effects of a drug
(usually measured by CPP) or to the aversive effects of a
drug (measured by CTA), they would be compared for their
propensity for drug taking. Conversely, if two particular
lines or strains were described in terms of their drug
consumption (either high or low), their relative sensitivities
to both the rewarding and the aversive effects would
subsequently be compared.
In mice, several selectively bred lines have been used to
examine the relationship between ethanol consumption
and the sensitivity to either the rewarding or the aversive
effects of ethanol. For example, Phillips et al. (2005) used
short-term selective breeding to create mouse lines
different in their free choice ethanol consumption or
ethanol-induced conditioned taste avoidance. After four
generations of selective breeding, high-drinking mice
(i.e. greater ethanol self-administration) showed greater
ethanol-induced CPP compared with low-drinking mice.
In contrast, mice selectively bred for greater sensitivity to
the aversive effects of ethanol (as evidenced by their
greater suppression of a drug-paired saccharin solution)
showed reduced ethanol consumption when given the
opportunity to consume 10% ethanol and had a lower
overall ethanol preference ratio than did mice selectively
bred for weaker sensitivity to the aversive effects of the
drug. Similar results have been reported in another study
that selectively bred mice for high and low ethanol
preference (Chester et al., 2003): mice that showed
higher ethanol preference showed attenuated taste
avoidance to 2 and 4 g/kg ethanol compared with those
of mice with low ethanol preference.
One of the most widely used inbred mouse strains is the
C57BL/6J (C57) mouse, which has been noted for its high
level of ethanol consumption (see Cunningham et al.,
2009). When compared with other strains, such as the
DBA/2J (DBA) mouse, which shows low levels of ethanol
consumption, the C57 strain consistently consumes more
ethanol (Horowitz and Whitney, 1975; Risinger and
Cunningham, 1992, 1995, 1998). When these two strains
are compared for their sensitivity to ethanol, DBA mice
show consistently greater CTAs than C57 mice at various
doses of ethanol (Horowitz and Whitney, 1975; Risinger
and Cunningham, 1992, 1995, 1998; see also Balknap et al.,
1978).
Selected lines of rats also support the above-mentioned
work with ethanol. For example, Froehlich et al. (1988)
reported that ethanol-preferring rats that consumed more
ethanol than ethanol-nonpreferring rats showed reduced
taste avoidance when conditioned with 1 g/kg ethanol
than their nonpreferring counterparts. In a related study,
University of Chile, low-ethanol-drinking rats consumed
less ethanol than high-ethanol-drinking rats, and showed
greater sensitivity to the aversive effects of ethanol,
evidenced by significant ethanol-induced CTA at 1.5 g/kg
(which was not evident in high-drinking rats) and
stronger ethanol-induced CTA at 2 g/kg than their highdrinking controls (Quintanilla et al., 2001). The selectively bred Wistar Kyoto (WKY) strain, which consumes
less ethanol than Marshall (M520) rats, acquired taste
avoidance at a lower dose than M520 rats (i.e. they
showed higher sensitivity to the aversive effects of
ethanol; Cannon and Carrell, 1987).
Although the above-mentioned rat strains have been used
to document the relative sensitivities to drugs of abuse,
primarily ethanol, the major work in rats in relation to drug
use is with the Fischer (F344) and Lewis (LEW) inbred rat
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Balance of reward and aversion Verendeev and Riley 371
strains. F344 and LEW rats, which differ in a number of
behavioral and physiological characteristics (most notably in
the regulation of the hypothalamic–pituitary–adrenal axis,
wherein F344 rats are significantly more reactive to various
physical and psychological stressors than LEW rats), have
also been reported to differ in their sensitivity to the
rewarding and aversive effects of drugs of abuse as well as
in their self-administration (see Kosten and Ambrosio,
2002). Assessment of differences between these strains in
their responsivity to the rewarding and aversive effects of
drugs in relation to self-administration provides further
support for the position that both drug reward and drug
aversion should be considered in the analysis of drug-taking
behavior.
Specifically, F344 rats have been described to be less
sensitive to the rewarding effects of morphine (as measured
by CPP; Guitart et al., 1992; although see Davis et al., 2007)
and more sensitive to its aversive effects (as measured by
CTA; Lancellotti et al., 2001) than LEW rats. When these
two strains are compared in morphine self-administration,
F344 rats consistently take less morphine than LEW rats
(Ambrosio et al., 1995). When examined with cocaine,
however, the results are less straightforward. Specifically,
LEW rats show a greater CTA response than F344 rats
(Glowa et al., 1994; Grigson and Freet, 2000), but selfadminister cocaine to a greater degree than F344 rats
(Kosten et al., 1997; although see Haile and Kosten,
2001; Haile et al., 2005; Freeman and Riley, 2009 for a
discussion of how the aversive effects of cocaine may limit
the escalation of cocaine self-administration). Although
these results appear inconsistent with the position that a
drug’s aversive effects limit drug taking, it is important to
emphasize that drug taking is a function of the balance
between drug reward and drug aversion. Therefore, even
though LEW rats are more sensitive to the aversive effects of
cocaine than F344 rats (see above), LEW rats also appear to
be much more sensitive to the rewarding effects of cocaine,
as evidenced by the fact that LEW rats show more robust
cocaine-induced place preference compared with the F344
strain (Guitart et al., 1992). This pattern of differential
sensitivity to both the rewarding and the aversive effects of
cocaine in LEW and F344 rats further underlies the
importance of considering the relative sensitivity to both
the rewarding and the aversive effects of drugs rather than
sensitivity to either of these effects alone.
Balance of reward and aversion
So far, we have described studies in separate groups of
animals and comparisons across separate studies. Although
mostly consistent with the position that drug use is a
function of both the rewarding and the aversive effects of
drugs, for more conclusive support, the role of drug reward
and aversion in drug self-administration should be assessed
in the same animals. If drug taking is a function of both its
rewarding and aversive effects, drug intake should reflect
the relative contribution of these effects. To date, no
published work exists on such assessments of reward,
aversion, and self-administration in the same animal.
Preliminary data from our laboratory using the combined
CTA/CPP procedure, followed by drug self-administration
suggest that rats most sensitive to the aversive effects of
morphine (as measured by CTA) self-administer less
morphine than rats least sensitive to its aversive effects
(Verendeev et al., 2012). Although supportive of the
position that the balance of reward and aversion is
important in (and predictive of) drug self-administration,
such analysis awaits critical evaluation and replication.
Conclusion
This and other studies show that drugs of abuse are not
simple stimuli that produce only rewarding effects.
Rather, drugs of abuse are complex pharmacological
compounds that produce both positive rewarding and
negative aversive effects. In this paper, we have
attempted to show that both of these effects should be
taken into account in our attempts to model drug-taking
behavior, and we have provided evidence from drug
history and selectively bred mouse and rat strains, as well
as from recent work directly assessing the role of drug
reward and aversion in drug taking, that support this
position. If this view is correct, drug self-administration
should no longer be simply viewed only as a function of
drug reward. The aversive effects of drugs should be
taken into consideration in our attempts to understand
drug use, abuse, and addiction.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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