Original Article ADDICTIVE
DISORDERS
Neurobiological Approach to Treatment
of Addiction
Targeting the Syndrome of Anhedonia
O. V. Tcheremissine, MD, and E. M. Krupitsky, MD, PhD
Abstract
Recent models of addiction have provided well-
described, testable theories of addictive behavior.
Drug addiction includes 2 important characteris-
tics, chronic compulsive or uncontrollable drug
use and a withdrawal syndrome when use of the
drug is stopped. The withdrawal syndrome is a
complex phenomenon that presents serious diffi-
culties in definition, measurement, and therapeu-
tics. This article discusses the syndrome of anhe-
donia from the current neurobiological prospec-
tive. In light of new findings, the authors present
their data showing that the pharmacological treat-
ment of the syndrome of anhedonia may offer new
avenues in relapse prevention.
Key Words: addiction, syndrome of anhedonia,
citalopram, memantine, treatment
(Addict Disord Their Treatment 2004;3:43–49)
A major issue facing virtually all areas of
clinical psychiatry is the gap between re-
search and practice and the associated call
for clinical utility of treatments. This gap is
particularly apparent in an area of substance
abuse treatment. Dramatic advances in the
neurosciences and the behavioral sciences
during the last 2 decades have revolutionized
our understanding of drug abuse and addic-
tion.1 Scientists have identified specific neu-
ral circuits, receptors, and major biochemical
cascades within cell that follow a drug admin-
istration. The effects of a variety of drugs of
abuse on the brain have been studied in acute
and chronic administrations in numerous ani-
mal and human studies. The growing body of
data from clinical and in experimental set-
tings supports the idea that an occasional use
of drugs of abuse is distinct from repeated
drug use and the emergence of chronic drug
43
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TREATMENT
Volume 3, Number 1
March 2004
addiction.2 Not only does acute drug admin-
istration modify brain functions, but pro-
longed or chronic drug use causes pervasive
changes in brain functions that persist long
after the drug administration. Significant ef-
fects of chronic use have been identified for
many drugs at all levels: molecular, cellular,
and functional.3,4
This line of research provided a solid
basis for a conclusion that virtually all drugs
of abuse have common effects, either directly
or indirectly, on a single neuronal pathway.
This pathway is the mesolimbic reward sys-
tem.2,5–7 Activation of this system is a com-
mon element in what keeps drug users taking
drugs. This mechanism is not unique to any
drugs of abuse or class of drugs in particular.
The mesolimbic dopamine system has been
extensively investigated as a critical neural
substrate for the rewarding actions of drugs
of abuse and as a site in the brain where From the Human
Psychopharmacology Laboratory,
drugs induce plasticity to cause addiction.8–11 Department of Psychiatry and
Perhaps this view is too compartmentalized Behavioral Science, University of
Texas,-Houston Health Science
given the attention to the complexity of ad- Center (Dr Tcheremissine); and
dictive behavior. Drugs of abuse have been the St. Petersburg Research
Center of Addiction and
shown to produce molecular and cellular ad-
Psychopharmacology, affiliated
aptations in many brain regions, which sug- with St. Petersburg State Pavlov
gests that drug-induced plasticity well out- Medical University, Russia (Dr
Krupitsky).
side of the mesolimbic dopamine system
Reprints: Oleg V. Tcheremissine,
likely contributes to all aspects of addic- MD, Department of Psychiatry
tion.12–15 and Behavioral Science,
Neuroadaptive changes induced by University of Texas,-Houston
Health Science Center, 1300
chronic drug and alcohol use have been im- Moursund Street, Houston,
plicated in affective dysregularities, anxiety, Texas 77030-3497 (e-mail:
Oleg.V.Tcheremissine@
and increased sensitivity to stress, symptoms uth.tmc.edu).
that emerge during withdrawal and may mo- Copyright © 2004 by
tivate continued drug use or contribute to Lippincott Williams & Wilkins
44 ADDICTIVE Tcheremissine and Krupitsky
DISORDERS
& THEIR
TREATMENT
Volume 3, Number 1
March 2004 relapse risk during abstinence.16,17 There-
fore, drug addiction can be characterized as a
set of recurring processes (intoxication, with-
drawal, and craving) that lead to the relaps-
ing nature of the disorder. Craving for a drug
is a cardinal feature of addictive disorders and
is a clinically significant phenomenon be-
cause of its potential to trigger drug use and
relapse. Craving is associated with learned re-
sponse that links the drug and its environ-
ment to a drug induced experience, often de-
scribed as pleasurable or intense. The neuro-
anoatomical substrates for consolidation of
this memory are likely to involve amygdala,
hippocampus, but activation of the thalamo-
orbitofrontal circuit and the anterior cingu-
lated might be a defining element in the ac-
tual experience of craving. Recently, Chil-
dress et al18 have hypothesized that brain
structures activated during cocaine craving
may be among those activated by cocaine it-
self, including the dopamine-innervated lim-
bic regions (the amygdala, anterior cingu-
lated, temporal pole, hippocampus, and orbi-
tofrontal cortex) implicated in cocaine’s
pleasurable effects. In a series of experi-
ments, they tested whether limbic-related re-
gions may be differently activated during cue-
induced cocaine craving by measuring re-
gional blood flow in cocaine-dependent and
cocaine-naive subjects during exposure to
non-drug-related and cocaine-related videos
in a single positron emission tomography
(PET) session. The results, as expected, con-
firmed that the limbic regions demonstrated
a significant increase in regional cerebral
blood flow in response to the cocaine video
within the cocaine subjects group. These
findings in the amygdala are supported by the
recent report of positive correlations be-
tween changes in cue-induced craving and
changes in glucose metabolism (another in-
dex of synaptic activity) in the medial tem-
poral lobe.19 In addition, subjects in the co-
caine group reported a strong desire for a
drug, while cocaine-naive subjects did not re-
port any significant changes.
The findings in the amygdala and ante-
rior cingulate during cue-induced craving
© 2004 Lippincott Williams & Wilkins
were consistent with the importance of these
2 regions in affective behavior and emotional
learning. But if addiction is based on a mecha-
nism of memory similar to those that have
been investigated in invertebrate models,
such as Aplysia and Drosophila, different
treatment strategies of addiction disorders
need to be developed.11 At present, the neu-
roimaging techniques, gene targeting, and
availability of specific agonists increasingly
enrich our understanding of the neurophar-
macology of these disorders and antagonists
modulate processes of neurotransmission. Al-
though current pharmacological treatments
for addiction disorders based on new knowl-
edge are helpful to some patients, for the
most part, the advances in addiction treat-
ment to date have addressed the physical de-
pendence and withdrawal states that accom-
pany some drugs of abuse. The notion of
treating drug dependence with a medication
has been controversial in the past, and there
are many of those who are philosophically
opposed.20 Furthermore, this way of thinking
is reinforced through many administrative
policies and third party payers.20
It is essential to acknowledge that from
a clinical perspective, practitioners are often
concerned with respect to severity of intoxi-
cation and/or physical withdrawal. Perhaps
no clinicians will object to using medications
during these periods of acute distress, espe-
cially given attention to a higher rate of mor-
tality. However, the assessment of the ben-
efits of substance abuse treatments has fo-
cused mainly on abstinence or reduction in
substance use. The impact of this type of
treatment is rather limited because it does
not target the core clinical symptoms of ad-
diction, namely, drug craving and relapse to
drug use even after prolonged abstinence.12
Over time, repeated drug exposure causes
adaptations in the brain’s reward pathways.
Consequently, during periods of active drug
use or shortly after ceasing drug intake, the
ability of natural rewards to activate the re-
ward pathways is diminished, and the indi-
viduals experience depressed mood and lack
of motivation. This period of inability to de-
 Neurobiological Approach to Treatment of Addiction ADDICTIVE
rive pleasure from situations and stimuli that
usually induce pleasure has been described
as a syndrome of Anhedonia (SA).22–24
ANIMAL MODEL OF THE NEGATIVE
AFFECTIVE/MOTIVATIONAL STATE
OR SYNDROME OF ANHEDONIA
High rate of relapse to drug use is the
most difficult clinical problem in the treat-
25
ment of human drug addiction. Therefore, a
major goal of preclinical research in labora-
tory animals is to explore behavioral, envi-
ronmental, and neural mechanisms underly-
ing drug relapse and to test for potential
medications that prevent relapse. Most pre-
clinical research has focused on the reinforc-
ing effects of drugs of abuse and neural
mechanisms mediating these effects,26,27 the
discriminative stimulus effects of drugs,28
and behavioral and neural adaptations result-
ing from repeated non-contingent exposure
to drugs.9 The animal models commonly
used are diverse and are developed originally
based on the behavioral consequences of
drug of abuse, stress, or genetic manipula-
tion.29 Most recently, it has become clear that
a more useful strategy might be to model one
clear-cut behavioral output relevant to the ad-
diction as a disease as opposed to numerous
attempts to model an addictive state, which
involves a variety of behavior, ranging from
craving to intoxication and withdrawal. Ab-
stinence from chronic administration of vari-
ous drugs of abuse (ie, cocaine, opiates, etha-
nol) results in withdrawal syndromes largely
unique to each drug class. These differences
in withdrawal symptoms are expected given
the vastly different pharmacodynamic mech-
anisms of action of sedative/hypnotic, opiate,
and stimulant drug and the unique neuroana-
tomical localization of receptors with which
these different drugs interact. However, one
symptom that appears common to these
withdrawal symptoms is a negative affec-
tive/motivational state or SA. Thus, especially
from a clinical perspective, it is important to
continue to develop animal models of the ef-
fects of withdrawal from prolonged drug ex-
45
DISORDERS
& THEIR
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Volume 3, Number 1
posure, including models of SA, employing March 2004
objective behavior measurements.
In psychiatry, anhedonia is usually de-
fined as lack of interest and pleasure. “Anhe-
donia” can be defined also as the inability to
derive pleasure from normally pleasurable
stimuli.30 The animal model of SA has em-
ployed an intracranial self-stimulation (ICSS)
reward threshold. It is believed that ICSS
thresholds provide a measure of reward be-
cause, operationally, both animals and hu-
mans will work to obtain stimulation of some
parts of their own brain. Furthermore, it is
also argued that ICSS activates the same neu-
ronal substrates that mediate the rewarding
effects of natural reinforcers (eg, water, food)
and of drugs of abuse (eg, stimulants, opiates,
ethanol). Thus, ICSS is a very useful approach
to study of reward (hedonia), anhedonia, and
motivation because it directly activates the
reward system(s), bypassing much of the in-
put side of the circuit. During ICSS paradigm
procedure, rats are allowed to self-administer
a drug abuse for prolonged periods of time,
after which their ICSS thresholds are deter-
mined. The self-administration paradigm al-
lowed animals to self- administer the drug at
doses and rates that are presumably most re-
inforcing to them, paralleling human drug
use. All animals (rats) are implanted with self-
stimulating electrodes in their brains. Rats are
trained in a discrete-trial current-intensity
ICSS threshold procedure; subsequently they
are subjected to chronic drug administration.
This self-stimulation paradigm provides a
quantitative index that serves to assess the
magnitude of withdrawal symptoms as a
time-dependent elevation in ICSS thresholds
is observed following removal from the
abused drug.
Numerous preclinical studies have
shown that after termination of chronic ad-
ministration of different drugs of abuse, in-
cluding D-amphetamine, morphine, nicotine,
phencyclidine (PCP), and ethanol,31–36 rats
exhibited elevated ICSS current thresholds.
Thus, the results suggest that decreased func-
tion of reward systems or SA is a common
element of withdrawal from chronic admin-
46 ADDICTIVE Tcheremissine and Krupitsky
DISORDERS
& THEIR
TREATMENT
Volume 3, Number 1
March 2004 istration of several diverse classes of abused
drugs. This knowledge about underlying
mechanisms of withdrawal could lead to the
discovery of new pharmacological treat-
ments for SA. It is generally recognized that
rigorous experimental analysis of psychopa-
thology in humans is limited, particularly
with respect to elucidating the biologic
mechanisms underlying disorders and in
evaluating the potential efficacy of novel
therapies.
An animal model of psychiatry is espe-
cially valuable if it has face, etiologic, and a
predictive validity.37 That is, if the model ex-
hibits symptoms similar to the human condi-
tion, if it has the same etiology as the human
condition it tries to examine, and if it predicts
phenomena observed in humans. It is impor-
tant to acknowledge that this animal model
of withdrawal from major drugs of abuse has
both face and etiologic validity. The predic-
tive validity of this model is yet to be deter-
mined by evaluating the effect of pharmaco-
logical treatments of SA.
SYNDROME OF ANHEDONIA
IN CLINICAL STUDIES
Germane to this publication, in a clini-
cal sample, we defined affective, cognitive,
and behavioral components of SA.24 The af-
fective component is characterized by symp-
toms of anxiety, irritability, tension, sadness,
nervousness, feelings of unknown psycho-
logic discomfort, loss of interest in many as-
pects of everyday life, lack of motivation, and
disturbance of sleep. The cognitive compo-
nent of SA is represented by thoughts, fanta-
sies, memories, and dreams about drug use.
The behavioral component of SA is often rep-
resented by different activities aimed to ob-
tain drugs of abuse. In addition, we observed
the behavioral component through patients’
interactions involving discussions of previous
experiences of drug use. We developed a
special scale to assess the severity of SA and
each of its 3 components, and demonstrated
that SA persists in recently detoxified heroin
addicts from several weeks to several months
© 2004 Lippincott Williams & Wilkins
and might often be a reason for relapse to
heroin.24
Concerning relapse prevention, most
current addiction treatment interventions
based on classic conditioning focus on the
extinction of subjectively experienced crav-
ing elicited by exposure to a drug-related
stimulus.38 However, to date, it is not clear to
what extent these processes can be modified
by the pharmacological interventions. The
search for novel pharmacologic agents able
to optimize treatment of addiction is an im-
portant component in the prevention of fu-
ture relapses and stabilization of remission.
Previously, we have proposed to initiate the
psychopharmacological interventions during
a period of protracted withdrawal or SA as a
potential new avenue in relapse preven-
tion.39,40 This hypothesis was largely tested
on human participants addicted to heroin.
First of all, we studied citalopram, a selective
serotonin inhibitor (SSRI), as a new pharma-
cologic treatment of SA.39 The choice of an-
tidepressants as possible medication for SA
was based on the fact that depressive symp-
toms are the most prominent features of SA.
In a single blind randomized clinical trial we
compared the effect of citalopram on SA with
the tricyclic antidepressant amitriptyline and
placebo. Immediately after detoxification, 73
heroin addiction patients were randomly as-
signed to 1 of 3 groups: 26 patients received
20 mg/d citalopram during 3 weeks; 24 pa-
tients received 75 mg/d amitriptyline; and 23
patients received placebo. The results of this
randomized, single-blind, placebo-controlled
study showed that both medications, citalo-
pram and amitriptyline, are more effective
than placebo in treatment of SA. However,
patients in the amitriptyline group reported a
statistically greater number of side effects in
comparison with patients in the 2 other
groups.
In spite of the fact that citalopram sig-
nificantly reduced the severity of SA in pa-
tients with heroin addiction, there were no
significant differences between groups in the
dropout rate. Therefore, we continued our
search for more effective medications for SA
 Neurobiological Approach to Treatment of Addiction ADDICTIVE
among N-methyl-D-aspartate (NMDA) recep-
tor antagonists.40 There is a growing body of
evidence suggesting that NMDA receptor an-
tagonists effectively counteract somatic and
behavioral symptoms of the opioid with-
drawal syndrome in humans and in labora-
tory animals.41,42 Based on preclinical data,
NMDA receptor blockade reduces the devel-
opment and expression of drug-conditioned
behaviors.43 The opioid withdrawal is known
to facilitate a wide range of behavior, includ-
ing aggressive behavior. In an animal model
of opioid withdrawal, Sukhotina and Be-
spalov44 demonstrated that two low-affinity
NMDA receptor channel blockers (meman-
tine and MRZ 2/579) dose-dependently re-
duced the expression of aggressive behavior
while having no significant effect on the in-
tensity of non-aggressive social contacts. At
present, there is only 1 NMDA receptor an-
tagonist, memantine, registered for clinical
use in Russia and Europe. Memantine (Akati-
nol, MERZ+Co., Germany) is used in Europe
for the treatment of Parkinson disease and
senile dementias. Memantine also has antide-
pressant-like effects and has a number of ben-
eficial effects in elderly patients.45
The aim of our next study was to evalu-
ate efficacy of memantine in the treatment of
protracted withdrawal (SA) in recently de-
toxified heroin addicts. Following standard
detoxification procedures (7–10 days), 67
heroin addicts were randomly assigned to 1
of 3 treatment groups: memantine, amitryp-
tiline, or placebo. While remaining in-patient,
subjects received one of the following medi-
cations: memantine (initial dose of 10 mg/d
was gradually increased to the final dose of
30 mg/d over a period of 1 week), amitryp-
tiline (75 mg/d), or placebo for a period of 3
weeks. Patients from all treatment groups re-
ceived standard psychotherapy and counsel-
ing and were required to attain abstinence
from heroin by providing heroin-free urine
toxicology screen prior to starting medica-
tions and at the end of each treatment week.
The study design was single blind. Outcome
measures included treatment retention,
heroin craving (Visual Analog Scale), depres-
47
DISORDERS
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Volume 3, Number 1
sion (Zung scale), anxiety (Spielberger scale), March 2004
and anhedonia (Anhedonia syndrome scale)
scores. Results of this study showed that both
memantine and amitryptiline significantly re-
duced heroin craving, depression, state and
trait anxiety, and anhedonia scores at the end
of the 3-week treatment period, while pla-
cebo did not have any significant effects. The
drop-out rate in the memantine group was
significantly lower than that in either the pla-
cebo or amitryptiline groups. The average
number of side effects was higher in the ami-
tryptiline group compared with other groups.
Thus, memantine appears to be an effective
and safe medication for protracted withdrawal
(SA) and relapse prevention in recently detoxi-
fied heroin addicts. These data provide a ratio-
nale for further studies on the use of meman-
tine in heroin dependence treatment.40
CONCLUSIONS
Affective dysregulations, including SA,
increase chances of individuals with history
of drug dependence to relapse and, there-
fore, might be identified as potential thera-
peutic targets.
With regard to a neural basis for the
affective symptoms of withdrawal from drugs
of abuse, Koob and Bloom46 have argued that
as dependence develops, neuroadaptations
occur within the same brain circuits that me-
diate the reinforcing or rewarding effects of
these drugs following chronic administra-
tion, leading to the expression of negative
affective signs of withdrawal upon drug ab-
stinence. The growing body of data suggests
that withdrawal from ethanol, opiates, PCP,
cocaine, and amphetamines may lead to simi-
lar alterations in reward circuitry. For ex-
ample, cocaine withdrawal is accompanied
by decreases in dopamine release in the
nucleus accumbens, and the time course of
this alteration in dopamine transmission cor-
relates with the course of ICSS threshold el-
evations produced by cocaine withdrawal.32,47
Withdrawal from opiates and ethanol also re-
sults in decreases in dopamine transmission
in the nucleus accumbens. Whether such
changes in dopamine transmission are suffi-
48 ADDICTIVE Tcheremissine and Krupitsky
DISORDERS
& THEIR
TREATMENT
Volume 3, Number 1
March 2004 cient to produce changes sufficient to ac-
count for the negative affective state con-
sequences of withdrawal is not known.
Furthermore, it is possible that other neuro-
transmitter systems within the brain reward
circuitry may also contribute to these effects.
In the general search for effective pharmaco-
logical interventions in addictive disorders,
our clinical data demonstrate that pharmaco-
logical agents with vastly different mecha-
nisms of action (ie, SSRI and NMDA receptor
antagonists) produce similar clinical results
in terms of improvement of the symptoms of
affective dysregularities.
In conclusion, identification of the
mechanisms that are involved in neuroadap-
tations within brain circuitry in response to
the chronic administration of drugs of abuse,
and pharmacological agents able to modify
these changes may provide a key for a better
understanding of addiction and more suc-
cessful treatment approaches not only to ad-
dictive disorders but also to other psychopa-
thologies of mood and affect.
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