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آرشيو موضوعي |
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Relapse to drug-seeking: neural and molecular mechanisms
David W. Self*
and Eric J. Nestler
Division of Molecular Psychiatry, Center for Genes and Behavior,
Yale University School of Medicine and Connecticut Mental Health
Center, 34 Park Street, New Haven, CT 06508, USA
Available online 18 June 1999
Article Outline
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1. Introduction
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2. Drug-induced relapse to drug-seeking behavior
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3. Cue-induced relapse to drug-seeking behavior
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4. Stress-induced relapse to drug-seeking behavior
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5. Opponent vs. proponent processes as triggers of
relapse
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6. Receptor mechanisms of dopamine-induced relapse
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7. Possible role of drug-induced neuroadaptations in the
NAc cAMP second messenger system in relapse
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8. Molecular basis of drug-induced neuroadaptations
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9. Summary
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Acknowledgements
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References
1. Introduction
Over the past several decades, there have
been tremendous advances in our understanding of the
neurobiology of drug addiction. Much of this work has
focused on the neurobiological mechanisms of drug reward,
which is viewed as a central factor in drug abuse (Koob
and Bloom, 1988;
Wise, 1990;
Fibiger et al., 1992;
Self and Nestler, 1995). Only more recently have studies
focused on the neurobiological mechanisms of relapse, which
is perhaps the core motivational symptom of compulsive drug
taking and intense drug craving. A better understanding of
the mechanisms of relapse could lead to more effective
treatment strategies for addictive disorders.
It is generally believed that the same
neural systems involved in drug reward and drug-associated
learning are also involved in relapse, since these phenomena
can both elicit similar ‘drug-seeking' behavior. However,
there are basically two theories that have diametrically
opposite views on the role of brain reward pathways in
mediating relapse to drug-seeking. One theory suggests that
relapse is triggered by drug-like, or proponent, processes
that activate reward pathways in a manner directionally
similar to the acute effects of the drug themselves (Stewart
et al., 1984;
Wise and Bozarth, 1987;
Robinson and Berridge, 1993;
Self and Nestler, 1995). Another theory suggests that
drug-opposite, or opponent, processes induce relapse by
producing a hypofunctional state of reward pathways which
leads to dysphoria or anxiety during withdrawal (Solomon
and Corbitt, 1974;
Koob and Le Moal, 1997). In this case, drug-seeking
behavior represents an attempt to alleviate discomfort.
Given that drug-seeking and drug craving
can persist despite long periods of abstinence, both
theories postulate that relatively long-term drug-induced
neuroadaptations in brain reward and other regions underlie
proponent and opponent processes (Fig.
1). A major gap in our current knowledge is identifying
stable neuroadaptations that underlie these phenomena.
Fig. 1. Both learning and pharmacological factors
contribute to neuroadaptations to chronic drug use. These neuroadaptations
can be manifested as either opponent (drug-opposite) or proponent
(drug-like) processes.
One major mechanism for producing such
neuroadaptations is through the direct pharmacological
effects of repeated drug exposure on brain cells. This type
of neuroadaptation is exemplified by the classic studies of
Nirenberg and colleagues on opiate tolerance and dependence
(e.g.
Sharma et al., 1975). In these studies, chronic exposure
to morphine was found to up-regulate the cyclic AMP (cAMP)
pathway in cultured cells as a result of homeostatic
processes. Similar neuroadaptations have more recently been
demonstrated in specific brain neurons (Nestler
and Aghajanian, 1997). These neuroadaptations result in
tolerance to the physiological effects of the opiate at the
level of individual cells, and opposite physiological
changes when the opiate is withdrawn. In a motivational
sense, similar drug-induced neuroadaptations could also
underlie tolerance to the rewarding effect of drugs and
produce aversive consequences during drug withdrawal,
thereby representing opponent processes. Conversely, the
direct pharmacological effects of repeated drug exposure can
produce proponent processes such as sensitization of
cellular responses to the neurotransmitters dopamine and
glutamate (Henry
and White, 1991;
White et al., 1995), which can increase sensitivity to
the rewarding effects of drugs (Carlezon
et al., 1997).
A second major mechanism of
neuroadaptation produced by repeated drug exposure underlies
the powerful learned associations that are formed between
the rewarding effects of drugs and specific environmental
stimuli related to the drug-taking experience. These
otherwise neutral environmental stimuli acquire the ability
to trigger both drug- and withdrawal-like responses in
addicted subjects when subsequently presented in the absence
of the drug (Wikler,
1973;
Siegel, 1983;
O'Brien et al., 1992). While such ‘conditioned stimuli'
or ‘cues' can trigger either mild euphoria or severe
dysphoria, in both cases, the addicted subjects report an
intense desire to self-administer their drug of choice.
Similar proponent and opponent conditioned effects have been
reported in animals (Wikler,
1973;
Eikelboom and Stewart, 1982;
Siegel, 1983;
Robinson and Berridge, 1993).
Although the direct (unconditioned)
pharmacological influence of chronic drug exposure can
produce neuroadaptations independent of drug-associated
learning (e.g.
Self et al., 1995), the conditioned effects of drugs can
alter the manifestation of these processes (Wikler,
1973;
Eikelboom and Stewart, 1982;
Siegel, 1983;
Robinson and Berridge, 1993), such that both conditioned
and unconditioned factors ultimately contribute to the
magnitude and expression of drug-associated neuroadaptations
(Fig.
1). Ultimately, our understanding of drug addiction will
require the elucidation of how the unconditioned and
conditioned effects of drug exposure, as well as opponent
and proponent processes, interact to induce relapse to
drug-seeking. However, before the contribution of these
complex interactions can be fully understood, it is
important first to identify the neural systems that mediate
relapse to drug-seeking.
Drug craving and drug-seeking are
subjective descriptions that cannot be directly measured in
laboratory animals. However, relapse is an operant event
that can be measured directly when a laboratory animal
reinitiates a particular behavioral response, such as a
lever-press that delivered drug injections on previous
occasions during drug self-administration. Relapse to a
prior behavioral response, often referred to as
reinstatement, is thought to reflect the induction of
drug-seeking following extinction from drug
self-administration, when the animal's responses are no
longer reinforced by the drug injections. The ability of
specific experimenter-delivered stimuli to induce an animal
to initiate responding at a ‘drug-paired' lever is then
measured. Stimuli that effectively induce such responding
are sometimes called ‘primers' because they are thought to
initiate a renewed interest in drug-seeking. Although there
are other animal models of drug craving and drug-seeking
(e.g.
Markou et al., 1993;
Robinson and Berridge, 1993), the reinstatement paradigm
dissociates measures of relapse from other behavioral
phenomena, such as reward, extinction, and conditioned
reward, that may or may not reflect similar neurobiological
processes. It is important to emphasize, however, that
relapse to responding associated with drug
self-administration is the behavior measured in the
laboratory; subjective descriptions like drug-seeking can
only be inferred from this behavior.
2. Drug-induced relapse to drug-seeking behavior
A powerful trigger of relapse in the
reinstatement paradigm is an experimenter-delivered priming
injection of the self-administered drug after extinction
from drug self-administration. This has been demonstrated
for opiates and psychostimulants (Gerber
and Stretch, 1975;
de Wit and Stewart, 1981 and
de Wit and Stewart, 1983;
Slikker et al., 1984), but these drugs fail to reinstate
responding in animals trained to self-administer
barbiturates (Slikker
et al., 1984). Conversely, barbiturates, benzodiazepines
and ethanol all fail to reinstate responding for
psychostimulants (Gerber
and Stretch, 1975;
de Wit and Stewart, 1981;
Slikker et al., 1984;
Comer et al., 1993). Since the ability of various drugs
to induce relapse coincides with their ability to mimic the
subjective effects of the self-administered drug,
investigators originally concluded that the subjective
effects of a particular drug are a primary determinant of
whether the drug could induce relapse to drug-seeking
behavior. However, recent studies suggest that it is neither
necessary (Shaham
and Stewart, 1995a and
Shaham and Stewart, 1995b) nor sufficient (Self
et al., 1996a) for priming stimuli that induce relapse
to also have subjective effects similar to those produced by
the self-administered drug. Moreover, a recent study has
found that the incentive motivational properties of morphine
occur in the absence of detectable subjective effects in
animals measured by drug discrimination, further suggesting
separate neural substrates for motivational and subjective
drug effects (Jaeger
and van der Kooy, 1996).
Interestingly, opiates can reinstate
responding in animals trained to self-administer
psychostimulants (de
Wit and Stewart, 1981;
Slikker et al., 1984), and vice versa (de
Wit and Stewart, 1983). This ‘cross-priming' could
reflect activation of a common neural substrate by the two
drug classes. Indeed, both opiates and psychostimulants can
produce rewarding effects by activating the mesolimbic
dopamine system (Wise
and Bozarth, 1987;
Di Chiara and Imperato, 1988), consisting of
dopaminergic neurons in the ventral tegmental area (VTA) and
their target neurons in the nucleus accumbens (NAc).
Considerable evidence suggests that the ability of opiates
and psychostimulants to trigger relapse to drug-seeking
behavior also involves their ability to activate the
mesolimbic dopamine system. Microinfusion of amphetamine
directly into the NAc, where it causes local dopamine
release, effectively reinstates heroin-seeking behavior (Stewart
and Vezina, 1988). Similarly, application of morphine
directly into the VTA, where it activates dopamine neurons
via disinhibition (Johnson
and North, 1992), and consequently increases dopamine
release in the NAc (Leone
et al., 1991), can reinstate both heroin- and
cocaine-seeking behavior (Stewart
et al., 1984). Injections of morphine into other brain
regions rich in opiate receptors, including the NAc, are
ineffective at inducing relapse to drug-seeking behavior.
Further evidence for dopamine involvement in drug-induced
relapse is the fact that several directly acting
dopaminergic agonists are powerful inducers of relapse to
both cocaine- and heroin-seeking behavior (de
Wit and Stewart, 1983;
Wise et al., 1990;
Self et al., 1996b), and dopamine antagonists can block
the priming effects of heroin, amphetamine and cocaine (Ettenberg,
1990;
Shaham and Stewart, 1996;
Weissenborn et al., 1996). Taken together, these studies
suggest that drug-induced dopamine release in the NAc is
both necessary and sufficient for opiate and psychostimulant
drugs to induce relapse to drug-seeking behavior (Fig.
2).
Fig. 2. Diagrammatic representation of the primary
pathways through which stress, drugs of abuse, and drug-associated stimuli
are hypothesized to trigger relapse to drug-seeking behavior. Stress and
drug-associated stimuli can activate excitatory glutamate (Glu) projections
to the ventral tegmental area (VTA) from the prefrontal cortex (PfC) and
amygdala (Amyg), respectively, while drugs of abuse stimulate dopamine (DA)
release from VTA dopamine neurons projecting to the nucleus accumbens (NAc).
Amyg projections to the PfC represent a secondary pathway through which
drug-associated stimuli could access VTA dopamine neurons. Similarly,
stress-induced relapse may utilize corticotropin releasing factor (CRF) and
the hypothalamo–pituitary–adrenal (HPA) axis, and subsequent corticosterone
(Cort) secretion to activate VTA dopamine neurons. Although dopamine release
in the NAc may be a final common neurochemical event that triggers relapse
by all three stimuli, stress and CRF may also act on other unknown brain
regions through dopamine-independent mechanisms to trigger relapse to
drug-seeking behavior.
3. Cue-induced relapse to drug-seeking behavior
A second trigger of relapse in the
reinstatement paradigm is the presentation of
drug-associated stimuli or cues. In animals, reports of
cue-induced relapse to drug-seeking behavior are sparse (de
Wit and Stewart, 1981;
Meil and See, 1997), but reports of cue-induced drug
craving in humans are numerous (see Introduction). Moreover,
the priming induced by drug-associated stimuli in animals is
relatively weak when compared to the priming induced by the
self-administered drug (de
Wit and Stewart, 1981). Nevertheless, the fact that
these drug-associated stimuli can trigger drug-seeking
behavior has led investigators to hypothesize that these
stimuli activate the mesolimbic dopamine system (Stewart
et al., 1984;
Robinson and Berridge, 1993;
Wise, 1994). At present, this hypothesis remains
equivocal, because some studies have found that the
conditioned behavioral effects of cocaine are not
necessarily associated with an increase in dopamine release
in the NAc (Brown
and Fibiger, 1992). However, at least two studies have
reported enhanced dopamine release in the NAc following
presentation of drug-associated cues (Fontana
et al., 1993;
Di Ciano et al., 1995). In addition, others have found
that dopamine neurons in the VTA are activated by
environmental stimuli associated with non-drug rewards, and
these cues also elicit reward-seeking behavior (Schultz
et al., 1993;
Mirenowicz and Schultz, 1996). Although elusive, the
question of dopamine involvement in conditioned drug effects
is crucial to our understanding of how drug-associated cues
access motivational systems to trigger relapse.
Already established is a role for the
amygdala in the priming effects of drug-associated cues.
Meil and See (1997) recently reported that excitatory
amino acid lesions of the basolateral nucleus of the
amygdala attenuate the ability of cocaine-associated cues to
induce relapse to cocaine-seeking behavior. These lesions
effectively block cue-induced relapse even when the amygdala
is lesioned after cue conditioning already had occurred,
indicating that the amygdala is part of an important neural
pathway through which cocaine-associated cues access and
activate incentive motivational systems. Similar lesions of
the amygdala were found to block the conditioned
motivational, but not the conditioned locomotor, effects of
cocaine (Brown
and Fibiger, 1993), suggesting separate neural
substrates for each of these conditioned effects.
The descending outputs of the amygdala
are thought to be excited by sensory information from
conditioned stimuli (LeDoux,
1993). One of the descending outputs is an excitatory
amino acid projection from the central nucleus to VTA
dopamine neurons (see
Fig. 2) (Gonzales
and Chesselet, 1990;
Wallace et al., 1992), and stimulation of this pathway
can excite VTA dopamine neurons through both mono- and
poly-synaptic pathways (Maeda
and Mogenson, 1981), presumably leading to increased
dopamine levels in the NAc.
Fig. 2 illustrates this direct pathway whereby
drug-associated stimuli could activate the mesolimbic
dopamine system via excitatory inputs, leading to dopamine
release in the NAc and relapse to drug-seeking. However,
amygdala projections to other brain regions such as the
prefrontal cortex (PfC) could form secondary pathways
through which drug-associated stimuli activate VTA dopamine
neurons (McDonald,
1991). Amygdala projections to terminal regions in the
NAc apparently make synaptic contacts with NAc perikarya
rather than dopamine terminals (Johnson
et al., 1994), and thus are not be expected to directly
stimulate dopamine release.
4. Stress-induced relapse to drug-seeking behavior
Previously, Shaham and Stewart (Shaham
and Stewart, 1995a;
Shaham et al., 1996) reported that a brief presentation
of intermittent footshock stress induces a robust and
prolonged reinstatement of heroin-seeking behavior in rats
with prior heroin self-administration experience. This
stressor effectively induced heroin-seeking behavior in both
opiate-dependent and non-dependent animals, and was capable
of inducing relapse even after 6 weeks of withdrawal from
heroin. A similar priming effect of footshock stress on
cocaine-seeking behavior has since been demonstrated
following prolonged extinction from cocaine
self-administration (Erb
et al., 1996;
Ahmed and Koob, 1997). In some cases, the ability of
stress to induce drug-seeking behavior in animals was
greater than priming injections of the drug itself.
As with drugs and conditioned stimuli,
stress-induced relapse to drug-seeking behavior also may
involve activation of dopamine receptors in the NAc. This
notion is supported by the finding that stress-induced
elevations in NAc dopamine levels correlate temporally with
reinstatement of heroin-seeking behavior (Shaham
and Stewart, 1995b). Moreover, stress-induced relapse to
this behavior can be partially attenuated by pretreatment
with dopamine antagonists (Shaham
and Stewart, 1996). The primary neural pathway through
which stress can stimulate dopamine release in the NAc may
involve stress effects on the PfC (Moghaddam,
1993) and, consequently, activation of an excitatory
projection from the PfC to the VTA (Fig.
2). This projection forms monosynaptic inputs to VTA
dopaminergic neurons (Sesack
and Pickel, 1992), and can trigger dopamine release in
the NAc (Murase
et al., 1993). Although the PfC also sends excitatory
projections to the NAc (Sesack
et al., 1989;
Brog et al., 1993), recent studies have found that PfC
regulation of NAc dopamine levels is mediated primarily via
activation of glutamate receptors on VTA dopamine neurons,
and not on dopamine terminals in the NAc (Taber
et al., 1995;
Karreman and Moghaddam, 1996).
Fig. 2 shows that stress could also activate or enhance
mesolimbic dopamine transmission through release of
corticotropin releasing factor (CRF). Shaham and colleagues
have recently found that intracerebroventricular (ICV)
infusions of CRF mimicked the induction of heroin-seeking
behavior triggered by stress, and similar infusions of a
peptide CRF antagonist partially reduced stress-induced
relapse (Shaham
et al., 1997). ICV CRF administration has been reported
to increase dopamine release in the hypothalamus and
prefrontal cortex (Lavicky
and Dunn, 1993;
Song et al., 1995), although CRF effects on dopamine
release in the NAc have not been reported. In addition, CRF
could also potentiate activity in VTA dopamine neurons
through its effect on the hypothalamo–pituitary–adrenal (HPA)
axis, because systemic corticosterone injections increase
the sensitivity of VTA dopamine neurons to excitatory
inputs, and lead to greater dopamine release in the NAc (Overton
et al., 1996;
Piazza et al., 1996). However, while stress-induced
relapse to cocaine-seeking behavior could rely on the
HPA axis and corticosterone secretion (Piazza
et al., 1994;
Deroche et al., 1997), stress-induced relapse of
heroin-seeking behavior can apparently occur
independently of corticosterone secretion (Shaham
et al., 1997).
Together, these studies suggest that
stress can activate VTA dopamine neurons through activation
of the PfC, and through CRF–HPA–corticosterone feedback on
the VTA-NAc pathway (Fig.
2). However, stress was found to be less effective than
priming injections of heroin at stimulating dopamine release
in the NAc, despite greater induction of heroin-seeking
behavior by the stressor (Shaham
et al., 1996). This may suggest that stress-induced
relapse likely involves dopamine-independent mechanisms as
well (Fig.
2).
5. Opponent vs. proponent processes as triggers of
relapse
It is clear from these studies that
proponent processes are powerful inducers of relapse in
animal models of drug-seeking behavior because, without
exception, stimuli that induce relapse are also capable of
releasing dopamine in the NAc. In contrast, several studies
have found that opponent processes fail to induce relapse in
these animal models. For example, priming injections of
opiate antagonists fail to induce relapse and actually
suppress drug-seeking behavior in non-opiate-dependent
animals (Stewart
and Wise, 1992). Even in opiate-dependent animals,
antagonist-precipitated withdrawal fails to induce
heroin-seeking behavior, despite withdrawal-induced
decreases in dopamine levels in the NAc (Shaham
et al., 1996). Similarly, dopamine receptor antagonists
fail to induce heroin- or cocaine-seeking behavior (Shaham
and Stewart, 1996;
Weissenborn et al., 1996). The inability of these
antagonist treatments to induce relapse contrasts sharply
with their ability to produce aversive consequences (Shippenberg
and Herz, 1987;
Stinus et al., 1990), suggesting that opponent
motivational processes do not trigger relapse. Thus, animal
studies agree with reports of drug-like, and even mood
elevating, symptoms of craving in cocaine addicts (Childress
et al., 1988). However, these animal studies are in
contrast with human reports of drug-craving associated with
drug-opposite symptoms such as dysphoria, especially in
opiate addicts and alcoholics (Childress
et al., 1988).
Although antagonist-precipitated
withdrawal fails to trigger relapse to drug-seeking behavior
in animals, spontaneous withdrawal in opiate-dependent
animals does induce relapse to heroin-seeking behavior
without any detectable change in NAc dopamine levels (Shaham
et al., 1996). This finding may be relevant to other
factors involved in maintaining daily drug use in active
drug abusers. In this sense, falling levels of opiate during
spontaneous withdrawal is an example of an opponent process
that could trigger drug craving and relapse on a day-to-day
basis, while proponent processes may be more important in
triggering relapse after longer periods of abstinence, when
withdrawal symptoms have dissipated.
Stress- and CRF-induced relapse
apparently have characteristics of proponent processes,
since both activate central dopamine release (Lavicky
and Dunn, 1993;
Song et al., 1995), and cocaine acutely elevates CRF
levels in the amygdala (Sarnyai
et al., 1993;
Richter et al., 1995). However, withdrawal from cocaine
(Sarnyai
et al., 1995), opiates (Katsumata
et al., 1995), ethanol (Pich
et al., 1995), or cannabinoids (Rodriguez
de Fonseca et al., 1997) is also associated with
elevated CRF levels in the amygdala, and this effect is
thought to mediate anxiogenic effects during drug
withdrawal. A critical question is whether CRF-induced
anxiety contributes to relapse to drug-seeking behavior and,
if so, would this effect be independent of CRF effects on
the mesolimbic dopamine system.
6. Receptor mechanisms of dopamine-induced relapse
The studies described in the preceding
sections suggest that relapse to drug-seeking can be
triggered by activation of post-synaptic dopamine receptors
on NAc neurons. Dopamine receptors are divided into two
general classes that are distinguishable by their structural
properties and opposite modulation of adenylyl cyclase (Sibley
et al., 1993). The D1-like receptors (D1
and D5) are positively coupled to adenylyl
cyclase activity, while the D2-like receptors (D2,
D3 and D4) are either negatively
coupled or have no detectable effect on the enzyme. The two
receptor classes also exert opposite effects on
phosphatidylinositol turnover. Neurons intrinsic to the NAc
express both D1-like and D2-like
dopamine receptors, but in somewhat different neuronal
populations (Meador-Woodruff
et al., 1991;
Curran and Watson, 1995 and
Gerfen and Wilson, 1996). In most cases, these receptors
produce similar, even synergistic, responses at the
physiological and behavioral levels (Waddington
and Daly, 1993;
White and Hu, 1993).
In contrast to these cooperative actions,
we found that systemic priming injections of D2-like,
but not D1-like, dopamine receptor agonists
induce a profound and prolonged relapse to cocaine-seeking
behavior in rats in the reinstatement paradigm (Self
et al., 1996a). These findings suggest that D2-like
receptors are primarily involved in inducing drug-seeking
behavior by priming stimuli that release dopamine in the NAc.
Although selective D1-like receptor agonists fail
to markedly induce cocaine-seeking behavior, D1
receptors may have a permissive role in the priming effects
mediated by D2 receptors, since both D1-
and D2 receptor antagonists can block the priming
effects of cocaine and heroin (Shaham
and Stewart, 1996;
Weissenborn et al., 1996). Further support for this idea
is the finding that relatively high doses of D1
antagonists are required to attenuate the priming effects of
cocaine and heroin compared to other drug-related behaviors.
Thus, transmission of D2-mediated priming signals
may require some minimal level of D1 receptor
activation. Interestingly, however, pretreatment with D1-like
agonists completely abolishes the ability of priming
injections of cocaine to induce relapse, whereas
pretreatment with D2-like agonists, at doses too
low to induce relapse on their own, greatly potentiates
priming with cocaine.
The opposing influence of D1-like
and D2-like dopamine receptor activation on
relapse to cocaine-seeking behavior is intriguing since both
D1 and D2 receptor agonists have
reinforcing properties (e.g.
Self and Stein, 1992;
Caine and Koob, 1993), have similar abilities to mimic
the subjective effects of cocaine (Callahan
et al., 1991;
Spealman et al., 1991;
Witkin et al., 1991), and stimulate locomotor activity (Self
et al., 1996b). One possible explanation for these
findings is that D2-like receptors mediate the
incentive to seek further drug reinforcement, while D1-like
receptors could mediate some aspect of drug reward related
to gratification, drive reduction, or satiety.
The psychostimulant caffeine also can
induce relapse to cocaine-seeking behavior, as well as
enhance the priming effects of cocaine (Worley
et al., 1994;
Self et al., 1996a). Caffeine's psychostimulant effects
are mediated by an antagonist action at striatal A2
adenosine receptors, which are positively coupled to
adenylyl cyclase. Moreover, a specific post-synaptic
interaction between A2 and D2
receptors has been found, where blockade of A2
adenosine receptors by caffeine enhances the affinity of D2
receptors for dopamine (Ferre
et al., 1992). This post-synaptic interaction could
underlie relapse to cocaine-seeking behavior induced by
caffeine by potentiating D2-mediated priming
signals.
Although many of the behavioral and
physiological responses of D1-like and D2-like
receptors in the NAc are similar (Waddington
and Daly, 1993;
White and Hu, 1993), the two receptor types have
opposite effects on adenylyl cyclase and
phosphatidylinositol turnover (see above), which could
possibly underlie their opposing effects on relapse to
drug-seeking behavior. In view of this, we recently found
that experimental modulation of the cAMP pathway in the NAc
has a profound effect on relapse to cocaine-seeking behavior
in rats with cocaine self-administration experience (Self
et al., 1998). In this study, membrane-permeable cAMP
analogs, Rp- and Sp-cAMPS, were infused bilaterally into the
NAc of rats in a reinstatement paradigm (Fig.
3). Rp-cAMPS inhibits the cAMP pathway by preventing
endogenous cAMP from activating cAMP-dependent protein
kinase (PKA). Infusion of the PKA inhibitor into the NAc
triggers relapse to cocaine-seeking behavior, and
pretreatment with a subthreshold dose of the kinase
inhibitor enhances the priming effects of intravenous
cocaine injections. Thus, NAc infusion of the PKA inhibitor
mimicked the effects of systemic priming injections of D2-like
agonists. This supports the hypothesis that D2-like
receptors may utilize inhibition of PKA activity, at least
in part, to induce relapse to drug-seeking behavior. In any
event, this finding suggests that PKA activity in certain
NAc neurons could play a pivotal role in regulating
incentive motivation during drug craving and relapse.
Fig. 3. Effects of intra-NAc infusions of the PKA
inhibitor Rp-cAMPS or the PKA activator Sp-cAMPS (both at 40 nmol/1 μl/side)
on the priming effects of intravenous cocaine injections (2.0 mg/kg) in the
reinstatement paradigm. These treatments were given after extinction from 2
h of intravenous cocaine self-administration, when only intravenous saline
injections were available. Hatch marks denote the times of each
self-infusion of cocaine in the cocaine phase and saline in the saline phase
(from
Self et al., 1998).
In contrast, intra-NAc infusion of the
PKA activator, Sp-cAMPS, masks or disrupts the priming
effects of cocaine, but also induces generalized behavioral
responses that cannot be attributed to relapse of
drug-seeking behavior (Self
et al., 1998). The fact that D1-like
agonists, which also stimulate PKA activity, fail to mimic
these latter effects may suggest that: (i) the behavioral
effects of Sp-cAMPS result from effects on NAc neurons that
do not contain D1-like receptors; (ii) D1-like
receptor responses in the NAc utilize additional signal
transduction pathways; or (iii) D1-like receptors
involved in suppressing drug-seeking are located outside the
NAc. Studies are currently underway to test whether
alternative signalling pathways and brain sites are utilized
by D1 receptors to attenuate relapse to
cocaine-seeking behavior.
7. Possible role of drug-induced neuroadaptations in the
NAc cAMP second messenger system in relapse
Previous work has identified
neuroadaptations in the NAc cAMP pathway after chronic
exposure to opiates, cocaine, or ethanol as shown in
Fig. 4 (see
Self and Nestler, 1995;
Nestler and Aghajanian, 1997). These neuroadaptations
are characterized by decreased levels of inhibitory G
proteins that inhibit cAMP formation, and by increased
levels of adenylyl cyclase and PKA activity, that can
persist for several weeks into withdrawal (Striplin
and Kalivas, 1993;
Self and Nestler, 1995;
Schoffelmeer et al., 1996;
Unterwald et al., 1996). Decreases in the level of
inhibitory G proteins, coupled with increases in the
biochemical machinery to synthesize and respond to cAMP, all
contribute to a generalized up-regulation of the NAc cAMP
pathway. These neuroadaptations probably result from the
direct pharmacological effect of repeated drug exposure
rather than from drug-associated learning, since they occur
to a similar extent whether animals learn to self-administer
drugs, or if they receive the same amount and pattern of
drug administration by passive infusions (Self
et al., 1995).
Fig. 4. Similarities in post-receptor neuroadaptations
in the NAc produced by chronic exposure to opiates, cocaine, or ethanol.
Chronic drug exposure decreased levels of inhibitory G proteins (Gi
and Go), and increased adenylyl cyclase (AC)
and of particulate and soluble cAMP-dependent protein kinase (PKA) activity
in NAc extracts. See
Self and Nestler (1995) and
Nestler and Aghajanian (1997) for references to
original data. Asterisks indicate that values differ from saline-treated
controls by χ2-test (*P<0.05).
In our recent report (Self
et al., 1998), we tested the effects of experimentally up-regulating the
cAMP pathway in the NAc on cocaine self-administration by infusing the PKA
activator, Sp-cAMPS, into the NAc.
Fig. 5 (upper panel) shows that experimental activation
of the PKA pathway in the NAc produces increases in cocaine
self-administration, resulting in a rightward shift in the cocaine
self-administration dose response curve. Since a similar effect is produced
by pretreating animals with dopamine antagonists (e.g.
Caine and Koob, 1994), this effect is usually
interpreted as a reduction in cocaine reward, and animals compensate by
increasing their drug intake. Similar increases in cocaine and heroin
self-administration are seen after inactivation of NAc inhibitory G proteins
with pertussis toxin (Self
et al., 1994). Thus, artificially mimicking the drug-induced
neuroadaptations in the NAc by sustained down-regulation of inhibitory G
proteins or by sustained increases in PKA activity both produce increases in
drug-self-administration. Taken together, these findings suggest that
drug-induced neuroadaptations in the NAc cAMP pathway represent an
intracellular mechanism of tolerance to the rewarding properties of drugs
and, hence, would constitute an opponent process type of neuroadaptation.
Possible mechanisms for PKA-induced tolerance to the rewarding effects of
cocaine could involve D1
receptor phosphorylation and desensitization caused by
sustained PKA activity (Sibley
et al., 1998).
Fig. 5. Effects of PKA activation in the NAc with
bilateral infusions of Sp-cAMPS (upper panel), and PKA inhibition with
Rp-cAMPS (lower panel) on the dose–response relationship for cocaine
self-administration. Self-administration rates are shown for the 2nd hour in
experiments with the PKA activator, and during the 1st hour of the test
session in experiments with the PKA inhibitor, when the cAMP analogs
produced their maximal behavioral effects. Sustained activation of PKA
produces an antagonist-like attenuation of cocaine effects in
self-administration, while inhibition of PKA activity acutely enhances
cocaine effects. The cAMP analogs were infused at doses of 40 and 80 nmol/1.0
μl/side). Data are from
Self et al. (1998). Asterisks indicate that values
differ from baseline values by paired t-test for the 40 or 80 nmol/side
dose (*P<0.05; **P<0.01; ***P=0.001).
Conversely, experimental inhibition of
NAc-PKA activity by infusing the PKA inhibitor, Rp-cAMPS,
directly into the NAc produces leftward shifts in the
cocaine self-administration dose–response curve, consistent
with an enhancement of cocaine effects (Fig.
5, lower panel). As with the relapse paradigm, the
effect of the PKA inhibitor on cocaine self-administration
resembles the effect of pretreatment with a D2-like
dopamine receptor agonist (Caine
and Koob, 1995). Taken together, these studies suggest
that acute inhibition of PKA activity in the NAc is a
proponent process that enhances cocaine reward, and triggers
relapse to drug-seeking behavior similar to priming stimuli
that release dopamine in the NAc.
The hypothesis that drug-induced
up-regulation of the NAc cAMP pathway increases the
probability of relapse seems paradoxical, given that acutely
it is inhibition, and not activation, of the pathway that
triggers relapse. However, it is possible that tonic or
sustained up-regulation of the NAc cAMP pathway could
enhance the responsiveness of the system to stimuli that
phasically inhibit it. This type of synergism is easily
demonstrated in vitro, where prior activation of
adenylyl cyclase dramatically augments the inhibitory
signals produced by subsequent D2-like receptor
activation (Battaglia
et al., 1985). A similar synergy may occur in vivo,
where tonic increases in the NAc-cAMP pathway caused by
chronic drug exposure enhance the relative signal strength
produced by phasic stimuli that inhibit cAMP activity during
drug withdrawal (Fig.
6). If so, the priming ability of stimuli that release
dopamine in the NAc, leading to D2-like
receptor-mediated inhibition of PKA activity, would be
markedly enhanced in addicted subjects. Although
hypothetical, this idea suggests that tonic opponent and
phasic proponent processes interact synergistically to
augment the incentive produced by priming stimuli. Studies
on conditioned reinforcement provide indirect support for
this hypothesis by finding that the incentive properties of
reward-associated stimuli, which are enhanced by acute
stimulation of D2-like receptors (Beninger
and Ranaldi, 1992), are also enhanced by tonic
up-regulation of the NAc cAMP pathway (Kelley
and Holahan, 1997). Thus, neuroadaptations in the NAc
cAMP system could produce tolerance to the rewarding effects
of drugs while simultaneously enhancing the incentive to
seek them, effects commonly reported in human drug abusers.
Fig. 6. Hypothetical illustration of
the synergistic interaction between opponent and
proponent processes in drug craving and relapse. In this
model, opponent processes such as tonic elevation of the
nucleus accumbens (NAc) cAMP pathway emerge during
addiction and withdrawal to modify the baseline from
which phasic proponent processes (arrows) that inhibit
cAMP formation trigger relapse to drug-seeking behavior.
The modified baseline enhances the relative signal
strength of the priming stimulus as reflected by a
greater decrease in cAMP activity. This inhibitory
signal is mediated through D2-like dopamine
receptors in response to dopamine that is released in
the NAc by stress, conditioned stimuli, and priming
injections of drugs.
8. Molecular basis of drug-induced neuroadaptations
The precise molecular mechanisms by which
chronic drug exposure leads to neuroadaptations in
inhibitory G proteins, the cAMP pathway, and other target
genes (e.g. receptors, transporters and neuropeptides, to
name a few) is still unknown, but several studies have found
that the long-term effects of repeated drug exposure involve
changes in gene expression (for review see
Self and Nestler, 1995;
Hyman, 1996;
Nestler and Aghajanian, 1997). Studies of the regulation
of gene expression by drugs of abuse have focused on two
families of transcription factors: cAMP Response Element
Binding protein (CREB), and the products of certain
immediate early genes (IEGs), such as c-fos and c-jun.
Most genes likely contain numerous response elements for
these and many other transcription factors, suggesting that
complex interactions among multiple mechanisms control the
expression of a given gene.
Chronic exposure to morphine reduces CREB
levels specifically in the NAc (Widnell
et al., 1996). In contrast, acute and repeated
administration of amphetamine increases CREB phosphorylation,
without changing the level of CREB (Cole
et al., 1995). This prolonged phosphorylation of CREB
may be due to drug-induced up-regulation of the cAMP
pathway, as described earlier. Involvement of CREB-regulated
gene expression in drug-induced neuroadaptations is
suggested by a recent study which found that disruption of
the α and δ isoforms of CREB blocks development of analgesic
tolerance and physical dependence to chronic opiate exposure
(Maldonado
et al., 1996). Preliminary work shows that changes in
CREB function in the NAc alter the locomotor-activating and
rewarding effects of cocaine (Self
et al., 1996b;
Lane et al., 1997). Along these lines it is possible
that drug-induced changes in CREB's transcriptional activity
lead to neuroadaptations that contribute to drug craving and
relapse to drug-seeking. Moreover, a general role for CREB
in long-term neuroplastic events is suggested by CREB's
involvement in long-term potentiation and other cellular
models of learning and memory [see
Nestler and Aghajanian (1997) for references] suggesting
that CREB could also mediate neuroadaptations that underlie
drug-associated learning.
Drug-induced neuroadaptations in the NAc
may also involve changes in the transcriptional activity of
IEGs. For example, certain Fos-like proteins or Fos-Related
Antigens, termed chronic FRAs, are not induced by acute drug
exposure, but are markedly induced in the NAc by chronic
cocaine, morphine, amphetamine or nicotine exposure (Hope
et al., 1994;
Nye and Nestler, 1996;
Pich et al., 1997). The chronic FRAs are known to be
highly stable isoforms of ΔFosB (Chen
et al., 1997). Moreover, mutant mice lacking the gene
for ΔFosB show heightened sensitivity to cocaine's locomotor
and rewarding effects (Hiroi
et al., 1997). These initial studies indirectly suggest
that ΔFosB-regulated gene transcription may be involved in
long-lasting opponent process neuroadaptations to repeated
drug exposure.
A major challenge of future research is
to further characterize drug-induced changes in CREB, ΔFosB,
and other transcription factors in the NAc and other brain
regions, and to identify the numerous target genes whose
expression is altered by these transcription factors.
Ultimately, it will be necessary to relate each of these
neuroadaptations to specific behavioral responses to drugs
of abuse, in particular to the propensity for relapse to
drug-seeking behavior.
9. Summary
A central determinant of addictive
disorders in people is increased risk of relapse to drug use
even after prolonged periods of abstinence. Recent advances
in animal models of relapse indicate that drug-seeking
behavior can be triggered by priming injections of the drugs
themselves, by drug-associated environmental stimuli, and by
footshock stress. The neural mechanisms underlying this
relapse can be viewed in general terms as drug-like or
proponent processes. Considerable evidence points to the
mesolimbic dopamine system, and more specifically to
activation of D2-like dopamine receptors in the
nucleus accumbens, as a crucial neural substrate utilized by
various stimuli that induce relapse. Drug-associated stimuli
and stress may activate this system via neural circuits from
the prefrontal cortex and amygdala as well as via the
hypothalamo–pituitary–adrenal axis. There is also evidence
for dopamine-independent mechanisms in relapse as well. A
major effort of current research is to identify the
long-lasting neuroadaptations within these various brain
regions that contribute to relapse in addicted people. One
potential neuroadaptation is up-regulation of the cAMP
pathway in the nucleus accumbens, which occurs after chronic
drug exposure, and represents a drug-opposite or opponent
process. Modulation of this system has been related directly
to relapse to drug-seeking behavior. Given the long-lasting
nature of increased risk of relapse, it is likely that the
relevant neuroadaptations are mediated via drug-induced
changes in gene expression. A detailed understanding of the
neural and molecular basis of relapse will facilitate
efforts to develop truly effective treatments and preventive
measures.
Acknowledgements
This work was supported by grants from
the National Institute on Drug Abuse, and by the Abraham
Ribicoff Research facilities of the Connecticut Mental
Health Center. We thank Przemyslaw Bienkowski and Christina
Schad for their helpful comments on this manuscript
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