Cocaine and the Changing Brain
Cocaine Dependence And Withdrawal:
Neuroadaptive Changes In Brain Reward And Stress
Systems
Friedbert Weiss, Ph.D.
The Scripps Research Institute
La Jolla, CA
A growing body of evidence indicates that
chronic cocaine administration can produce
profound and long-lasting changes in brain
neurochemical and neuroendocrine systems.
At the behavioral level, evidence is
accumulating that chronic use of cocaine
compromises the neural mechanisms that
mediate positive reinforcement. This is
illustrated, for example, by findings that
cocaine acutely facilitates the rewarding
effects of intracranial self-stimulation, while
withdrawal after chronic use leads to an
impairment in the rewarding efficacy of
electrical brain stimulation (Markou and Koob
1991). Findings such as these have given
rise to the view that compulsive drug-seeking
behavior associated with cocaine (and other
drugs of abuse) may be the result of adaptive
processes within the central nervous system
that oppose the acute reinforcing actions of
drugs, leading both to a "blunting" of
mechanisms that mediate positive
reinforcement and the emergence of
affective changes during withdrawal that
may motivate continued use of the drug (for
example, anxiety, dysphoria, and depression)
during withdrawal (Koob and Bloom 1988;
Koob et al. 1993; Wise 1996).
The following discussion reviews both earlier
and recent studies that have sought to
identify the brain neurochemical processes
responsible for the compromised state of the
reward system after chronic cocaine abuse
and the significance of those processes in
the transition from controlled drug use to
compulsive drug-taking.
Neuroadaptive Changes Within Brain
Reward Circuitries
Intravenous self-administration in rodents has
been used successfully to study
cocaine-reinforced behavior. This
methodology has significantly advanced the
understanding of the neurobiological basis of
cocaine reinforcement and has established a
critical role for the mesoaccumbens dopamine
(DA) systems in cocaine's acute reinforcing
effects. More recently, studies employing
intracranial microdialysis measures of DA in
the nucleus accumbens (NAc) of cocaine
self-administering rats have confirmed the
significance of DA in cocaine reward and
extended our understanding of interactions
among cocaine, DA, and other transmitters in
this brain region in the regulation of
cocaine-seeking behavior.
When given the opportunity, both human
cocaine abusers and laboratory animals will
often self-administer cocaine in sustained
episodes that can last from several hours to
days. In humans, in particular, this so-called
binge pattern of cocaine abuse is associated
with severe abstinence syndrome. In
animals, termination of access to cocaine
after long-term unrestricted intravenous
self-administration produces behavioral
disruptions and reward deficits believed to be
indicative of dependence and withdrawal
(Markou and Koob 1991). Therefore, this
model was employed in conjunction with
intracranial microdialysis to study the
neurochemical consequences of long-term
cocaine self-administration and cocaine
withdrawal.
Dopamine.
Cocaine self-administration
produced persistent elevations in
extracellular DA concentrations in the NAc
that remained stable throughout 12- to
24-hour periods of drug availability.
Withdrawal from cocaine resulted in a marked
suppression of DA release below basal
levels prior to self-administration (Weiss et al.
1992b). Maximal inhibition of DA efflux was
reached within 2 to 4 hours postcocaine, and
the depression in extracellular DA levels did
not recover within a 12-hour monitoring
period. The degree of suppression of DA
release was positively correlated with the
number of hours of continuous cocaine
self-administration before withdrawal.
Interestingly, as shown in earlier work,
deficits in brain stimulation reward also
increased as a function of the duration of
continuous self-administration prior to
withdrawal and were reversible by
administration of bromocriptine (Markou and
Koob 1991, 1992; Weiss et al. 1995). These
data implicate a link between the
withdrawal-associated impairment in
mesolimbic DA neurotransmission and
behavioral abstinence symptoms as
measured by attenuated brain stimulation
reward. However, it is important to note that
brain stimulation reward deficits are already
evident shortly after termination of access to
cocaine, at a time when there is still some
residual elevation, rather than a deficit, in
accumbal extracellular DA levels. This
observation supports the hypothesis that
sustained dopaminergic stimulation by
long-term cocaine self-administration leads to
adaptation of brain mechanisms that mediate
positive reinforcement.
Serotonin.
Cocaine self-administration not
only increases extracellular DA levels in the
NAc but also produces similar elevations in
extracellular serotonin (5-HT). Given the
established role of 5-HT in depression, a
prominent cocaine withdrawal symptom, it
was of interest to determine whether cocaine
withdrawal exerts disruptive effects on 5-HT
neurotransmission.
Withdrawal after 12 hours of unrestricted
access to cocaine produced a substantial
suppression of 5-HT release in the NAc.
Compared with basal 5-HT levels in
cocaine-naive controls, 5-HT efflux as
measured by quantitative microdialysis
methods decreased by more than 50 percent
as early as 6 hours postcocaine (Parsons et
al. 1995). In contrast to the serotonergic
deficits after long-term cocaine
self-administration, only a trend toward
suppression of basal 5-HT release was
apparent in rats after 24 hours of abstinence
from daily 3-hour limited-access
self-administration. These findings are
consistent with several reports in the
literature of supersensitivity of 5-HT1a
autoreceptors and increased density of 5-HT
uptake sites after intermittent cocaine
administration, but they also suggest that
marked extracellular consequences of these
presynaptic changes become evident only
after prolonged periods of continuous
cocaine self-administration. Decreased
serotonergic transmission has been
implicated in symptoms of numerous
psychiatric disorders such as depression,
panic disorder, insomnia, impulsiveness, and
aggression-symptoms also associated with
cocaine abstinence. Therefore, the deficit in
extracellular 5-HT concentrations may
contribute directly to many aspects of the
cocaine withdrawal syndrome.
In addition to suppressing the release of 5-HT, withdrawal after long-term access to
intravenous cocaine altered the sensitivity of
5-HT1b receptors. Locomotor activation in
response to a 5-HT1b agonist (RU 24969)
was diminished during the first 2 days of
cocaine withdrawal, while a persistent
rebound supersensitivity to 5-HT1b receptor
activation emerged 1 week after cocaine
withdrawal. The initial subsensitivity is likely
to reflect an adaptive "downregulation" of
5-HT1b receptors that develops during
long-term cocaine self-administration to
compensate for the sustained
cocaine-induced increases in synaptic 5-HT
levels. Conversely, the subsequent
supersensitivity is presumably the result of
sustained extracellular 5-HT deficiency during
cocaine withdrawal. These findings implicate
5-HT1b receptors, both in the cocaine
withdrawal syndrome and in locomotor
sensitization produced by repeated cocaine
administration.
Recent studies have implicated the 5-HT1b
receptor in the acute reinforcing actions of
cocaine. The 5-HT1b agonists produced a
dose-dependent shift to the left in the
dose-effect function for self-administered
cocaine and elevated breaking points for
cocaine on a progressive ratio schedule
(Parsons et al., submitted). The enhancement
of cocaine reward by 5-HT1b receptor
activation appeared to result from an
augmentation in the accumulation of
extracellular DA in the NAc induced by
cocaine, a finding that suggests that 5-HT1b
receptors, via stimulation by endogenous
5-HT, may have a role in cocaine
reinforcement. The subsensitivity of 5-HT1b
receptors during the early withdrawal phase
is, therefore, interesting, not only with regard
to its role in cocaine withdrawal but also with
regard to the general hypothesis that
dependence may result from adaptation of
central reward mechanisms.
Changes In Brain Stress Systems
After Chronic Cocaine
Recently, much attention has been directed at
understanding the role of the
nonneuroendocrine corticotropin-releasing
factor (CRF) system in the central nucleus of
the amygdala (CeA) in the affective
consequences of stress and in withdrawal
from drugs of abuse. The CeA is part of a
complex neural circuitry regulating behavioral
and autonomic responsiveness to stressful
stimuli. In particular, CRF neurons in the CeA
are thought to have an essential role in the
mediation of emotional responses to stress,
such as anxiety. Anxiety and stress-like
symptoms are an integral part of drug
withdrawal syndromes, raising the possibility
that these withdrawal signs may involve
activation of CRF neuronal mechanisms in the
CeA.
Initial findings indicated that acute
intraperitoneal injections of cocaine increase
CRF release in the CeA of rats. This effect
was significantly enhanced by 2 weeks of
daily cocaine pretreatment, implicating CRF
mechanisms in the CeA in cocaine
sensitization as well as in the
cross-sensitization between stress and
psychostimulants (Richter et al. 1995). In
contrast to the effects of noncontingent,
intermittent cocaine administration, however,
CRF release in the CeA was significantly
suppressed by cocaine in self-administering
rats as measured after completion of 2
weeks of cocaine self-administration training.
Moreover, in these animals, cocaine
withdrawal after 12 hours of continuous
access to the drug produced a profound
increase in CRF release, which reached peak
levels of approximately 400 percent of
baseline between 11 and 12 hours
postcocaine (Richter and Weiss, submitted).
These data provide support for involvement
of CRF mechanisms in the CeA in the
motivational effects of cocaine. Central
administration of CRF has stress-like
anxiogenic and activational consequences in
rats that can be effectively reversed by
treatments that interfere with CRF
transmission in the CeA. The effects of
exogenous CRF resemble the behavioral
signs of cocaine withdrawal in animals; these
effects may be comparable to human
withdrawal symptoms such as anxiety,
agitation, irritability, restlessness, and
confusion. Thus, the activation of CRF
release in the CeA during withdrawal may
provide a neurochemical basis for aspects of
the cocaine abstinence syndrome. In
contrast, the suppression of CRF release by
cocaine during the self-administration stage
may implicate attenuation of CRF release in
the CeA as an element in the reinforcing
actions of cocaine. Finally, these data extend
previous observations on the activation of
CRF mechanisms in the CeA during opiate,
ethanol, and cannabinoid withdrawal and
implicate enhanced amygdaloid CRF release
as a common mechanism in symptoms of
anxiety and negative affect that are typically
associated with drug withdrawal syndromes
(de Fonseca et al. 1997; Merlo Pich et al.
1995).
The evidence of a hyperactivity within an
important brain stress regulatory center
during cocaine withdrawal is intriguing in
view of the established role of stress in drug
abuse and dependence. Stress is a major
determinant of relapse in humans and can
increase the intake of psychostimulant drugs;
it can also facilitate the acquisition of
psychostimulant self-administration in
laboratory animals. While many
stress-associated drug-seeking behaviors
may involve activation of the hypothalamic
CRF system and the
hypothalamic-pituitary-adrenal axis, the
present data support an essential role for
amygdalar CRF neurons in drug-seeking
behavior motivated by stress or anxiety
effects related to cocaine abstinence.
Studies examining the interaction between
stress and psychostimulant withdrawal
indicate that, in addition to disturbances in the
brain CRF system, chronic psychostimulant
exposure can disrupt normal stress
responses at other levels. For example, not
only did termination of daily amphetamine
treatment result in a long-lasting deficit in
extracellular DA concentrations in the NAc,
but also stimulation of DA release in response
to restraint stress, which is a typical
response to this stressor in drug-naive
animals, was no longer observed during
amphetamine withdrawal. In fact, restraint
stress produced a persistent reduction in
extracellular DA concentration below basal
levels that were already lowered by
withdrawal from chronic amphetamine
(Weiss et al., in press). Thus, certain forms
of stress may exacerbate the neurochemical
consequences of psychostimulant
withdrawal by further lowering extracellular
DA levels and, thereby, perhaps contribute to
the resumption of drug-seeking behavior and
increased likelihood of relapse associated
with stress. Moreover, the reversal of the
dopaminergic response to immobilization
stress was not confined to acute abstinence
but was still observed at the same magnitude
7 days postamphetamine. This persistent
suppression in DA release after stress may
reflect a disruption of mechanisms that
regulate affective homeostasis, leading to an
impairment in the ability to cope with stress or
emotional challenges. Such defects may
have important implications for emotional
states such as depression or helplessness
and for vulnerability to relapse over a
prolonged abstinence period.
Chronic Cocaine And Behavioral
Plasticity
The data discussed above identify
perturbations in brain reward and stress
systems as an important element in
neuroadaptive changes induced by chronic
cocaine. Another important factor associated
with chronic use of cocaine (and other drugs
of abuse) may involve plasticity within brain
circuitries that mediate conditioning effects or
stimulus-response associations. Indeed, the
classical conditioning of cocaine's
pharmacological effects with specific
drug-associated environmental stimuli is an
important aspect of its behavioral actions.
Cocaine-associated stimuli can mimic the
drug's locomotor-activating effects and
control place preference induced by repeated
pairing of cocaine injections with a specific
environment. The conditioning of cocaine's
rewarding actions with environmental stimuli
has important implications for its abuse
potential. Clinical observations suggest that
stimuli previously associated with availability
or self-administration of the drug can evoke
intense subjective feelings of craving and
can trigger episodes of relapse in abstinent
cocaine abuse patients.
Experimental studies of drug-seeking
behavior associated with drug-related stimuli
in rats indicate that incentive motivational
stimuli associated with cocaine can elicit and
maintain robust cocaine-seeking behavior in
the absence of drug availability. For example,
rats responding for presentation of
conditioned stimuli previously paired with
food or cocaine showed a strong shift in
preference for a cocaine- over a
food-associated stimulus after receiving a
noncontingent "priming" injection of cocaine.
This effect was particularly sensitive to
reversal by a dopamine D1 antagonist,
implicating activation of D1 receptors in the
motivational effects of cocaine under these
conditions.
In rats trained to self-administer cocaine
intravenously, presentation of a discriminative
stimulus previously predictive of cocaine
availability elicited significant and persistent
responding after extended periods of
abstinence and increased DA efflux in the
NAc. The reinstatement of cocaine-seeking
behavior was blocked by both dopamine D1
and D2 antagonists. Together, these
observations implicate activation of
dopaminergic mechanisms in the motivational
effects of drug-associated environmental
stimuli and drug-priming. Moreover, these
data suggest that cocaine-related cues may
exert a "priming" action since, like cocaine,
these stimuli increase extracellular levels of
DA in the NAc.
Summary
It has been proposed that drug addiction is
the result of neuroadaptive processes within
the central nervous system that oppose the
acute reinforcing actions of drugs of abuse
(Koob and Bloom 1988), leading to impairment
in the mechanisms that mediate positive
reinforcement and the emergence of
affective changes such as anxiety,
dysphoria, and depression during
withdrawal. The results reveal perturbations
in DA and 5-HT transmission in the
NAc-neurochemical systems that are
activated by cocaine self-administration and
are deficient during withdrawal-as potential
substrates for these affective changes. In
addition, the results implicate neuroadaptive
changes in extrahypothalamic CRF neurons
and other brain stress circuitries in the
motivational effects of psychostimulant
withdrawal. Finally, it appears that
environmental cues that become conditioned
to the positive reinforcing effects of cocaine
can mimic the pharmacological effect of this
agent and, thereby, can initiate and maintain
cocaine-seeking behavior.
Acknowledgment
This research was supported by National
Institute on Drug Abuse Grant No. DA-07348.
References
Rodriguez de Fonseca, F.; Carrera, M.R.A.;
Navarro,
M.; Koob,
G.F.; and
Weiss, F.
Activation of
corticotropin releasing
factor in
the limbic
system
during
cannabinoid
withdrawal.
Science
276:2050
-2054,
1997.
Koob, G.F., and Bloom, F.E. Cellular and
molecular
mechanisms of
drug
dependence.
Science
242:715-
723,
1988.
Koob, G.F.; Markou, A.; Weiss, F.; and
Schultei
s, G.
Opponent
process
and drug
dependence:
Neurobiological
mechanisms.
Semin
Neurosci
5:351-35
8, 1993.
Markou, A., and Koob, G.F. Postcocaine
anhedonia: An
animal
model of
cocaine
withdrawal.
Neuropsychopharmacolog
y
4:17-26,
1991.
Markou, A., and Koob, G.F. Bromocriptine
reverses
the
elevation
in
intracranial
self-stimulation
thresholds
observed
in a rat
model of
cocaine
withdrawal.
Neuropsychopharmacolog
y
7:213-22
4, 1992.
Pich, E.M.; Lorang, M.; Yeganeh, M.;
Rodriguez de
Fonseca,
F.;
Raber, J.;
Koob,
G.F.; and
Weiss, F.
Increase
of
extracellular
corticotropin-releasing
factor-like
immunoreactivity
levels in
the
amygdala
of awake
rats
during
restraint
stress
and
ethanol
withdrawal
as
measured by
microdialysis. J
Neurosci
15:5439-
5447,
1995.
Parsons, L.H.; Kerr, T.M.; Weiss, F.; and
Koob,
G.F.
Serotonin
-1B
receptor
stimulation
enhances
cocaine
reinforcement:
Behavioral and
neurochemical
studies in
rats. J
Neurosci,
submitted.
Parsons, L.H.; Koob, G.F.; and Weiss, F.
Serotonin
dysfunction in the
nucleus
accumbens of
rats
during
withdrawal
after
unlimited
access
to
intravenous
cocaine.
J
Pharmac
ol Exp
Ther
274:1182
-1191,
1995.
Richter, R.M.; Pich, E.M.; Koob, G.F.; and
Weiss, F.
Sensitization of
cocaine-stimulated
increase
in
extracellular
levels of
corticotropin-releasing
factor
from the
rat
amygdala
after
repeated
administration as
determined by
intracranial
microdialysis.
Neurosci
Lett
187:169-
172,
1995.
Richter, R.M., and Weiss, F. In vivo CRF
release
in rat
amygdala is
increased during
withdrawal
after
cocaine
self-administration
with
unlimited
access.
J
Neurosci,
submitted.
Weiss, F.; Hurd, Y.L.; Ungerstedt, U.; Markou,
A.;
Plotsky,
P.M.; and
Koob,
G.F.
Neurochemical
correlates of
cocaine
and
ethanol
self-administration
. In: The
Neurobiology of
Drug and
Alcohol
Addiction.
Kalivas,
P.W., and
Samson,
H.H.,
eds. Ann
N Y Acad
Sci
654:220-
241,
1992a.
Weiss, F.; Imperato, A.; Casu, M.A.; Mascia,
M.S.; and
Gessa,
G.L.
Opposite
effects
of stress
on
dopamine
release
in the
limbic
system
of
drug-naive and
chronically
amphetamine-treated rats.
Eur J
Pharmacol
337:219-
222,
1997.
Weiss, F.; Markou, A.; Lorang, M.T.; and
Koob,
G.F.
Basal
extracellular
dopamine
levels in
the
nucleus
acumbens are
decreased
during
cocaine
withdrawal
after
unlimited-
access
self-administration
. Brain
Res
593:314-
318,
1992b.
Weiss, F.; Parsons, L.H.; and Markou, A.
Neurochemistry of
cocaine
withdrawal.
In: The
Neurobiology of Cocaine: Cellular and Molecular Mechanisms. Hammer, Jr., R.L., ed. Boca Raton, FL: CRC Press, 1995. pp. 163-180.
Wise, R.A. Neurobiology of addiction. Curr Opin Neurobiol6:243-251, 1996.
[NIDA Home] [Contents] [Next Section] [Previous Section]
|