Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
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Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
Review
Conditioned taste aversion and drugs of abuse: History and interpretation
Andrey Verendeev ∗ , Anthony L. Riley
Department of Psychology, American University, 4400 Massachusetts Avenue, NW, Washington, DC 20016, USA
a r t i c l e
i n f o
Article history:
Received 14 March 2012
Received in revised form 3 August 2012
Accepted 9 August 2012
Keywords:
Conditioned taste aversion
Classical emetics
Radiation
Drugs of abuse
Sickness
Drug novelty
Reward comparison
Conditioned fear
Self-administration
a b s t r a c t
Conditioned taste aversion (CTA) learning describes a phenomenon wherein an animal learns to avoid
consumption of a particular taste or food following its pairing with an aversive stimulus. Although initially
demonstrated with radiation and classical emetics, CTAs have also been shown with drugs of abuse. The
ability of rewarding drugs to support CTA learning was described as paradoxical by many investigators,
and a number of attempts have been made to resolve this paradox. The present review offers a historical
perspective on the CTA literature with a particular focus on CTAs induced by self-administered drugs.
Specifically, this review describes and summarizes several interpretations of CTA learning that offer
possible mechanisms by which drugs of abuse support CTAs, including sickness, drug novelty, reward
comparison and conditioned fear. It is concluded that the reported “paradox” is no paradox at all in that
drugs of abuse are complex pharmacological compounds that produce multiple stimulus effects, not all
of which are positive reinforcing. Finally, a possible role of drug aversion in drug self-administration is
discussed.
© 2012 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
7.
8.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The role of sickness in conditioned taste aversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conditioned taste aversions and drugs of abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The role of drug novelty in conditioned taste aversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conditioned taste aversion and the reward comparison hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The mechanism of drug-induced conditioned taste aversion: The role of conditioned fear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conditioned taste aversion and drugs of abuse: Paradox revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion: The role of drug aversion in drug use and abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Conditioned taste aversion (CTA) learning describes a phenomenon wherein an animal learns to avoid consumption of a
particular taste or food following its pairing with an aversive stimulus. CTA was conceptually introduced in the 1950s and 1960s when
John Garcia and his colleagues published a series of papers demonstrating the nature of CTA as a learning phenomenon (see Freeman
and Riley, 2009 for a review of the history of CTA). In their initial
experimental demonstration of CTA, Garcia et al. (1955) gave rats a
pairing of a novel saccharin taste and exposure to gamma radiation,
following which they were given a choice between saccharin and
∗ Corresponding author. Tel.: +1 202 885 1720; fax: +1 202 885 1023.
E-mail address: andrey.verendeev@gmail.com (A. Verendeev).
0149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neubiorev.2012.08.004
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water in the absence of radiation. The authors reported that irradiated animals decreased their saccharin preference compared to
their initial preference and to sham-irradiated controls (see Fig. 1;
Garcia et al., 1955).
In subsequent years, several aspects of CTA were elucidated
that made it a very special (and specialized, see below) form of
learning. For example, the initial report by Garcia et al. (1955)
demonstrated the robust nature of CTA learning in that the decrease
in saccharin preference persisted for at least 30 days of continuous
saccharin/water exposure following the taste-radiation pairing (see
Fig. 1). Additionally, acquisition of CTA required few pairings (and
often only one; Garcia et al., 1955; Swank and Bernstein, 1994).
For instance, in the 1955 report a single pairing of saccharin and
radiation was enough for the rats to acquire a CTA and significantly suppress their saccharin preference. Moreover, CTA learning
occurred with long inter-stimulus delays. In one paper, Garcia and
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A. Verendeev, A.L. Riley / Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
Fig. 1. Conditioned taste aversion: first experimental demonstration. Median saccharin preferences scores [(saccharin solution intake/total fluid intake) × 100]
during extinction for groups initially given access to saccharin solution and concurrently exposed to gamma radiation (at 30 or 57 r). Redrawn from Garcia et al.
(1955).
his colleagues showed that aversions to saccharin were conditioned
even if injections of apomorphine (aversive stimulus) were delayed
for as long as 75 min following saccharin presentation (Garcia et al.,
1966; see also McLaurin and Scarborough, 1963; Revusky, 1968).
Finally, taste aversion learning was shown to be selective to gustatory stimuli. In one demonstration of this, rats selectively associated
saccharin with irradiation-induced nausea but not with foot shock;
conversely, rats selectively associated an audiovisual cue with the
foot shock but not radiation (Garcia and Koelling, 1966). These
demonstrations put CTA at odds with traditional learning theory
that held that learning occurred with multiple conditioning trials,
required short inter-stimulus intervals and was independent of the
nature of CS and US (i.e., most CSs and USs serve equally well in
conditioning) (Freeman and Riley, 2009).
The explanation of these inconsistencies with the learning theory of the day came in the form of the interpretation of CTA as a
specialized form of learning. As argued in the three early reviews of
the field (Garcia and Ervin, 1968; Revusky and Garcia, 1970; Rozin
and Kalat, 1971; see Freeman and Riley, 2009 for a review of these
papers), the exceptional nature of taste aversion learning (i.e., onetrial learning, long-delay learning and selective associations) made
sense in the light of the ecological context of the animal. Allowing for the normal time course of digestive function (i.e., some
delay between ingestion of food and the effects of its consumption), the ability to learn over long delays prevents the repeated
consumption of potentially poisonous foods. This “preparedness”
also extended to the selective nature of CTA that facilitated associations between biologically relevant stimuli (i.e., taste and sickness)
but retarded associations between biologically irrelevant stimuli
(i.e., audiovisual cue and sickness). Moreover, the advantage of onetrial learning allowed the animal to quickly recognize and avoid
potentially harmful substances.
2. The role of sickness in conditioned taste aversion
As described, the initial demonstrations of CTA used radiation
and other illness-inducing agents, such as lithium chloride (LiCl),
apomorphine and cyclophosphamide, all of which share the ability to produce gastrointestinal distress. It is not surprising then that
early studies suggested nausea, gastrointestinal illness and malaise
(terms used interchangeably) or general “toxicosis”1 as the mechanism by which different treatments (both pharmacological and
non-pharmacological) induced CTA (Garcia and Ervin, 1968; Garcia
et al., 1955; Garcia and Koelling, 1966). According to this general
view, the gastrointestinal distress produced by these agents served
as a US with which a taste stimulus (CS) was paired resulting in
a conditioned aversion to the taste and its avoidance upon subsequent exposure. This view fit well with the interpretation of CTA as
a specialized form of learning, evolved through natural selection to
allow organisms to avoid potentially dangerous (i.e., toxic) foods.
Support for this general position came from a number of studies
that demonstrated that lesions of the area postrema, a brain region
responsible for monitoring blood-borne toxins, attenuated taste
aversions produced by emetics and radiation (Berger et al., 1973;
Curtis et al., 1994; Ossenkopp and Giugno, 1985, 1989; Rabin et al.,
1983, 1984a,b; Ritter et al., 1980). Additional evidence came from
the demonstration that antiemetic drugs attenuated CTA learning
(Coil et al., 1978; Provenza et al., 1994; Racotta et al., 1997; Symonds
and Hall, 2000; although see Goudie et al., 1982; Rabin and Hunt,
1983 for opposing results).
A problem with this interpretation arose, however, when some
known toxins were reported ineffective in inducing taste aversions (see Riley and Tuck, 1985 for a list of well-known toxins
ineffective in producing CTA). For example, sodium cyanide (a
rodenticide) failed to produce taste aversion at near lethal doses
in rats (Nachman and Hartley, 1975). Failure to illicit CTA by
cyanide poisoning was also reported by Ionescu and Buresova
(1977; although see O’Connor and Matthews, 1997 for cyanideinduced CTA in possums). Similar results were reported for other
toxins such as strychnine (Nachman and Hartley, 1975), malonate
and gallamine (Ionescu and Buresova, 1977), as well as aluminum
chloride, warfarin and others (Riley and Tuck, 1985).
Additionally, Barker et al. (1977) showed that the degree of
visible sickness did not correlate well with the strength of taste
aversions that were produced by irradiation, LiCl or cyclophosphamide. Further, a number of antiemetic drugs, which are used
to reduce gastrointestinal distress, have been demonstrated to
be capable of inducing CTAs. Such ability, for example, has been
reported for scopolamine (Berger, 1972). Other illness-reducing
agents, such as tetrahydrocannabinol (THC), have been reported
to induce taste aversions as well (Amit et al., 1977; Corcoran et al.,
1974; Switzman et al., 1981). Moreover, pretreatment with either
scopolamine or the antiemetic prochlorperazine did not attenuate
aversions induced by LiCl, amphetamine or morphine (Goudie et al.,
1982).
As becomes evident from these observations, the ability of a
treatment to serve as an effective US within the CTA preparation
is not clearly dependent on its ability to produce sickness or toxicosis. As described above, non-toxic agents have been reported to
induce taste aversions; moreover, some well-known toxins have
been reported to fail to produce taste aversions. This led several
authors to conclude that sickness or general toxicity is not a necessary condition to produce a CTA (Barker et al., 1977; Berger, 1972;
Gamzu, 1977; Hunt and Amit, 1987), although it may be sufficient
for some compounds.
1
It is important to note that toxicity was often not defined, and the term was used
to mean a number of different things. Some researchers, for example, limited the
use of the term “toxicity” to discussion of the effects produced by classical toxins
such as LiCl and cyclophosphamide. For others, toxicity was defined in terms of
the drugs’ effects on feeding and drinking behavior (i.e., reduction in both feeding
and drinking). More frequently, however, the term was used to mean some form of
sickness or gastrointestinal distress (see, for example, Boland, 1973; Dantzer, 1980;
Gemberling et al., 1980; Lindberg et al., 1982 and others).
A. Verendeev, A.L. Riley / Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
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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)
Fig. 2. Conditioned taste aversion induced by a drug of abuse. Amount of saccharin
consumed in different groups of rats injected with various doses of amphetamine.
Redrawn from Table 1 of Cappell and LeBlanc (1971).
3. Conditioned taste aversions and drugs of abuse
This challenge to a sickness interpretation of CTA received additional support when it was demonstrated that CTAs could also be
induced by a variety of drugs of abuse, compounds taken for their
rewarding effects and not generally characterized as being illness
inducing. In one of the earlier reports on this, Cappell and LeBlanc
(1971) gave rats a novel saccharin solution to drink followed by an
injection of one of three doses of amphetamine (2, 4 or 8 mg/kg).
On the test day, saccharin consumption was measured and it
was reported that amphetamine significantly suppressed saccharin intake at all doses tested (i.e., amphetamine conditioned taste
aversions; see Fig. 2). Today, the list of psychoactive substances
capable of supporting taste aversion learning includes rewarding
drugs of every major class: morphine (Bechara and van der Kooy,
1985; Riley et al., 1978; Verendeev and Riley, 2011; White et al.,
1977), heroin (Davis et al., 2009; Grigson et al., 2000b; although
see Switzman et al., 1981), cocaine (Booth et al., 1977; Ferrari et al.,
1991; Glowa et al., 1994; Goudie et al., 1978), amphetamine (Booth
et al., 1977; Cappell and LeBlanc, 1971; Carey and Goodall, 1974;
Verendeev and Riley, 2011), nicotine (Etscorn et al., 1986; Iwamoto
and Williamson, 1984; Kumar et al., 1983; Pescatore et al., 2005;
Rinker et al., 2008), caffeine (Brockwell et al., 1991; Steigerwald
et al., 1988; Vishwanath et al., 2011; White and Mason, 1985),
ethanol (Cappell et al., 1973; Cunningham, 1979; Roma et al., 2006),
and THC (Corcoran et al., 1974; Fischer and Vail, 1980; Kay, 1975;
Parker and Gillies, 1995; see also Hunt and Amit, 1987 for a list of
rewarding drugs capable of inducing CTAs).
The finding that such aversion-inducing drugs are reliably taken
by animals (i.e., establish and maintain operant self administration;
see Weeks, 1962) and establish preferences for environments with
which they are associated (i.e., support place preference conditioning; see Bardo and Bevins, 2000) was considered paradoxical by
many (Gamzu, 1977; Goudie, 1979; Hunt and Amit, 1987; White
et al., 1977). How can drugs that are rewarding in both rats and
humans also produce avoidance of taste stimuli with which they
were previously paired? One way out of this dilemma was to suggest that drugs of abuse possess multiple stimulus effects, both
positive and negative. This interpretation, for example, was given
in a study (Wise et al., 1976) wherein individual rats both selfadministered intravenous apomorphine and subsequently avoided
a taste stimulus associated with the apomorphine injections. The
authors note:
“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
The position that a drug produces both positive and negative
effects was later supported by a series of studies that demonstrated
these dual properties of cocaine in a runway model. Specifically,
Ettenberg and Geist (1991, 1993) showed that although rats would
learn to run down a straight alley for intravenous injections of
cocaine, they would increase the running time to reach the goal
box with repeated sessions. This escalation in time was a function of an increase in the frequency of retreats as the animals
approached the goal box. This approach/avoidance conflict behavior was interpreted in terms of cocaine’s positive and negative
effects, respectively, an effect consistent with the earlier work by
Wise and his colleagues.
If drugs of abuse possess both positive and negative properties,
what is the nature of their negative (i.e., aversive) stimulus effects?
Early investigators suggested that by virtue of the shared ability of
both toxins and drugs of abuse to suppress consumption of solutions with which they were previously paired, drugs of abuse must
possess some properties similar to those of LiCl and other classical
toxins (see, for example, Cappell and LeBlanc, 1973, 1977; Elsmore
and Fletcher, 1972; Lester et al., 1970; Riley and Zellner, 1978). In
other words, drugs of abuse were deemed capable of producing
some form of gastrointestinal distress.
Subsequent work, however, failed to demonstrate this suggested ability of drugs of abuse to produce sickness. Berger (1972),
for example, reported that amphetamine, scopolamine and chlorpromazine all produce CTAs without visible signs of sickness. This
and other (e.g., Cappell and LeBlanc, 1977) studies led several investigators to conclude that sickness (i.e., gastrointestinal distress) is
not a necessary condition and cannot account for the ability of drugs
of abuse to produce CTAs (Gamzu, 1977; Goudie, 1979; Hunt and
Amit, 1987).
This interpretation, however, met with some criticism. The failure of drugs of abuse to produce visible signs of sickness while
maintaining their ability to suppress saccharin consumption at the
same dose may be interpreted in a number of ways. One way to
do so was to suggest that the mechanism underlying drug-induced
CTAs was different from that responsible for toxin-induced taste
aversions. However, this argument, as Riley and Tuck pointed out,
“rests upon the assumption that other behavioral measures are better indicators of a compound’s toxicity than the conditioned taste
aversion design” (Riley and Tuck, 1985, p. 273). They suggested that
another way to interpret these data is to view CTA as a more sensitive
measure of drug toxicity. In support of this, they noted that a number of compounds are effective in producing CTAs at doses much
smaller than generally required to produce any measurable effects
in other assays of drug toxicity (e.g., food and water consumption;
Riley and Tuck, 1985).
The direct test of the sickness account of CTA was made by
Parker and her colleagues in a series of assessments comparing
taste reactivity responses elicited by classical toxins (such as LiCl)
and reinforcing drugs (Parker, 1982, 1984, 1988, 1991, 1995; Parker
et al., 1984). Developed by Grill and Norgren (1978), the taste
reactivity (TR) test measures conditioned disgust using behavioral
responses elicited by the intraoral infusion of a taste that has been
previously paired with a nausea-inducing agent (Grill and Norgren,
1978; Parker, 1995; Parker et al., 2009). These conditioned disgust reactions, which presumably reflect the degree to which a
taste has become unpalatable for the animal, include gaping, chin
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A. Verendeev, A.L. Riley / Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
Fig. 3. Conditioned taste aversion and taste reactivity to drugs of abuse and LiCl. CTA (panel A) and aversive reactions (panel B).
Adapted from Parker (1995).
rubbing and paw treading (Grill and Norgren, 1978), and have
been documented using a number of classical toxins, such as LiCl,
cyclophosphamide and apomorphine (Berridge et al., 1981; Parker,
1998; Parker and Brosseau, 1990), as well as naloxone-precipitated
withdrawal (McDonald et al., 1997) and full body rotation (Cordick
et al., 1999; Ossenkopp et al., 2003).
Using the TR test, Parker and her colleagues compared the ability
of LiCl and a number of rewarding drugs at different doses to elicit
conditioned aversive TR responses. They showed that LiCl, but not
drugs of abuse, produced active rejection responses and that this
effect was not dependent on the magnitude of suppression of saccharin intake (with the only exception being high doses of nicotine;
see Fig. 3; Parker, 1995). According to Parker, although both drugs of
abuse and classical toxins decrease saccharin consumption, drugs
of abuse, unlike classical toxins, fail to produce conditioned aversive
reactions (although see Wheeler et al., 2008). This led her to conclude that sickness is not a necessary condition for the induction
of taste aversions and that the term “conditioned taste aversion”
was inappropriately applied to drug-induced suppression of saccharin intake. Instead, she suggested the term “conditioned taste
avoidance” be used to describe such behavioral suppression. Such a
term also differentiated conditioned nausea from the avoidance of
the taste stimulus (see below; see also Berger, 1972; Goudie et al.,
1982; Hunt and Amit, 1987).
4. The role of drug novelty in conditioned taste aversion
If gastrointestinal disturbance (i.e., nausea) is not the mechanism mediating saccharin suppression induced by drugs of abuse,
what is? One of the first non-sickness accounts of drug-induced
CTA was presented by Gamzu (1977) in the drug-novelty hypothesis. According to this view, drug treatment disrupts the “internal
milieu” of the animal and the pairing of the taste with this disruption results in the subsequent suppression of consumption of the
drug-associated taste. This view recognizes the homeostatic state
of the various physiological systems in the drug-naive animal and
the ability of a drug treatment to disrupt these systems and result
in a variety of internal stimuli which are quite novel to the animal
subject (see Gamzu, 1977). The ability of drugs of abuse to induce
CTA is then a function of their ability to disrupt these tightly regulated homeostatic states, which may be perceived as potentially
dangerous by the animal (see also Kalat and Rozin, 1973). These
novel states, it is important to note, are not necessarily aversive in
the traditional (i.e., gastrointestinal disturbance à la Garcia) view
of CTA (Gamzu, 1977).
The drug-novelty hypothesis makes at least two predictions
regarding the ability of rewarding drugs to suppress consumption
of otherwise palatable taste stimuli. First, a drug treatment that
induces a novel state for the animal should condition aversions to
a taste stimulus with which it is paired. Second, exposure to the
drug before a taste-drug pairing should render the drug relatively
ineffective as an aversion-inducing agent. Regarding the first prediction, many drugs have been shown to induce aversions at doses
that are behaviorally active in other assays (see Hunt and Amit,
1987). Presumably, these doses of drugs would induce a novel state
in a drug-naive animal. It should be noted, however, that a number of behaviorally active drugs are ineffective in supporting taste
aversion learning, e.g., strychnine (Nachman and Hartley, 1975),
cyanide (Ionescu and Buresova, 1977, although see O’Connor and
Matthews, 1997); malonate and gallamine (Ionescu and Buresova,
1977); aluminum chloride, warfarin and some others (Riley and
Tuck, 1985). Although suggestive that a drug’s novel state may
not be sufficient to induce an aversion, it should be noted that
because a compound may be behaviorally active it may not necessarily have perceived stimulus effects. Until such compounds
are tested for their discriminative effects, it remains unknown to
what extent their inability to support taste aversion conditioning
is evidence against the drug novelty hypothesis of taste aversion
learning.
The second prediction is largely supported by the existing drug
preexposure literature in that drug exposure (also known as US
preexposure) before a taste-drug pairing retards later acquisition
of the aversion (see Hall, 2009), which in CTA takes the form of
attenuated aversions (Braveman and Crane, 1977; Gamzu, 1977;
see Riley and Simpson, 2001 for a review of the US preexposure
effect in taste aversion conditioning). Although this effect has been
repeatedly shown for a number of drugs (see Riley and Simpson,
2001) and is consistent with the drug-novelty hypothesis, several investigators have shown that the effects of US preexposure
(i.e., attenuation of taste aversions) can be overridden with multiple conditioning trials. For example, Riley and Diamond (1998)
exposed rats to cocaine via either intraperitoneal (i.p.) or subcutaneous (s.c.) injections administered daily or spaced every fourth
day prior to repeated saccharin-cocaine pairings. They found that
both preexposure treatments initially resulted in an attenuation
of taste aversions. This attenuation, however, was no longer evident after repeated conditioning in the animals given s.c. injections.
For the animals receiving i.p. injections, the attenuation was less
pronounced than for subcutaneously-injected animals; however,
this US preexposure effect, too, was eliminated with prolonged
conditioning. Since, according to the drug-novelty hypothesis, pretreatment with the drug US should either eliminate or at least
reduce the ability of the drug to suppress consumption of the taste
CS later, the fact that chronic treatment with a drug results in conditioned suppression is not easily explained by the drug-novelty
hypothesis.
A. Verendeev, A.L. Riley / Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
The drug-novelty hypothesis was further advocated by Hunt and
Amit (1987) in their review of the CTA literature under the name of
“drug shyness”. The authors agreed with Gamzu in that it is the novelty of the drug state that mediates taste aversion learning. There
was, however, one important aspect in which the drug-shyness
hypothesis of Hunt and Amit was different from the drug-novelty
position of Gamzu: specifically, Hunt and Amit proposed that it is
the positive rewarding stimulus properties of drugs that provide
the novel state that mediates taste aversion learning. In other
words, they suggested a functional relationship between the positive rewarding and negative aversive effects of self-administered
drugs and argued that rather than being separate and dichotomous,
these effects have common discriminative characteristics. Whether
a drug experience has positive reinforcing or aversive punishing
effects depends on current environmental conditions as well as the
previous learning history of the animal subject (Hunt and Amit,
1987).
To support their position, they argued that pharmacological
manipulations that block the reinforcing effects of drugs also
attenuate their CTA-inducing properties (Sklar and Amit, 1977).
For example, pimozide, a dopamine receptor antagonist, which
had been shown to attenuate amphetamine- (Yokel and Wise,
1976) and cocaine- (De Wit and Wise, 1977) self-administration,
was also shown to attenuate both amphetamine- (Grupp, 1977)
and cocaine- (Hunt et al., 1985) induced CTAs. Although consistent with their position, there are several other studies that
show that pharmacological manipulations differentially affect drug
reward and aversion, which suggests that a drug’s rewarding and
aversive effects can be dissociable at least under some conditions (see below). Moreover, Hunt and Amit cite evidence from
the human drug literature that suggests that the initial drug
experience is predominantly aversive rather than euphoric in
nature (Jaffe and Martin, 1980; McAuffle, 1975; Tecce and Cole,
1974). This temporal dissociation further argues against a functional relationship between the rewarding and aversive effects of
drugs.
When one considers the growing literature that demonstrates
that drug reward and aversion are dissociable, it becomes evident that any hypothesis that proposes a functional relationship
between the rewarding and suppressive effects of drugs has to
deal with this dissociation. Given the evidence for such dissociation, it becomes almost impossible to defend a view of a
commonality of mechanism(s) underlying drug reward and aversion. We now turn to this growing body of evidence in light of
another and quite recent hypothesis, namely reward comparison,
that proposes a functional relationship between drug reward and
aversion.
5. Conditioned taste aversion and the reward comparison
hypothesis
Following the reports that intake of a gustatory stimulus is
avoided when paired with either illness-inducing agents, such
as LiCl or radiation, or a drug of abuse, it was reported that
rats also avoid consumption of a saccharin CS when it is paired
with a highly rewarding sucrose solution (Flaherty and Checke,
1982). This phenomenon came to be known as the anticipatory
contrast effect and was interpreted as avoidance of a rewarding
taste stimulus in anticipation of a more rewarding taste stimulus
(for a review see Flaherty, 1996). Given the parallel between the
sucrose-induced suppression of saccharin intake and the suppression induced by drugs of abuse (avoidance of taste CS; rewarding
US), Grigson (1997) reinterpreted the phenomenon of conditioned
taste aversions wherein rewarding drugs of abuse suppress intake
of rewarding saccharin in terms of a mechanism akin to anticipatory
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contrast (i.e., reward comparison). That is, according to the reward
comparison hypothesis, rats avoid consumption of the rewarding
saccharin solution in anticipation of a more rewarding drug. As
Grigson put it, “[r]ats decrease intake of a gustatory CS following
taste-drug pairings because the rewarding properties of the gustatory stimulus pale in comparison to those of the impending drug
of abuse” (Grigson, 1997, p. 134). This position was perhaps reinforced by the finding that drugs of abuse did not produce active
rejection responses in taste reactivity tests (see above), whereas
LiCl did (Parker, 1988, 1991, 1995; see Grigson, 1997; although see
Wheeler et al., 2008). Thus, saccharin avoidance induced by drugs
of abuse resembled more the suppression induced by a rewarding
sucrose solution than that following treatment with LiCl. It is in this
context that Grigson proposed the reward comparison hypothesis
(Grigson, 1997).
In the initial assessment of this hypothesis, Grigson (1997;
Experiments 1 and 2B) argued that suppression induced by drugs of
abuse should depend on the rewarding properties of the gustatory
CS. That is, given that the hypothesis assumes that two rewarding stimuli are compared, only CSs demonstrated to be rewarding
(albeit less than the drug US) should result in suppressed consumption. In an assessment of this prediction, Grigson reported
that when saccharin (a rewarding taste stimulus) was paired with
morphine or cocaine, consumption was subsequently suppressed.
On the other hand, when a more neutral (i.e., less rewarding)
NaCl solution was paired with either morphine or cocaine, consumption was not affected (see Figs. 1 and 2 of Grigson, 1997).
Interestingly, both solutions resulted in suppressed intake when
they were paired with LiCl, an effect consistent with the position
that LiCl is aversive and this aversive property induced aversions
to both tastes with which it was paired (see Fig. 4 of Grigson,
1997).
In the same paper, Grigson assessed the effects of different
concentrations of the saccharin CS on the suppressive effects of
morphine (Grigson, 1997; Experiment 3). The logic for this assessment stemmed from work by Flaherty who reported that reward
contrast increased with increased concentrations of saccharin (see
Flaherty, 1996; see also Flaherty et al., 1994). Grigson predicted
that if the suppression induced by drugs of abuse is due to reward
comparison then the degree of suppression should also vary with
the concentration of the saccharin solution. To test this, different
groups of rats received multiple pairings of saccharin and morphine. The groups differed in the concentration of the saccharin
CS. Consistent with the prediction, the suppressive effects of morphine increased with increasing concentrations of saccharin (see
Fig. 5 of Grigson, 1997).
Next, Grigson analyzed the effects of strain differences (LEW vs.
F344 rats) in the suppressive effects of cocaine (Grigson and Freet,
2000; see also Glowa et al., 1994). Given that these two strains differ
in their sensitivity to the rewarding effects of drugs, i.e., LEW rats
display greater cocaine-induced place preferences (Guitart et al.,
1992) and more readily acquire cocaine self-administration (Kosten
et al., 1997) than F344 rats, the authors predicted that the suppressive effects of cocaine would be more pronounced in LEW than in
F344 rats (i.e., the reward comparison would be greater in the LEW
rats). Consistent with this prediction, cocaine suppressed saccharin consumption in LEW rats to a greater degree than in the F344
strain.
Further support for the reward comparison hypothesis was
provided by an assessment of the effects of bilateral lesions of
the gustatory thalamus on morphine-induced suppression. These
lesions had previously been reported to disrupt the development of
anticipatory contrast following saccharin-sucrose pairings (Reilly
and Pritchard, 1996) but had no impact on the avoidance of a saccharin solution previously paired with LiCl (Scalera et al., 1997).
It was predicted that if the suppressive effects of morphine are
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due to reward comparison (and not a function of a traditional
CTA like that with LiCl), then the bilateral lesions of the gustatory
thalamus should also disrupt morphine-induced suppression. As
predicted, lesions of the gustatory thalamus disrupted morphineinduced suppression of saccharin consumption but had no impact
on the LiCl-induced suppression of sweet-tasting alanine (Grigson
et al., 2000a).
Although supportive of the reward comparison hypothesis, the
aforementioned work is not without criticism. According to Grigson
(1997), if the reduction in intake induced by drugs of abuse is due
to reward comparison then only a rewarding CS should result in
suppression following the taste-drug pairing. However, a number
of studies report that drugs of abuse support suppression of presumably neutral CSs. For example, a recent study by Lin et al. (2009)
reported that rats suppressed consumption of a NaCl solution following its pairing with morphine. In that study, rats had access to
a NaCl solution and were intraperitoneally injected with 15 mg/kg
morphine. One group of rats then received excitotoxic lesions of
the insular cortex, and the other group received sham lesions. Animals that received sham lesions and were treated with morphine
suppressed their intake of NaCl relative to their sham-lesioned controls that were injected with saline. Similar NaCl aversions have
been shown with d-amphetamine (Bielavska and Bures, 1994) and
following second-order conditioning with morphine (Bevins et al.,
1996).
Additionally, Grigson argued that the ability of drugs of abuse,
but not of LiCl, to induce taste aversions should vary with increased
palatability of the CS (Grigson, 1997). In line with this prediction, Grigson demonstrated greater suppressive effects of morphine
with increasing concentrations of the saccharin cue (see above).
Although supportive of her model, there are several concerns with
this analysis. For example, no assessment was concurrently made
on the suppressive effects of LiCl and thus the prediction that the
palatability of the CS is a central characteristic to reward comparison, but “irrelevant to CTA learning”, was not directly tested
(Grigson, 1997). Furthermore, considerable data suggest that the
suppressive effects of LiCl do increase with increasing concentrations of the saccharin cue. For example, as early as 1971 Garcia
documented the relationship between degree of aversion and the
concentration of saccharin solution. When the dose of LiCl was held
constant, suppression of 0.1% saccharin solution was greater than
suppression of 0.025% saccharin, and suppression of 0.35% and 0.7%
solutions was greater than that of 0.1% saccharin (Garcia, 1971).
Similar findings have been reported in other studies that paired different concentrations of saccharin with LiCl (Gilley and Franchina,
1985; Huang and Hsiao, 2008; Iraola and Alonso, 1995) or other
classical toxins such as cyclophosphamide (Braun and Rosenthal,
1976; Dragoin, 1971) or radiation (Barker, 1976). These data suggest that the degree of suppression induced by both drugs of abuse
and classical toxins may be a function of salience of the conditioned stimulus (e.g., saccharin), with higher concentrations more
easily associable with the US. Finally, one should proceed cautiously in assuming that the increasing concentrations of saccharin
equate with increasing palatability (i.e., rewarding value) of the
saccharin solution. It may actually be the case that the reverse
is true (see, for example, Dess, 1993). Unfortunately, no attempt
was made by Grigson to demonstrate that increasing concentrations of saccharin resulted in increased preference (i.e., palatability)
of the saccharin solution. This assumption, therefore, was left
untested.
Although the work with different strains and cocaine appears
to be generally consistent with the reward comparison position
in that the suppressive effects of cocaine (Glowa et al., 1994;
Grigson and Freet, 2000), but not LiCl (Foynes and Riley, 2004)
are greater in the presumably more drug-sensitive LEW rats, data
from studies that use other rewarding drugs are not consistent
with this position. For example, although LEW rats exhibit faster
acquisition of morphine self-administration (Ambrosio et al., 1995;
Martin et al., 1999, 2003; Sanchez-Cardoso et al., 2007; Suzuki
et al., 1988b) and morphine-induced place preference (Guitart et al.,
1992; but see Davis et al., 2007) than F344 rats, these strains actually reverse in their display of morphine-induced taste aversions
(i.e., the F344 strain shows greater morphine-induced taste aversions than the LEW strain; Davis et al., 2009; Gomez-Serrano et al.,
2009; Lancellotti et al., 2001). Similar findings have been reported
for other drugs of abuse such as nicotine (Brower et al., 2002; Horan
et al., 1997; Pescatore et al., 2005; but see Suzuki et al., 1999) and
ethanol (Roma et al., 2006; Suzuki et al., 1988a; see Riley et al.,
2009 for a review of strain differences in self-administration, conditioned place preference (CPP) and CTA in LEW and F344 rats).
Moreover, even the strain effect with cocaine can be overridden by
a higher dose (50 mg/kg) of the drug (LEW = F344; see Glowa et al.,
1994).
Lesion data are also not decisively supportive of the reward comparison hypothesis. For example, although lesions of the gustatory
thalamus do disrupt morphine- (Grigson et al., 2000a) and cocaine(but not LiCl-) induced suppression of consumption, this disruptive effect is dose-dependent and is no longer evident when higher
doses of cocaine are used as the US (Grigson et al., 2009). Moreover, a recent study by Geddes et al. (2008) found that whereas
bilateral lesions of the insular gustatory cortex fully disrupted the
suppressive effects of morphine (15 and 30 mg/kg, s.c.), these same
lesions only attenuated (10 mg/kg, i.p.) or had no effect (20 mg/kg,
i.p.) on cocaine-induced suppression. These lesions also had no
impact on LiCl-induced suppression. Furthermore, it should be
noted that the evidence from the lesion studies is indirect, as these
results only provide evidence that the anatomical mediation of
morphine- and cocaine-induced suppression is different from suppression induced by LiCl. For the data to be conclusively supportive,
it should be demonstrated that lesions that block or attenuate suppression induced by drugs of abuse should also block or attenuate
the rewarding effects of such drugs (as measured by place preference or self-administration). A recent study by Sellings et al.
(2008) investigated the effects of 6-OHDA lesions of the nucleus
accumbens core vs. medial shell on nicotine-induced CPP and CTA.
Lesions of the medial shell, but not core, reduced nicotine-induced
place preferences, whereas lesions of the core, but not medial shell,
fully disrupted nicotine-induced taste aversions. In other words,
the rewarding and aversive effects of nicotine were anatomically
dissociable.
In addition to the abovementioned criticisms, there are other
data that are not easily reconcilable with the reward comparison
hypothesis. For example, Simpson and Riley (2005) examined the
effects of morphine preexposure on morphine-induced place preferences and taste aversions. Rats received subcutaneous injections
of 5 mg/kg morphine every other day for a total of 5 injections. The
rats were then trained in a combined CTA/CPP procedure wherein
a single injection of morphine (1 or 5 mg/kg) was administered
to produce both a CTA and a CPP. It was found that preexposure
to morphine attenuated taste aversions but enhanced place preferences within the same animals. That the same pharmacological
manipulation affects drug reward and aversion in an opposing manner strongly argues that these drug effects are dissociable. Similar
dissociation of rewarding and aversive effects of morphine has been
reported by Martin et al. (1988) and Gaiardi et al. (1991). Moreover,
separate assessments of drug preexposure on morphine’s rewarding and aversive properties have also shown differential effects,
i.e., enhancement of its rewarding effects (Harris and Aston-Jones,
2003; He et al., 2004; Manzanedo et al., 2005) but attenuation of
its aversive effects (Cappell et al., 1975; Dacanay and Riley, 1982;
Domjan and Siegel, 1983; LeBlanc and Cappell, 1974; Riley et al.,
1984).
A. Verendeev, A.L. Riley / Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
Additional evidence for dissociation of rewarding and aversive effects of drugs of abuse comes from data that show that
adolescent rats respond differently to the rewarding and aversive
effects of drugs compared to adult rats. For example, adolescent
rats, compared to adults, are more sensitive to the rewarding
effects of nicotine but less sensitive to the aversive effects of the
drug (Shram et al., 2006). Specifically, in this study nicotine produced dose-dependent place preferences in adolescent, but not
adult, rats (see Fig. 1 of Shram et al., 2006); when paired with
a novel saccharin solution, the same doses of nicotine produced
dose-dependent saccharin suppression in adult, but not adolescent, rats (see Fig. 3 of Shram et al., 2006; see also Wilmouth and
Spear, 2004). If saccharin suppression is dependent on the ability
of drugs to produce reward, these two (i.e., reward and suppression) should co-vary. However, this study did not demonstrate
such a relationship. Age-dependent differences in the sensitivity
to the rewarding (Badanich et al., 2006; Brenhouse and Andersen,
2008; Brenhouse et al., 2008; Zakharova et al., 2009a,b) and aversive (Infurna and Spear, 1979; Philpot et al., 2003; Quinn et al.,
2008; Schramm-Sapyta et al., 2006, 2007) effects have been documented for other drugs as well (although see Aberg et al., 2007;
Adriani and Laviola, 2003; Balda et al., 2006 for a reversal in age sensitivity to drug reward in rats and mice; see Schramm-Sapyta et al.,
2009 for a review on age-dependent differences in drug reward and
aversion).
Recently, we (Verendeev and Riley, 2011) directly tested the
reward comparison model by examining the relationship between
the ability of morphine and amphetamine to condition taste aversions and place preferences in individual subjects. According to
the reward comparison hypothesis, there should be a direct relationship between the ability of drugs to produce place preferences
and taste aversions, since, for Grigson, it is the rewarding effects
that condition both place preference and suppression of intake. We
examined this relationship using a combined CTA/CPP procedure
with two different classes of drugs (i.e., opiates and psychostimulants) and 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 their change from baseline in
saccharin consumption and change from baseline in time spent on
the drug-paired side (DPS) of the CPP apparatus.
Two interesting findings emerged. First, individual subjects differed greatly 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 their aversive effects or vice versa; or, individual subjects were sensitive to
both or neither of these effects. Second, there was no relationship
between the ability of either drug to produce a place preference and
its ability to produce a taste aversion (see Fig. 4). Specifically, animals were divided into High and Low responders for all conditions
and the relationships between their change in saccharin consumption and change in time spent on the DPS were analyzed. We found
no significant relationship between the two in any of the conditions,
except for one: animals given 5 mg/kg amphetamine that displayed
strongest aversions were less likely to show an increase (or showed
an actual decrease) in time spent on the DPS (i.e., a relationship
opposite to what reward comparison would predict).
Together, a host of behavioral (e.g., Schramm-Sapyta et al., 2009;
Shram et al., 2006; Verendeev and Riley, 2011), anatomical (e.g.,
Sellings et al., 2008) and pharmacological (e.g., Simpson and Riley,
2005) data argue that the rewarding and aversive effects of drugs of
abuse can be (and are likely) dissociated, leading to the conclusion
that the rewarding effects of drugs do not mediate the suppression
of intake in the conditioned taste aversion preparation. It is important to note, however, that the nature of such suppression remains
to be determined (see below).
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Fig. 4. Lack of relationship between the rewarding and aversive effects of morphine.
Correlational analysis of the relationship between change in time spent on the drugpaired side and change in saccharin consumption for animal subjects injected with
5 mg/kg morphine, s.c. Visual analysis reveals substantial individual variability in
sensitivity to both the rewarding and aversive effects of morphine. Included in the
graph are Pearson’s r, p value, as well as the line of best fit for the given relationship.
See also Verendeev and Riley (2011).
6. The mechanism of drug-induced conditioned taste
aversion: The role of conditioned fear
If CTAs induced by drugs of abuse are not mediated by the drugs’
rewarding effects, as discussed above, what then is the nature
of the suppression of consumption of taste stimuli produced by
these psychoactive drugs? As previously mentioned, a number of
possible mechanisms have been proposed, e.g., nausea (Elsmore
and Fletcher, 1972; Lester et al., 1970; Riley and Zellner, 1978),
novelty (Gamzu, 1977; Hunt and Amit, 1987), reward comparison
(Grigson, 1997), but none has been without criticism. In this section, we would like to examine yet another hypothesis that has been
recently summarized by Parker and her colleagues (Parker et al.,
2009), according to which it is conditioned fear that mediates the
drug-induced suppression of drinking.
One important aspect of this view is that it acknowledges the
tightly regulated homeostatic state of the animal (cf. Gamzu, 1977)
and the ability of a drug treatment to disrupt this homeostasis. In
animals such as the rat that are incapable of vomiting, any disruption in homeostasis following consumption must be perceived
as dangerous. Any food associated with this disruption evokes a
conditioned fear response which results in the avoidance of the
food associated with the disruption in homeostasis. Interestingly,
when a novel saccharin solution is paired with drugs of abuse in
species capable of emesis (e.g., house musk shrew Suncus murinus),
a different ingestive pattern emerges from that of a rat. For these
animals, disruptions in homeostatsis do not necessarily evoke a fear
response given that true toxins can be removed from the digestive
track via vomiting. Consequently, disruptions in homeostasis that
do not evoke vomiting do not induce fear and should not induce a
taste aversion to foods associated with them. In a test of this prediction with shrews, Parker et al. (2002) paired a novel sucrose
or saccharin solution with morphine and amphetamine at doses
(20 mg/kg each) that also produced conditioned place preference
in the same species. These doses of morphine (Simpson and Riley,
2005; White et al., 1977) and amphetamine (Cappell and LeBlanc,
1971; Wise et al., 1976) also exceeded those necessary to produce
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conditioned suppression in the rat (see also Turenne et al., 1996;
Verendeev and Riley, 2011). They reported that shrews developed a
conditioned taste preference for the drug-paired flavors. In shrews,
the ability to vomit allows the animal to be “less careful”. That is,
toxicosis is dealt with by removing the toxic substance from the
ingestive tract by vomiting. Drugs of abuse fail to induce conditioned avoidance of taste stimuli due to the lack of a fear response
in these animals to such states. From this analysis, Parker et al.
concluded that the ability of rewarding drugs to condition taste
avoidance varies with the ability of the species to vomit (see also
Davis et al., 1986).
To further investigate the conditioned fear hypothesis, Parker
examined whether rewarding drugs actually elicited conditioned
fear in rats. In one assessment of this, Rana and Parker (2007)
examined the ability of LiCl- and amphetamine-paired flavors to
elicit fear in the fear-potentiated acoustic startle response (ASR).
The ASR had been previously shown to be enhanced in the presence of shock-paired cues, but attenuated in the presence of cues
that had been paired with sickness (see Parker et al., 2009). If the
drug-paired flavor elicits conditioned fear, it would be expected
to potentiate the ASR; however, if the drug-paired flavor elicits
conditioned sickness, then it would be expected to attenuate the
ASR. As predicted by the conditioned fear hypothesis, Rana and
Parker found that intraoral infusion of amphetamine-paired saccharin potentiated the startle response (akin to shock-paired cue),
but presentation of LiCl-paired saccharin attenuated the startle
response, akin to other treatments that make rats sick (Rana and
Parker, 2007).
Furthermore, when nausea produced by LiCl was inhibited by
pretreatment with the antiemetic ondansetron, LiCl-paired saccharin solution no longer blunted the ASR, but instead was found
to elicit a response similar to the amphetamine-paired saccharin (i.e., potentiated startle response). Interestingly, other studies
by Parker and her colleagues have shown that pretreatment with
ondansetron interfered with LiCl-induced rejection reactions in the
TR test, but had no effect on LiCl-induced suppression within the
CTA preparation (Limebeer and Parker, 2000). This seems to suggest then that even in the absence of nausea the changes in affective
homeostasis produced by LiCl treatment become selectively associated with the novel taste in the CTA preparation resulting in the
avoidance of the taste stimulus (Parker et al., 2009). These findings
not only lend further support for the conditioned fear interpretation
of taste avoidance, but also provide an explanation for the failure of
antiemetic drugs to block suppression of drinking induced by classical toxins (see, for example, Goudie et al., 1982). Moreover, the
ability of antiemetic agents to produce taste avoidance on their own
(see, for example, Amit et al., 1977; Berger, 1972; Corcoran et al.,
1974; Switzman et al., 1981; see the section “The role of sickness
in conditioned taste aversion” above) is also easily explained by
the conditioned fear hypothesis, according to which drugs (including antiemetic drugs) that disrupt homeostatic state of the animal
are capable of producing conditioned suppression of the taste with
which they are paired.
Taken together, these and other findings by Parker and her colleagues offer the following interpretation of the conditioned taste
avoidance induced by psychoactive drugs. First, there is a qualitative difference in CTAs induced by rewarding drugs and CTAs
produced by classical emetics (such as LiCl) and other illnessinducing treatments (as measured by the TR test; Parker, 1988,
1991, 1995; Parker et al., 2009). Second, drugs of abuse produce
conditioned taste avoidance (i.e., suppression of drug-paired taste
CS) but do not produce conditioned taste aversion (i.e., change
in palatability of the taste stimulus; Parker, 1982, 1991, 1995;
Parker et al., 2009). Third, drugs of abuse produce conditioned taste
avoidance via conditioned fear, wherein a change in homeostasis
following a drug treatment becomes readily associated with the
flavor of the taste stimulus, and the taste is subsequently avoided
because it comes to signal potential danger to the animal (Parker
et al., 2009). Fourth, nausea is not necessary to condition taste
avoidance for either drugs of abuse (which do not produce gastrointestinal sickness) or for LiCl (as discussed above, pretreatment with
antiemetics fails to block LiCl-induced suppression of saccharin
intake; Goudie et al., 1982; Limebeer and Parker, 2000), but might
be sufficient to do so (as shown, for example, in case of rotationinduced suppression of a taste stimulus; Braun and McIntosh, 1973;
Cordick et al., 1999; Green and Rachlin, 1973; Sakai and Yamamoto,
1997). Fifth, nausea is necessary to produce conditioned taste aversion (again, measured by rejection responses in the TR test; Parker,
1982, 1995, 1998; Parker et al., 2009).
One interesting question that follows from this analysis is
whether the conditioned fear evoked by disruption in homeostasis is similar in nature to fear induced by exteroceptive stimuli,
such as foot shock. Although both preparations investigate conditioned fear, the two have not been systematically examined
under the identical experimental conditions. Nevertheless, a recent
study suggests that the conditioned fear induced by disruption
in homeostasis may share some neurobiological substrate with
the conditioned fear induced by exteroceptive stimuli. Rana and
Parker (2008) reported that lesions of the basolateral amygdala
(BLA) attenuated LiCl-induced suppression of saccharin consumption (i.e., reduced conditioned fear) in rats, an effect consistent
with other studies showing the importance of BLA in the establishment of conditioned fear (Killcross et al., 1997; Selden et al., 1991).
Interestingly, lesions of BLA did not affect LiCl-induced conditioned
disgust reactions, which further supported the position that conditioned suppression of drinking is mediated by conditioned fear but
not conditioned disgust (see above).
Although the conditioned fear account of taste aversion learning is well supported (see above), there are several issues that
remain to be further addressed. For example, if fear is involved in
the conditioning of taste aversions, it might be expected that foot
shock, which readily conditions fear in the rat (see Maren et al.,
1997; Maren and Fanselow, 1996), would in turn induce taste aversions. Although there is evidence that shock can be effective in
such a preparation (Braveman, 1977; Delamater and Treit, 1988;
Dess et al., 1988a,b; Hankins et al., 1976; Klunder and O’Boyle,
1979; Krane and Wagner, 1975; Miller et al., 1989; Nakajima, 2004;
Revusky and Reilly, 1989), others have failed to find any evidence
of its ability to induce aversions (Domjan and Wilson, 1972; Garcia
and Koelling, 1966; Garcia et al., 1970; Green et al., 1972; Lasiter
and Braun, 1981; Miller and Domjan, 1981). Interestingly, in several
of the papers that have reported shock-induced taste aversions, if
the same shock is given prior to or during taste aversion conditioning when a taste is paired with radiation or a general emetic such
as LiCl or apomorphine, the taste aversions are weakened (see Dess
et al., 1988b; Revusky and Reilly, 1989; Braveman, 1977; though
see Lasiter and Braun, 1981). Further, taste-illness and taste-shock
associations can be dissociated by the patterns of aversions generated (Klunder and O’Boyle, 1979; Miller et al., 1989; Rusiniak et al.,
1982), the various delays that can be supported by each (Krane and
Wagner, 1975) as well as the effects of a pharmacological challenge
(Delamater and Treit, 1988).
Further, although the conditioned fear hypothesis provides one
possible mechanism for the conditioned taste avoidance induced
by drugs of abuse – namely, disruption of homeostasis and the
subsequent fear associated with it – it does not address the specific nature of the disruption. What exactly is disrupted by the
drug injection? The answer may depend on the specific drug, e.g.,
anxiogenesis (cocaine; Ettenberg and Geist, 1991, 1993), hypothermia (ethanol; Cunningham et al., 1988; Cunningham and Niehus,
1989) and is likely affected by a number of factors, such as the
route of administration (Busse et al., 2005; Ferrari et al., 1991;
A. Verendeev, A.L. Riley / Neuroscience and Biobehavioral Reviews 36 (2012) 2193–2205
Mayer and Parker, 1993), dose (Jensen et al., 1990; Nathan and
Vogel, 1975; Parker, 1991; Riley et al., 1978), temporal parameters (Freeman and Riley, 2005), sex (Cailhol and Mormede, 2002;
Randall-Thompson and Riley, 2003; van Haaren and Hughes, 1990),
specific neurochemical systems affected (Goudie et al., 1975;
Serafine and Riley, 2012; Sklar and Amit, 1977; see also Hunt and
Amit, 1987), centrally- vs. peripherally-mediated action (Bechara
et al., 1987; Davis et al., 2012; Freeman et al., 2005; Rabin and Hunt,
1989), genetics (Glowa et al., 1994; Grabus et al., 2004; Lancellotti
et al., 2001; Roma et al., 2006), environmental conditions (GomezSerrano et al., 2009; Roma et al., 2007; Roma et al., 2008) and other
factors.
7. Conditioned taste aversion and drugs of abuse: Paradox
revisited
As discussed above, a number of authors have noted the seeming
paradox whereby drugs of abuse that are freely self-administered
by both humans and animals (presumably due to their rewarding
effects) also suppress the consumption of food and taste stimuli
with which they are paired (Gamzu, 1977; Goudie, 1979; Hunt and
Amit, 1987; White et al., 1977). This might indeed be viewed as
paradoxical if drugs of abuse are considered in the sense of being
simple pharmacological agents with positive rewarding effects
only. This description of psychoactive drugs, however, may be
too narrow in that drugs of abuse may possess multiple stimulus effects, not all of which are positive reinforcing (Koob and Le
Moal, 2006; Lynch and Carroll, 2001; Stolerman, 1992). When one
considers the multiplicity of a drug’s stimulus effects, the ability
of a drug of abuse to be self administered and to condition a place
preference and produce taste avoidance at the same time ceases to
be a paradox. As envisioned early on by Wise et al. (1976), drugs of
abuse are complex pharmacological compounds with both positive
and negative effects (see also Riley et al., 2009).
Although assessments of drug reward and aversion are usually done in separate experiments and often in separate studies
and under different experimental conditions, a number of studies have examined these effects at the same time and in the same
animals. For example, White et al. (1977) examined the ability of
morphine to produce reward (as measured by runway speed to
obtain food located in a goalbox) and aversion (measured by consumption of the food) at the same time. They found that the same
morphine injections both increased the running speed to reach the
goal box and reduced the amount of food consumed. Moreover,
Wise et al. (1976) reported that rats avoided saccharin associated with either experimenter-administered amphetamine or
self-administered apomorphine. We (Verendeev and Riley, 2011)
reported that rats both preferred a distinctive environment (i.e.,
formed a CPP) and avoided a saccharin taste (i.e., formed a CTA)
that have been paired with the same injection of either morphine
or amphetamine.
These and other (Cunningham, 1979; Reicher and Holman,
1977; Roma et al., 2006; Simpson and Riley, 2005; Ettenberg
and Geist, 1991, 1993) studies suggest that both positive rewarding and negative aversive effects can be demonstrated under the
same experimental conditions. However, although drug reward
and drug aversion can be produced by the same drug injection,
these effects are most likely dissociated and independent of each
other (Verendeev and Riley, 2011; see above). The presence of both
positive rewarding and negative aversive effects and their apparent dissociation from each other suggest that both of these effects
should be examined in any attempt to model drug use and addiction. In conclusion of this review on conditioned taste aversion, we
would like to discuss a possible role of drug aversion in drug taking
behavior.
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8. Conclusion: The role of drug aversion in drug use and
abuse
Drugs of abuse clearly possess rewarding properties, the understanding of which is important in the on-going attempt to model
their abuse potential (see Riley et al., 2009). However, instead of
being viewed as simple pharmacological stimuli, drugs of abuse
should be recognized as complex pharmacological compounds with
multiple stimulus effects, some of which are positive and others
that are aversive (see above). It is important to note, however,
that the drugs’ aversive effects have either been largely ignored in
attempts to model drug use and abuse or given minimal attention.
For example, Meyer and Quenzer (2005) review a number of models
of drug abuse and dependence, including the physical dependence
model, the positive reinforcement model, opponent process model
and incentive-sensitization model, none of which mentions a drug’s
acute aversive effects. According to Meyer and Quenzer, however, a
comprehensive model of drug use and dependence should, in addition to the positive reinforcing effects of drugs, include the aversive
effects of drugs as well. Other factors involved in development and
maintenance of compulsive drug use include the discriminative
subjective effects of drugs, the stimuli conditioned to drug effects,
and other risk and protective factors (see Meyer and Quenzer, 2005,
pp. 207–212).
One of the few attempts to assess the role of the aversive effects
of a drug and its self-administration was recently summarized by
Cunningham and his colleagues in their analysis of the genetic
influences on ethanol-induced taste aversions and ethanol intake
(Cunningham et al., 2009). Using 15 different inbred mouse strains,
the authors examined their sensitivity to the aversive effects of
2 g/kg ethanol (see also Broadbent et al., 2002) and then correlated these differences with 10% ethanol intake reported for these
strains in an earlier study (Belknap et al., 1993). A significant correlation was reported between the sensitivity to the aversive effects
of ethanol and ethanol consumption, such that strains of mice more
sensitive to the aversive effects of the drug (i.e., greater taste aversion) showed less ethanol self-administration (i.e., less ethanol
intake) and vice versa (see also Cannon et al., 1994 and Risinger
and Cunningham, 1998; for a related analysis with the F344 and
LEW rat strains, see Riley et al., 2009; Riley, 2011).
It becomes evident then that to better understand drug vulnerability in both animal and human subjects, one has to understand the
ability of drugs to produce both effects and the interplay between
the two. Indeed, it has been suggested by several authors that drug
taking behavior may be a function of the relative balance between
drug reward and aversion (Gaiardi et al., 1991; Riley and Simpson,
2001; Stolerman and D’Mello, 1981; see also Riley et al., 2009).
According to this view, drug taking is a function of the balance
between reward and aversion, with the drug’s aversive effects serving as a limiting factor. If so, successful modeling of drug taking
behavior (both problem and non-problem 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.
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