Physiology & Behavior 103 (2011) 69–78
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Physiology & Behavior
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h b
The paradox of drug taking: The role of the aversive effects of drugs
Anthony L. Riley ⁎
Psychopharmacology Laboratory, Department of Psychology, American University, Washington, DC 20016, USA
a r t i c l e
i n f o
Article history:
Received 1 September 2010
Received in revised form 25 October 2010
Accepted 17 November 2010
Keywords:
Taste aversions
Balance of reward and aversion
Drugs of abuse
a b s t r a c t
In 1991, Woods described the paradoxical nature of eating, specifically, that it produced aversive and negative
effects. He noted in this analysis the multiple physiological and behavior adaptations, both learned and
unlearned, that were aimed at regulating food intake and reducing its aversive, disruptive effects. From this
position, he argued that consumption reflected a balance of the positive and aversive effects of eating. The
present review extends this analysis to drug use and abuse, i.e., that drug taking itself also is a balance of
reward and aversion. Although traditionally the analysis of drug use and abuse has focused on a drug's
positive and negative rewarding effects, the present review highlights the aversive effects of these same
drugs, e.g., cocaine, morphine, alcohol, and describes such effects as protective in nature. This balance and the
manner by which it can be impacted by subject and experiential factors are described with a focus on genetic
models of drug abuse using the Lewis and Fischer inbred rat strains.
© 2010 Elsevier Inc. All rights reserved.
1. Food regulation
In 1991, Woods began a paper entitled “The Eating Paradox: How
We Tolerate Foods” with the statement “I find myself in the hapless
position of having to speak out against the virtues of eating. For a
person who not only loves to eat but was trained in experimental
psychology, this is nothing less than heresy” [1]. So with a title
proclaiming a paradox regarding feeding and a self proclaimed heresy
to come, Woods began what I think is one of his seminal papers in the
field, in this case the toleration, and not general acceptance, of food.
The paper fundamentally was about the disruptive nature of food to
general homeostasis and the adaptations allowing food to be
tolerated.
In his overview, Woods highlighted the many physiological
problems associated with the chronic and excessive intake of food
and the many homeostatic mechanisms that allow us to circumvent
these problems as we eat. Thus, eating is like drug tolerance in that we
adapt to the homeostatic disruption of food much as we adapt or
become tolerant to the disruption of the exogenous administration of
a drug. In his analysis, Woods raised a host of interesting questions
about eating and made some predictions he viewed would be
consistent with his rather unique take on food intake1.
Woods noted that a host of characteristics of food intake reflect
adaptations to limit the aversive or deleterious effects of eating.
⁎ Tel.: +1 202 885 1720; fax: +1 202 885 1023.
E-mail address: alriley@american.edu.
1
Note that Hertel and Eilkelboom [101] have recently reported that animals
induced to binge eat as a consequence of being exposed to alternating periods of food
deprivation and ad-lib access formed aversions to a saccharin solution made
concurrently available. As Woods [1] predicted, large meals can be aversive.
0031-9384/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.physbeh.2010.11.021
Beyond these characterizations, however, is the point that feeding
really is a challenge to which we have to adapt and that understanding
this rather unique position provides a more comprehensive account of
feeding and its regulation than one which focuses only on the positive
value of food.
2. The role of reward in drug taking
Although Woods' immediate concerns were related to feeding and
its regulation, this broad-based approach can and should be applied to
other issues as well. The following brief analysis describes another
phenomenon for which a limited and traditional analysis provides an
incomplete understanding, specifically, the phenomena of drug use
and abuse; the paradoxical position is that drug taking requires an
understanding of drug toxicity and aversiveness.2
To begin this argument, a traditional account of drug taking needs
some description. Accounts of drug-taking behavior invariably begin
and often end with an overview of the rewarding effects of a drug
[2,3]. Such rewarding effects are generally positive or negative in
nature. That is, one may initiate and continue the taking of a drug
because the drug produces some euphoric effect, induces creativity
and/or produces a pleasant feeling, consequences the majority of us
would define as positively rewarding. Initial drug taking can also be
maintained by negative reward as a drug may, for example, relieve
2
There are likely other issues that would benefit from similar analyses. Interestingly, Bernstein and Borson [102] argued that an awareness of the aversive effects of a
number of manipulations would be insightful to understanding the etiology of a
variety of disorders, e.g., cancer anorexia, anorexia nervosa, eating deficits associated
with depression and internal bypass and vagotomy surgery.
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A.L. Riley / Physiology & Behavior 103 (2011) 69–78
social anxiety or relieve boredom. Independent of whether positive or
negative reward, or some combination, is involved, drug taking occurs
and is initially maintained by a reward process. The picture changes
quite dramatically with chronic drug use as drug taking escalates and
spirals out of control [2–5]. Specifically, several factors are involved
with chronic drug taking that shift the control from positive to
negative reward, and this shift may occur for a number of reasons. For
example, the drug's positive rewarding effects weaken with tolerance.
To maintain any positive effects under these conditions requires an
increase in the amount taken or the frequency with which it is taken.
Conversely, the processes underlying tolerance produce classical
withdrawal symptoms in the absence of the drug [6,7]. Behaviors such
as drug taking that reduce these effects are negatively rewarded. In
addition, other physiological effects, e.g., stress related [2], are
recruited with chronic drug use, and further drug taking is negatively
rewarded by their removal. Independent of whether one is discussing
initial or escalating drug use, it is clear that the major factor driving or
maintaining drug self-administration is reward and understanding
the multifaceted patterns of such drug taking necessitates an
understanding of reward and the changes in such reward with, and
consequent to, further drug taking.
3. The affective properties of drugs
Although it would be difficult to argue that such reward principles
are not involved in drug taking, with such a position one might have
only a partial picture of the myriad of factors that might underlie drug
use and abuse. We have argued, along with others [8–12], that drugs,
like food, have both rewarding and aversive effects and it is the balance
of these effects which determines the likelihood that a drug will be
taken.3 Although the rewarding effects of drugs of abuse are well
established and characterized in their ability to maintain drug selfadministration [13], a variety of these drugs also produce conditioned
taste aversions, an index of a drug's aversive effects [14–16]. In the initial
demonstration of taste aversion learning, animals given access to a novel
taste followed by radiation subsequently avoided consumption of the
taste ([17]; see also [18–21]; for a history of taste aversion learning, see
[22]). Although originally demonstrated with radiation as the aversive
agent, such aversions were soon reported to be conditioned by a host of
compounds, almost all of which were classified as aversive by other
indices of toxicity. Interestingly, and often considered paradoxically
[15,23–25], a wide variety of drugs of abuse have also been reported to
induce aversions, suggesting that such drugs have both rewarding and
aversive effects. Such effects have often been reported at the same time
in the same animal, indicating that the rewarding and aversive effects of
these drugs are not simply a function of the specific parameters under
which they are tested [26,27] (see also [28–30]).
Although drug taking is generally described to be a function of its
rewarding effects, the results from work with drug-induced taste
aversions suggest that drug taking might also be impacted by its
aversive effects. We are suggesting that the overall hedonic effect of a
drug, and thus its likelihood of use and abuse, is a function of the
balance between these rewarding and aversive effects. This balance is
illustrated for a hypothetical drug in Fig. 1 which depicts the pattern
of drug self-administration with increases in drug dose. Typically, the
self-administration of a drug follows an inverted U-shaped function
(blue line) such that its self-administration increases with increasing
doses to some asymptotic level and then decreases with further
increases in the dose. The ascending part of the curve presumably
reflects increases in the drug's rewarding effects; the descending
function presumably reflects saturation of receptors or an attainment
3
This same position was actually described by Woods [1] when he talked of the
functional balance reached between the positive and aversive effects of food intake
and how specific patterns of intake affected this balance (see page 499).
Fig. 1. A hypothetical model for the manner by which a balance between the rewarding
and aversive affective properties of a drug might influence total drug intake. When a drug
of abuse is administered at low doses, the subjective effects are primarily rewarding
(green-dashed line), leading to dose-dependent increases in drug intake or selfadministration (blue-solid line). However, as the dose of the drug increases, aversive
drug effects (red-dotted line) begin to influence the amount of drug self-administered (in
their balance with the drug's rewarding effects), leading to lower levels of overall intake.
The intensity of the aversive effects experienced during initial drug use impacts the
probability of future drug taking. Changes in the aversive effects (resulting from
experience with the drug or specific characteristics of the individual) impact a user's
likelihood of subsequent use or abuse of the drug.
Reprinted from Kohut and Riley [55] with permission from Springer-Verlag.
of some maximal rewarding effect (green line) that requires less of
the drug as dose increases [31]. Although these patterns may certainly
be influenced as described, other factors, in this case the drug's
aversive effects (red line), also increase with dose. As the aversive and
toxic effects of the drug increase, the balance between reward and
aversion shifts and reduces drug self-administration.
4. Factors affecting the aversive effects of drugs
Traditionally, the focus on drug taking has been on reward and
what factors affect it, e.g., dose of the drug, route of administration,
drug history, and sex. What the current position argues is that the
focus needs to be wider to include the drug's aversive effects and the
myriad of factors known to impact them. As illustrated in Table 1, the
range of factors that are known to affect a drug's aversive effects is
extensive and includes experiential variables such as drug history,
drug interactions, stress levels and circadian cycle and subject
variables such as sex, age and strain.
5. Genetic contribution to drug toxicity
Over the past 30 years, my laboratory has examined a number of
these factors, specifically, drug history, sex, drug interactions and
genetic influences. It is the latter which will be examined in more detail
in the present review. Investigations of the possible impact of genetic
Table 1
Factors affecting the aversive effects of drug.
Deprivation level
Age
Social context
Physical dependence
Body weight
Drug dose
Drug history
Strain of animal
Species
Sex
Housing condition
Ambient temperature
Drug route
Drug duration
Spacing of drug
Hormonal levels
A.L. Riley / Physiology & Behavior 103 (2011) 69–78
influences on the aversive effects of drugs include drug-induced taste
aversion learning in transgenic mice and quantitative trait loci mapping
relative to aversions and drug intake (for reviews, see [10,32]).
On area that has received considerable attention in aversion
learning is the analysis of inbred rat strains. Such strains are derived
from full-sibling matings for at least 20 consecutive generations, as
opposed to selectively bred strains in which the constituent members
are unrelated [33]. Two of the most popular strains in such
investigations are the C57BL/6 J (C57) and DBA/2 J (DBA) mice in
which these strains have been examined primarily for their ability to
acquire alcohol-induced taste aversions [34–36]. In these assessments,
the DBA mice acquire alcohol-induced aversions at lower doses and
display more robust alcohol-induced aversions than the C57 strain.
Cunningham and his colleagues [32] have argued that these differences in aversive reactions to alcohol are likely responsible for their
differences in oral alcohol self-administration where C57 mice
consume more alcohol than DBA mice [37]. In support of this position,
Broadbent et al. [38] examined alcohol-induced taste aversions and
oral self-administration of alcohol in 15 inbred mouse strains and
reported a significant inverse correlation between these two behaviors
(see also [36,39] for related comparisons). This analysis suggests that
the overall self-administration of alcohol in these inbred strains is
highly impacted by the perceived aversiveness of alcohol where
alcohol consumption is limited by such aversive reactions.
My laboratory has done parallel work with the inbred Fischer
(F344) and Lewis (LEW) rat strains that are genetically divergent and
whose behavioral differences have been well documented (for
reviews, see [10,40–42]). One area in which these animals differ
dramatically is in their intake of drugs. With few exceptions, the LEW
animals are reported to self-administer more cocaine, morphine and
alcohol than the F344 strains [43–46]. Further, the LEW rats display
greater preferences for environments associated with morphine, i.e., a
conditioned place preference, than the F344 strain and do so at lower
doses [47–49]. Because of these differences, these strains have been
used as animal models to examine the role of specific genotypes in
drug-taking behavior, a use supported by the fact that they also differ
in the biochemical and neurophysiological substrates thought to
mediate drug reward. For example, Nestler and his colleagues have
examined brain stem systems involved in morphine withdrawal and
the role of mesolimbic activity in the rewarding properties of drugs of
abuse [48,50,51] and reported clear and distinct strain differences in
the biochemical and neurophysiological activity in these brain areas.
Such differences argued that these strains have different responses to
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the rewarding effects of drugs, and thereby different likelihoods of
taking these drugs, at the outset (Fig. 2).
6. Comparisons of the F344 and Lew inbred rat strains
Given the position that drug use is a function of the balance between
the drug's rewarding and aversive effects, we have extended these
analyses to assess the aversive effects of drugs in the F344 and LEW
strains, specifically if, and to what degree, the two strains might differ in
the acquisition of taste aversions induced by drugs known to be
rewarding and for which the two strains differ in their rewarding effects
(for reviews, see [10,52,53]). The present review focuses on the opiates.
In one of the first assessments, we used morphine sulfate as the
aversive agent. Morphine sulfate was chosen for several reasons. First,
it is a compound that supports self-administration and conditions
place preferences in both outbred rats and in the LEW and F344
strains. Interestingly, both the rate and amount of morphine selfadministration is greater in the LEW rat as compared to the F344
strain [47,48]. Secondly, morphine readily conditions taste aversions
in outbred animals, so the procedures for inducing such aversions
have been well characterized [29,54].
In this study [55], male F344 and LEW rats were allowed 20-min
access to a novel saccharin solution to drink followed immediately by
an intraperitoneal (ip) injection of vehicle, 18, 32 or 50 mg/kg
morphine. All subjects were then given 3 water-recovery days in
which they were allowed 20-min access to water with no injections.
This cycle was repeated three times at which point subjects were given
saccharin in a final aversion test. Control subjects from each strain
readily consumed the saccharin solution, increasing its consumption
over repeated exposures with the dissipation of neophobia to the
novel saccharin [56]. Morphine-injected F344 rats displayed robust
aversions to the morphine-associated saccharin, decreasing consumption over the repeated conditioning trials. Interestingly, these
aversions were not dose-dependent in that all doses of morphine
induced aversions of comparable levels in F344 rats.
Conversely, no dose of morphine induced aversions in the LEW
strain. Paralleling the conclusions of Cunningham et al. [32] relative to
C57 and DBA mouse strains, we argued that the differences between
the F344 and LEW strains in morphine self-administration
(LEW N F344) may be due to the fact that morphine is aversive in
the F344 strain instead of, or in addition to, any differences in
morphine's rewarding effects.
Fig. 2. Saccharin consumption over repeated conditioning trials in which rats from the F344 and LEW strains were given pairings of saccharin and vehicle or varying doses of
morphine (10.0, 32.0 or 56.0 mg/kg). *Indicates that F344 rats drank significantly less saccharin than LEW rats (p b 0.05).
Reprinted from Lancellotti et al. [57] with permission from Elsevier.
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A.L. Riley / Physiology & Behavior 103 (2011) 69–78
7. The aversive effects of drugs: caveats
Instead of focusing solely on explanations regarding reward when
discussing different patterns of drug intake, this interpretation argues
that other factors may be involved in modulating this behavior, i.e., the
possible aversiveness of the drug itself. Although consistent with our
earlier stated position of self-administration being a function of the
balance between the drug's aversive and rewarding effects, this
conclusion is based on one specific interpretation of the results from
the Lancellotti et al. [55] study and that is that the differences in the
acquisition of the aversion are a function of differences in morphine's
aversive effects. This is an assumption and one that has been nicely
addressed by others who have examined taste aversion learning and the
interpretations of the changes that one might see with various
manipulations, e.g., transgenic mutations, lesions [10,32]. As described,
in this preparation animals are given a novel solution to drink and then
injected with one of a number of compounds. The aversiveness of the
compound is indexed by the subsequent decrease in consumption
of the solution due to its association with the drug's aversive effects. A
re-presentation of Table 1 with inclusion of additional factors and a
change of title illustrates that taste aversion learning can be affected by
many variables that may or may not impact the aversiveness of the drug,
e.g., CS intensity, CS–US delay, number of conditioning trials.
Simply interpreting any differences in aversion learning between
strains as due to differences or changes in aversiveness may be
incorrect. As noted, such concerns were raised by Cunningham et al.
[32] in an analysis of genetic differences in aversion learning that
focused primarily on inbred and selectively bred mouse strains. As he
and his colleagues noted, differences in aversion learning may reflect
a variety of factors, many of which directly impact learning and
memory and not necessarily the aversive effects of a drug (see
Figure. 19.2, page 413). In fact, sensitivity to the aversive effects of the
specific drug being assayed is only one entry in their table, and only a
few entries in ours, see Table 2. To make conclusions about drug
aversiveness, these other factors must be experimentally removed as
possible bases for any differences reported (see also [57]).
Evidence that the strain differences we report with morphine are
not due to some of these factors known to affect taste aversion
learning but instead to drug aversiveness comes from other work that
we have done with the F344 and LEW strain [58]. Specifically, we have
examined the ability of cocaine to induce taste aversions in the F344
and LEW rat strains under conditions similar to that described for
morphine. As with our work with morphine, both groups of subjects
injected with vehicle consumed saccharin on the initial exposure and
maintained this high level throughout conditioning. Interestingly, and
unlike with morphine, LEW subjects displayed significantly stronger
cocaine-induced aversions than the F344 rats at the two highest doses
of cocaine (see Fig. 3), suggesting that cocaine is more aversive for this
strain, a conclusion opposite to that we made with morphine (see also
[59,60]; though see [49]).4
Together, the data from the work with morphine [55] and cocaine
[58] argue that differences between the F344 and LEW strains are not
a function of strain differences in a variety of factors that could be
affecting aversion learning (see [32]). In each assessment, the same
conditioning and testing procedures were used. If the differences with
morphine were a function of these general issues that affect learning
and memory, the differences with cocaine (LEW N F344) should be in
the same direction as those with morphine (F344 N LEW) and not
opposite. Some factors(s) other than those affecting basic learning
4
Since our initial reports with morphine and cocaine, we have extended our
analysis of aversion learning with the LEW and F344 strain to a host of other drugs
including alcohol ([103]) nicotine [104] and heroin [67]. In each case, the F344 strain
displays greater taste aversions than the LEW rats. Interestingly, there are no strain
differences for aversions induced by LiCl [105], the opiate agonists U50488H and SNC80 [106]) and naloxone-precipitated withdrawal [107].
Table 2
Factors affecting taste aversion learning.
Deprivation level
Age
Social context
Physical dependence
Body weight
Drug dose
Drug history
Strain of animal
CS variety
CS exposure (novelty)
Number of conditioning trials
Deprivation level
Social context
Physical dependence
Species
Sex
Housing condition
Ambient temperature
Drug route
Drug duration
Spacing of drug
Hormonal levels
CS concentration
CS–US interval
Amount of solution
Test delay
Housing condition
Body weight
and memory must be at play. We have argued it is differential
sensitivity of the two strains to the aversive effects of morphine and
cocaine.
8. The nature of aversive?
Stating this is one thing. Documenting its basis is yet another issue.
Part of the problem in such documenting is the lack of consensus as to
what it is about a drug that makes it successful in inducing an
aversion. The debate about the nature of the aversive effects of drugs
is longstanding and has generated many hypotheses. Beginning with
the work of Garcia and his colleagues [17], it was speculated that
aversions were mediated by malaise produced by the aversioninducing agent. Problems arose, however, when compounds with
known toxicity failed to induce aversions (for a review, see [16]) and
drugs that were generally thought to be rewarding were shown to be
quite effective as aversion-inducing agents [14,61]. These extensions
forced new hypotheses such as drug novelty, stress and disruptions in
homeostasis as possible bases for aversion learning (for excellent
reviews, see [15,23,25,62–64]; see also [65,66]). Each hypothesis has
strengths and weaknesses, but after more than 50 years there is still
no agreement.
Despite this lack of consensus, we have begun this process by
examining some specifics with morphine and other opiates. In this
work, we have argued that morphine likely induces taste aversions by
its activity at the mu receptor because LEW and F344 rats do not differ
in aversions induced by the kappa agonist U50,488H and the delta
agonist SNC80 [67]. Further, its actions at the mu receptor are likely
central because LEW and F344 rats do not differ in aversions induced
by the peripherally acting mu opiate agonist loperamide [52]. Stating
that morphine is acting centrally at mu receptors to induce its
aversive effects, however, does not indicate what brain areas might be
involved.
We have begun examining this by measuring the effects of
morphine and cocaine on c-Fos activity [68] (for reviews on c-Fos and
its activity in taste processing and aversion learning, see [69–74]) in
brain areas implicated in aversion learning [57,75,76].5 Interestingly,
we found that both morphine and cocaine at doses and by routes of
administration that are effective in inducing a taste aversion resulted
in c-Fos activity in these brain areas. More importantly, these brain
areas were differentially activated in the LEW and F344 strains. That
is, when morphine was administered to LEW and F344 rats, it
produced more c-Fos activity in aversion-related areas in the F344 rat
than the LEW strain, an effect consistent with the fact that F344 rats
5
This is not to suggest that these are the only areas implicated in aversion learning.
In fact, a number of specific brain nuclei, including the basolateral and central
amygdala and the insular cortex, appear to play important roles in taste processing as
well as associative function (for reviews, see [57,69,71,108]).
A.L. Riley / Physiology & Behavior 103 (2011) 69–78
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Fig. 3. Saccharin consumption over repeated conditioning trials in which rats from the F344 and LEW strains were given pairings of saccharin and vehicle or varying doses of cocaine (18.0,
32.0 or 50.0 mg/kg). *Indicates that LEW rats drank significantly less saccharin than F344 rats (pb 0.05). Reprinted from Glowa et al. [60] with permission from Springer-Verlag.
display greater morphine-induced taste aversions than the LEW strain
(see Fig. 4 (left panel)).
Conversely, when cocaine was administered, it produced greater cFos activity in aversion-related areas in the LEW rat than the F344
strain, again an effect consistent with the fact that LEW rats display
greater cocaine-induced taste aversions than the F344 strain (see
Fig. 4 (right panel)). When c-Fos activity was examined in brain areas
associated with motor activation, e.g., caudate nucleus, c-Fos activity
was activated by cocaine only and comparably in LEW and F344 rats.
Interestingly, cocaine and morphine induced comparable levels of cFos activation in brain reward areas, e.g., nucleus accumbens shell
[68].
9. Environmental modulation of F344/LEW phenotypes
The basic position that drug use and abuse might be a function of
the balance of the aversive and rewarding effects of a drug is one that
we have argued should be considered when discussing general drug
Fig. 4. c-Fos activation in the PBN and LPN (left panel) and iNTS, cTS and AP (right panel) in the F344 and LEW rat strains following injections of saline, morphine or cocaine. Left
panel: #significant difference from saline (p b 0.05); ##significant difference from saline (p b 0.01); **significant strain difference (p b 0.01). Right panel: #significant difference from
saline (p b 0.05); ##significant difference from saline (p b 0.01); *significant strain difference (p b 0.05); **significant strain difference (p b 0.01).
Reprinted from Grabus et al. [70] with permission from Elsevier.
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A.L. Riley / Physiology & Behavior 103 (2011) 69–78
vulnerability [10,52,53]. The current focus on the F344 and LEW
strains was chosen just to illustrate one of many factors that might
impact a drug's aversive effects and thereby its abuse vulnerability. As
noted, the specific focus on these two strains was on the possible role
of genotype in this analysis.
The fact that the F344 and LEW strains display differential
sensitivity to the aversive and rewarding effects of a drug is clear.
That this response is mediated or constrained by specific genotypes is
less clear. Generations of brother/sister matings have certainly yielded
homogenous (within) and distinct (between) genotypes. However,
the specific phenotypic expression of aversion and reward can be
clearly impacted by a host of environmental challenges. In one of our
first assessments of this, we examined the effects of stress on the
acquisition of morphine-induced place preferences in the F344 and
LEW strains [47]. In this procedure, we paired the non-preferred side
of a conditioned place preference chamber with various doses of
morphine in rats of both strains (for reviews of place preference
conditioning, see [77,78]). Some groups of each strain were injected
with the benzodiazepine inverse agonist DCDM and placed in
restraint tubes prior to morphine place preference conditioning;
other groups of each strain were injected chronically with the
nonpeptide CRH Type 1 antagonist antalarmin prior to conditioning.
Thus, animals were either stressed or had stress reduced, respectively,
and the effects of these stress manipulations on conditioning were
assessed. Such manipulations in outbred rats have been reported to
affect both place preference conditioning and HPA activity [79–82]. In
non-treated subjects, clear dose–response place preferences were
conditioned with morphine which were strain dependent
(LEW N F344). The effects of stress induction and reduction were
interesting in that stress induction reduced morphine-induced CPP in
the LEW rats with no effect in the F344, and stress reduction increased
morphine-induced place preferences in the F344 strain and decreased
CPP in the LEW strain (see Fig. 5).
The issue here is less the specific direction of the effects of these
stress manipulations than the fact that the aforementioned differences
between the rewarding effects of morphine in these two genetically
divergent strains can clearly be modulated by environmental
challenges, in this case, stress. We have recently run related
assessments in which we examined stress and morphine-induced
taste aversions in F344 and LEW rats. In this assessment [83], we
examined the effects of diurnal cyclicity on the acquisition and
expression of morphine-induced taste aversions. The two strains have
been reported to differ significantly in their circadian cycles of
corticosterone [84,85], and our position was that if morphine-induced
Fig. 5. Mean difference in time (s) spent on the drug-paired side between the preconditioning and postconditioning tests for Sprague–Dawley (D), LEW (L) and F344 (F) animals
exposed to either vehicle/home cage (V) or DCCM /restraint stress (D) (left panel) or vehicle (V) or antalarmin (A) (right panel) and conditioned with 1, 4 or 10 mg/kg morphine.
Left panel: *indicates that groups pretreated with antalarmin (A) differed from groups pretreated with vehicle (V) (all p's b 0.05). Right panel: *indicates that animals pretreated with
DCCM (D) and restraint stress differed from animals pretreated with vehicle (V) (all p's b 0.05).
Reprinted from Grakalic et al. [49] with permission from Springer-Verlag.
A.L. Riley / Physiology & Behavior 103 (2011) 69–78
taste aversions were mediated or impacted by stress in these animals
then their different corticosterone cycles would likely affect the
acquisition of such aversions.
Specifically, different groups of F344 and LEW rats were given a
novel saccharin solution to drink and injected ip with varying doses
of morphine. The procedural difference from our prior work was that
we did this conditioning at different times of the animals' day–night
cycle. When we injected 3.2 mg/kg morphine during the day, we
replicated the F344/LEW differences in morphine-induced taste
aversion learning, i.e., F344 rats displayed significantly stronger
aversions than LEW rats (see Fig. 6). However, when we conditioned
with this same dose at night, all groups showed an aversion with no
differences among groups (F344 = LEW = SD). Thus, the clear strain
differences we reported with morphine, differences we use to talk of
genetic differences between the two strains, can be impacted and in
this case eliminated by changes in the training and testing
procedures. That the effect of circadian cyclicity was dependent
upon the dose of morphine further illustrates the complex nature of
75
the effects of genotype on behavior and their modulation by
environmental factors.
We have also examined the impact of maternal behavior on the
genotypic differences reported in morphine-induced taste aversion
learning between the F344 and LEW strains [86]. Specifically, at birth
F344 pups were cross-fostered to LEW dams and LEW pups were crossfostered to F344 dams. Control LEW and F344 pups were in-fostered to
dams of their own strain. When all pups were 90 days of age, they were
run through our typical morphine-induced taste aversion procedure. As
expected from our earlier work [55], in-fostered F344 rats displayed
robust aversions to the morphine-paired saccharin solution while infostered LEW pups did not avoid the morphine-associated saccharin
(see Fig. 7). An interesting finding was produced in the cross-fostered
pups. Specifically, cross-fostered F344 subjects, i.e., those raised by a
LEW dam, displayed weaker taste aversions relative to the in-fostered
F344 rats. Further, cross-fostered LEW pups reared by F344 dams now
displayed taste aversions. The two cross-fostered groups displayed
aversions intermediate to their in-fostered pairs.
Fig. 6. Mean (± SEM) saccharin consumption on the taste aversion test expressed as a percentage of Trial 1 consumption ([saccharin consumption during test / saccharin
consumption during trial 1] * 100) for Sprague–Dawley (SD), Lewis (LEW) and Fischer (F344) rats trained during the light phase (left side of each panel) or dark phase (right side of
each panel) with 3.2 mg/kg morphine (Panel A), 10.0 mg/kg morphine (Panel B), or saline (Panel C). *indicates that SD rats drank significantly more than LEW and F344 rats
(p b 0.05). #indicates that F344 rats drank less than SD and LEW rats (p b 0.05).
Reprinted from Gomez-Serrano et al. [85] with permission from Elsevier.
76
A.L. Riley / Physiology & Behavior 103 (2011) 69–78
Fig. 7. Saccharin consumption over repeated conditioning trials in which female rats
from the F344 and LEW strains were given pairings of saccharin and vehicle or
morphine (32 mg/kg) (from Gomez-Serrano & Riley [88]). Group F/L refers to F344
pups reared by LEW dams and L/F refers to LEW pups reared by F344 dams. Groups F/F
and L/L refer to F344 and LEW pups reared by unrelated dams of their own strain. Trials
2 and 3: *indicates that Group FF drank significantly less than Groups LL, LF and FL (all
p's b 0.05). Trials 4 and Final Test: *indicates that Group FF drank significantly less than
Group LL. #indicates that Group LL drank significantly more than Groups LF, FL and FF
(all p's b 0.05).
These results parallel other work from our lab examining the effects
of cross-fostering in that with few exceptions, e.g., carrageenan-induced
inflammation [87], the phenotypic displays that are characteristic of the
LEW and F344 strains can be modulated by which strain raises the LEW
and F344 pups [87,88]. Further, this effect of modulation by crossfostering is not limited to morphine-induced taste aversions in that
cross-fostering effects have also been produced when cocaine is the
aversion-inducing agent [60,89]. Interestingly, the effects of crossfostering are only evident in the F344 strain for cocaine, i.e., the effects
are asymmetrical, an effect we have also seen with several other
behavioral indices, e.g., open-field activity [88]. The basis for the effects
of cross-fostering on the display of aversion learning is not known, but
the fact that these two strains display dramatically different maternal
behavior with LEW more elaborate than F344 [87] suggests that
epigenetic factors along the lines reported by Meaney and his colleagues
in their analysis of the relationship between maternal behavior and
stress [90–92] may modulate and/or mediate the behavioral effects
reported with aversion learning.
due to the fact that much is known about its rewarding effects in
general and in the F344 and LEW animal model. Other drugs, e.g.,
alcohol, nicotine, cocaine and caffeine, have also been analyzed in
relation to their ability to induce aversions in the F344 and LEW rat
strains, and with few exceptions, it is the F344 strain which shows the
greatest drug-induced taste aversions, indicative of a greater
sensitivity to the aversive effects of these drugs. There is an exception,
however, and this exception may be meaningful in the discussion of
the balance of reward and aversion in drug intake. As noted earlier,
this exception is cocaine. First, LEW rats self-administer cocaine at a
higher rate than do F344 rats, suggesting a greater sensitivity to
cocaine's rewarding effects in the LEW strain. At the same time, the
LEW strain displays stronger cocaine-induced taste aversions (see
above), suggesting that the LEW strain is also more sensitive to
cocaine's aversive effects. The issue becomes how the LEW strain
displays greater self-administration of cocaine than the F344 strain
despite the drug being more aversive.
When one talks about the balance between aversion and reward,
one might expect that there is relationship between the two, i.e., if the
rewarding effect is high, the aversive effect might be expected to be
low (and vice versa). This is not necessarily the case. It may be, yet it is
not necessary. In fact, when the specific relationship between reward
and aversion has been examined in individual subjects [99], the
effects are unrelated, i.e., a strong aversion does not predict a weak
place preference (and vice versa). Similar relationships, or the lack,
thereof, have been reported in serial assessments [100] and cross
procedure comparisons [38]. What is important is the relative balance
of the two. A drug can be both rewarding and aversive. It is their
balance that determines the likelihood of its self-administration. As
described, cocaine is both rewarding and aversive in the LEW strain,
and given that the drug is readily self-administered suggests that this
balance leans more to drug reward, i.e., its rewarding effects are
stronger than its aversive effects. When a drug is rewarding with no
aversive effects, the story seems simple; it become complicated when
the two affective properties are not inversely related. However, even
under these conditions one can predict abuse liability if the relative
contribution of the factors is known.
11. Conclusions
10. Balance of reward and aversion: caveats
The purpose of the present overview is to discuss the possible role
of the aversive effects of drugs to their use and abuse. This overview is
not meant in any way to challenge the role of a drug's rewarding
effects in such vulnerability, but only to argue that an analysis of the
multifaceted effects of a drug may give a more complete understanding of the various factors important in drug-taking behavior and thus
greater insights into its etiology and treatment [12]. In this context,
the current overview is similar to that of Woods [1] who argued that
an awareness of both the aversive and rewarding effects of food intake
gives a better and more complete understanding of eating and its
regulation.
While we and others have argued the importance of the
examination of both factors, there are some important caveats to
consider. First, and as noted above, both factors must be concurrently
examined, not only to document the role each may play in drug intake
but also to see their relative contributions and their possible
interaction. Second, although we have used the genetics of drug
taking to illustrate this point, it is important to note that this is only
one factor from a list of many (see Table 1) known to impact the
aversive effects of a drug and thereby the vulnerability to drug taking.
It is only recently that such factors have been examined in relation to
aversion learning and their contribution to drug use been discussed,
e.g., see [93–98] for discussions of adolescent aversion learning.
In addition to focusing on only one factor in the present review,
only a single drug was discussed, i.e., morphine. Morphine was chosen
The purpose of this short review is not to be exhaustive in the
analysis of factors that may impact the aversive effects of drugs.
Instead, it is to illustrate that this affective component of drugs may be
important to understanding drug-taking behavior. It is similar to what
Woods attempted to highlight in his original paper in 1991. Like the
regulation of food intake, the regulation of drug taking is multifaceted.
Recognition of the multiple factors involved in this regulation is
essential to developing models aimed at understanding its etiology
and treatment.
Acknowledgements
The research from this lab on which this review was based was
supported by grants from the MacArthur and Mellon Foundations. The
author would like to thank Jennifer L. Cobuzzi, Jennifer A. Rinker and
Katherine M. Serafine for technical support. Requests for reprints
should be sent to Anthony L. Riley, Psychopharmacology Laboratory,
Department of Psychology, American University, Washington, DC
20016, USA.
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