(2) 1 page article reviews

Understanding the changes in the brain which occur in the transition from normal to addictive behavior has major implications in public health. Here we postulate that while reward circuits (nucleus accumbens, amygdala), which have been central to theories of drug addiction, may be crucial to initiate drug self-administration, the addictive state also involves disruption of circuits involved with compulsive behaviors and with drive. We postulate that intermittent dopaminergic activation of reward circuits secondary to drug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit. This is supported by imaging studies showing that in drug abusers studied during protracted withdrawal, the orbitofrontal cortex is hypoactive in proportion to the levels of dopamine D2 receptors in the striatum. In contrast, when drug abusers are tested shortly after last cocaine use or during drug-induced craving, the orbitofrontal cortex is hyper- metabolic in proportion to the intensity of the craving. Because the orbitofrontal cortex is involved with drive and with compulsive repetitive behaviors, its abnormal activation in the addicted subject could explain why compulsive drug self-administration occurs even with tolerance to the pleasurable drug effects and in the presence of adverse reactions. This model implies that pleasure per se is not enough to maintain compulsive drug administration in the drug- addicted subject and that drugs that could interfere with the activation of the striato-thalamo-orbitofrontal circuit could be beneficial in the treatment of drug addiction.

Research on drug addiction has focused on the mechanism

underlying the reinforcing effects of drugs of abuse. This

research has led to the identification of neuronal circuits and

neurotransmitters involved with drug reinforcement. Of particu-

lar relevance to drug reinforcement is the dopamine (DA)

system. It has been postulated that the ability of drugs of abuse

to increase DA in limbic brain regions (nucleus accumbens,

amygdala) is crucial for their reinforcing effects (Koob and

Bloom, 1988; Pontieri et al., 1996). However, the role of DA in

drug addiction is much less clear. Also, while the reinforcing

effects of drugs of abuse may explain the initial drug-taking

behavior, reinforcement per se is insufficient in explaining the

compulsive drug intake and the loss of control in the addicted

subject. In fact, self-administration of drugs occurs even when

there is tolerance to the pleasurable responses (Fischman et al.,

1985) and sometimes even in the presence of adverse drug

effects (Koob and Bloom, 1988). It has been postulated that drug

addiction is the result of changes in the DA system and in the

reward circuits involved in drug reinforcement secondary to

chronic drug administration (Dackis and Gold, 1985; Epping-

Jordan et al., 1998). However, it is also possible that brain

circuits other than those regulating the pleasurable responses to

drugs of abuse are involved with drug addiction.

In analyzing which circuit(s) other than those involved with

reward processes are involved with addiction it is important to

realize that the key symptoms of drug addiction in humans are

compulsive drug intake and the intense drive to take the drug at

the expense of other behaviors (American Psychiatric Associa-

tion, 1994). We therefore postulate that circuits involved with

drive and perseverative behaviors are involved with drug

addiction. More specifically we postulate that intermittent DA

stimulation secondary to chronic drug use leads to disruption

of the orbitofrontal cortex via the striato-thalamo-orbitofrontal

circuit, which is a circuit involved in regulating drive (Stuss

and Benson, 1986). The dysfunction of this circuit results in the

compulsive behavior in addicted subjects and the exaggerated

motivation to procure and administer the drug regardless of

its adverse consequences. This hypothesis is corroborated by

imaging studies showing disruption of striatal, thalamic and

orbitofrontal brain regions in drug abusers (Volkow et al.,

1996a). This review summarizes those studies concentrating

primarily in the orbitofrontal cortex and on studies of cocaine

and alcohol addiction. This review also provides a brief descrip-

tion of the anatomy, function and pathology of the orbitofrontal

cortex that is relevant to addiction and proposes a new model

of drug addiction that invokes both conscious (craving, loss of

control, drug preoccupation) and unconscious processes (con-

ditioned expectation, compulsivity, impulsivity, obsessiveness)

which result from dysfunction of the striato-thalamo-orbito-

frontal circuit.

Anatomy and Function of the Orbitofrontal Cortex Relevant to Addiction The orbitofrontal cortex is an area that is neuronatomicaly

connected with brain areas known to be involved with the

reinforcing effects of drugs of abuse. More specifically, the

nucleus accumbens, which is considered to be the target for

the reinforcing effects of drugs of abuse (Koob and Bloom, 1988;

Pontieri et al., 1996), projects to the orbitofrontal cortex via the

mediodorsal nucleus of the thalamus (Ray and Price, 1993). In

turn, the orbitofrontal cortex provides dense projections to the

nucleus accumbens (Haber et al., 1995). The orbitofrontal

cortex also receives direct projections from DA cells in the

ventral tegmental area (Oades and Halliday, 1987), which is the

DA nucleus associated with drug reinforcing effects (Koob and

Bloom, 1988). In addition, the orbitofrontal cortex also receives

direct and indirect (via thalamus) projections from other limbic

brain regions known to be involved with drug reinforcement,

such as amygdala, cingulate gyrus and hippocampus (Ray and

Price, 1993; Carmichael et al., 1995). This makes the orbito-

frontal cortex not only a direct target for the effects of drugs of

abuse but also a region that could integrate information from

various limbic areas and, because of its reciprocal connections, a

region that in turn could also modulate the response of these

limbic brain regions to drug administration (Fig. 1).

Among the various functions of the orbitofrontal cortex, its

role in reward-related behaviors are of most relevance when

Addiction, a Disease of Compulsion and Drive: Involvement of the Orbitofrontal Cortex

Nora D. Volkow1,3 and Joanna S. Fowler2

1 Medical and

2 Chemistry Departments, Brookhaven National

Laborator y, Upton, N Y 11973 and 3 Department of Psychiatry,

SUN Y-Stony Brook, Stony Brook, N Y 11794, USA

Cerebral Cortex Mar 2000;10:318–325; 1047–3211/00/$4.00© Oxford University Press 2000

analyzing its potential involvement in drug addiction. To start

with, in laboratory animals placement of stimulation electrodes

into the orbitofrontal cortex readily induces self-stimulation

(Phillips et al., 1979). These effects appear to be modulated by

DA since they are blocked by the administration of DA receptor

antagonists (Phillips et al., 1979). It is also well recognized that

the orbitofrontal cortex, in addition to processing information

about the rewarding properties of stimuli (Aou et al., 1983;

Tremblay and Schulz, 1999), is also involved in modifying an

animal’s behavior when the reinforcing characteristics of these

stimuli change (Thorpe et al., 1983) and in learning stimulus–

reinforcement associations (Rolls, 1996; Schoenbaum et al.,

1998). Though these functions have been characterized for

physiological reinforcers such as food (Aou et al., 1983), it

is likely that they subser ve a similar role for pharmacological

reinforcers.

In laborator y animals damage of the orbital frontal cortex

results in impairment of reversal of stimulus–reinforcement

associations, and leads to perseveration and resistance to extinc-

tion of reward-associated behaviors (Butter et al., 1963; Johnson,

1971). This is reminiscent of what happens to drug addicts who

frequently claim that once they start taking the drug they cannot

stop even when the drug is no longer pleasurable.

Another function of relevance for this review is the involve-

ment of the orbitofrontal cortex in motivational states (Tucker et

al., 1995). Because it is believed that striato-cortical circuits are

important in the inhibition of common responses in contexts in

which they are not adequate (Marsden and Obeso, 1994), the

dysfunction of the striato-thalamo-orbitofrontal circuit second-

ary to chronic drug use could participate in the inappropriately

intense motivation to procure and self-administer the drug in

addicted subjects.

However, very few animal studies have directly investigated

the role of the orbitofrontal cortex in drug reinforcement. This

subject is covered in greater detail elsewhere (Porrino and Lyons,

2000). Here we want to note that these studies implicate the

orbitofrontal cortex on the conditioned responses that drugs of

abuse elicit. For example, rats exposed to an environment in

which they had previously received cocaine showed activation

of the orbitofrontal cortex but not the nucleus accumbens

(Brown et al., 1992). A lso rats with lesions of the orbital frontal

cortex do not show cocaine-conditioned place preference (Isaac

et al., 1989). Similarly lesions of the thalamic mediodorsal

nucleus (including the paraventricular nucleus) have been

shown to disrupt conditioned reinforced behaviors (Mc A lona

et al., 1993; Young and Deutch, 1998) and to attenuate cocaine

self-administration (Weissenborn et al., 1998). This is relevant

because conditioned responses induced by drugs of abuse have

been implicated in the craving elicited in humans by exposure

to stimuli associated with the drug administration (i.e stress,

money, syringes, street) (O’Brien et al., 1998). This craving

response, in turn, is one of the factors that contributes to relapse

in drug abusers (McKay, 1999).

We also want to note that in DA transporter knockout mice,

self-administration of cocaine results in activation of the

orbitofrontal cortex (Rocha et al., 1998). This latter finding

is particularly intriguing in that in these animals drug self-

administration was not associated with activation of the nucleus

accumbens, which is recognized as the target for the reinforcing

effects of drugs of abuse. Thus this study suggests the import-

ance of the orbitofrontal cortex in maintaining drug self-adminis-

tration under conditions in which the nucleus accumbens is not

necessarily activated.

Though not for drug-related stimuli, imaging studies in human

subjects have also corroborated the involvement of the orbito-

frontal cortex in reinforced behaviors and in conditioned

responses. For example, activation of the orbitofrontal cortex

in human subjects has been reported when performance in a

cognitive task is associated with monetar y reward but not

when it is not (Thut et al., 1997), and also when expecting a

conditioned stimulus (Hugdahl et al., 1995).

Orbitofrontal Cortex Pathology in Human Subjects In humans, pathology in the orbitofrontal cortex and striatum

has been reported in patients with obsessive compulsive

disorders (Baxter et al., 1987; Modell et al., 1989; Insel, 1992),

which share with addiction the compulsive quality of the behav-

ior. Moreover, in patients with Tourette’s syndrome, obsessions,

compulsions and impulsivity, all of which are behaviors present

in drug addiction, were found to be associated with increases

in metabolic activity in the orbitofrontal cortex and striatum

(Braun et al., 1995). A lso a recent case report on a patient with a

vascular lesion of the orbitofrontal cortex describes a syndrome

of compulsive illegal car borrowing that led to frequent in-

carceration and that was described by the subject as inducing a

pleasurable relief (Cohen et al., 1999).

Of interest for this review are also reports implicating the

thalamus with compulsive behaviors. Noteworthy are clinical

case studies describing compulsive self-stimulation in patients

with stimulating electrodes implanted in the thalamus (Schmidt

et al., 1981; Portenoy et al., 1986). The compulsive self-

stimulation in these patients was described as reminiscent of the

compulsive drug self-administration seen in addicted subjects.

Imaging Studies in Substance Abusers Most of the imaging studies involved with addiction have used

positron emission tomography (PET) in conjunction with 2-

deoxy-2-[ 18

F]f luoro-D-glucose, an analog of glucose, to measure

regional brain glucose metabolism. Because brain glucose

metabolism serves as an indicator of brain function, this strategy

allows mapping of the brain regions that change as a function of

drug administration or of drug withdrawal and enables the

identification of any correspondences between changes in

regional brain function and symptoms in drug abusers. However,

various molecular targets involved in DA neurotransmission and

that of other neurotransmitters, such as receptors, transporters

and enzymes, have also been investigated. The relatively low

radiation dose from the positron emitters has allowed the

measurement of more than one molecular target in a given

subject.

Figure 1. Neuroanatomic diagram of the connections of the orbitofrontal cortex that are pertinent for drug reinforcement and addiction. VTA = ventral tegmental area, NA = nucleus accumbens, TH = thalamus, OFC = orbitofrontal cortex.

Cerebral Cortex Mar 2000, V 10 N 3 319

Imaging Studies in Cocaine Addiction

Activity of the Orbitofrontal Cortex during

Detoxification

Studies assessing changes at different times after detoxification

have been carried out on cocaine abusers and alcoholic subjects.

In the case of cocaine abusers, these studies have shown that

during early withdrawal (within 1 week of last cocaine use)

metabolism in the orbitofrontal cortex and striatum was sig-

nificantly higher than that in controls (Volkow et al., 1991).

The metabolism in the orbitofrontal cortex was significantly

correlated with the intensity of the craving; the higher the

metabolism, the more intense the craving.

In contrast, cocaine abusers studied during protracted

withdrawal had significant reductions in several frontal regions,

including the orbitofrontal cortex and anterior cingulate gyrus,

when compared with non-abusing controls (Volkow et al.,

1992). These decreases persisted even when subjects were

re-tested 3–4 months after the initial detoxification period.

Dopamine and the Activity of Orbitofrontal Cortex

To test if the disruptions in activity of the orbitofrontal cortex

and anterior cingulate gyrus in the detoxified cocaine abusers

were due to changes in DA brain activity, we examined the

relationship between changes in DA D2 receptors and changes

in regional metabolism. When compared with controls, cocaine

abusers (within 1 month of last cocaine use) showed signifi-

cantly lower DA D2 receptor levels in the striatum and these

reductions persisted 3–4 months after detoxification. Decreases

in striatal D2 receptor levels were associated with decreased

metabolism in the orbitofrontal cortex and in the anterior

cingulate gyrus (Volkow et al., 1993a). Subjects with the lowest

levels of D2 receptors showed the lowest metabolic values in

these brain regions (Fig. 2).

The association of metabolism in the orbitofrontal cortex and

cingulate gyrus with striatal DA D2 receptors was interpreted as

ref lecting either an indirect regulation by DA of these regions via

striato-thalamo-cortical projections (Nauta, 1979; Heimer et al.,

1985; Haber, 1986) or the cortical regulation of striatal DA D2

receptors via cortico-striatal pathways (Le Moal and Simon,

1991). The former case would imply a primary defect in DA

pathways whereas the latter would imply a primary defect in

the orbitofrontal cortex and in the cingulate gyrus in cocaine

abusers.

Because the reductions in metabolism in the orbitofrontal

cortex and cingulate gyrus in cocaine abusers were correlated

with D2 receptor levels it was of interest to assess if increasing

synaptic DA activity could reverse these metabolic changes. For

this purpose a study was done that evaluated the effects of

DA increases (achieved by the administration of the psycho-

stimulant drug methylphenidate) on regional brain glucose

metabolism in detoxified cocaine abusers. Methylphenidate

(MP) increased metabolism in the anterior cingulate gyrus,

Figure 3. Regional brain metabolic images of a cocaine abuser in whom methylphenidate induced intense craving and one in whom it did not. Notice the activation of the right orbitofrontal cortex (R OFC) and of the right putamen (R PUT) in the subject reporting intense craving.

Figure 2. Relationship between regional brain glucose metabolism in cingulate gyrus (r = 0.64, df 24, P < 0.0005) and orbitofrontal cortex (r = 0.71, df 24, P < 0.0001) and dopamine D2 receptor availability (Ratio Index) in the striatum in detoxified cocaine abusers.

320 The Orbitofrontal Cortex and Drug Addiction • Volkow and Fowler

right thalamus and cerebellum. In addition, in cocaine abusers

in whom MP induced significant levels of craving (but not in

those in whom it did not) MP increased metabolism in the right

orbitofrontal cortex and right striatum (Fig. 3).

The increase in metabolic activity in the cingulate gyrus after

MP administration suggests that its hypometabolism in cocaine

abusers ref lects in part decreased DA activation. In contrast, MP

only increased metabolism in the orbitofrontal cortex in those

subjects in whom it enhanced craving. This would suggest that

hypometabolic activity of the orbitofrontal cortex in the

detoxified cocaine abusers is likely to involve disruption of other

neurotransmitters apart from DA (i.e glutamate, serotonin,

GABA). This would also suggest that while DA enhancement may

be necessar y it is not sufficient by itself to activate the

orbitofrontal cortex.

Since the orbitofrontal cortex is involved with the perception

of salience of reinforcing stimuli, the differential activation of

the orbitofrontal cortex in subjects that reported intense craving

could ref lect its participation as a function of the perceived

reinforcing effects of MP. However, because orbitofrontal cortex

activation has also been linked with expectation of a stimulus

(Hugdahl et al., 1995), its activation in subjects in whom MP

induced craving could ref lect the expectation in these subjects

of receiving another dose of MP. Moreover, the activation of

a circuit that signals an expected reward may be consciously

perceived as craving. That the correlation with craving was also

observed in the striatum most likely ref lects its neuroanatomical

connections with the orbitofrontal cortex via the striato-thalamo-

orbitofrontal circuit (Johnson et al., 1968).

Activation of the orbitofrontal cortex by MP, a drug pharmaco-

logically similar to cocaine (Volkow et al., 1995), may be one

of the mechanisms by which cocaine elicits craving and the

subsequent compulsive dr ug administration in the addicted

subject.

The Orbitofrontal Cortex and Cocaine Craving

Hyperactivity of the orbitofrontal cortex appears to be

associated with self-reports of cocaine craving. This was noted,

as described in the previous sections, in cocaine abusers tested

shortly after last use of cocaine and when MP administration

resulted in an increase in the intensity of the craving.

Activation of the orbitofrontal cortex has also been demon-

strated in studies that were designed to assess the brain regions

that became activated during exposure to stimuli designed to

elicit cocaine craving. For one study cocaine craving was elicited

by a cocaine theme interview (preparation of cocaine for self-

administration). Regional brain glucose metabolism during the

cocaine theme inter view was compared with that during a

neutral theme interview (family genogram). The cocaine theme

interview significantly increased metabolism in the orbitofrontal

cortex and left insular cortex when compared with the neutral

theme interview (Wang et al., 1999). Increased metabolism of

the orbitofrontal cortex in addition to activation in the amygdala,

prefrontal cortex and cerebellum was also reported in a study

that used a videotape of cocaine scenes designed to elicit craving

(Grant et al., 1996). However, a study that measured changes in

cerebral blood f low (CBF) in response to a videotape of cocaine

reported activation of the cingulate gyrus and the amygdala but

not of the orbitofrontal cortex during craving (Childress et al.,

1999). The reason for this failure to detect activation of the

orbitofrontal cortex is unclear.

Dopamine Stimulation, the Thalamus and Cocaine

Craving

Changes in DA concentration in the human brain can be tested

with PET using [ 11

C]raclopride, a ligand whose binding to the

DA D2 receptor is sensitive to competition with endogenous

DA (Ross and Jackson, 1989; Seeman et al., 1989; Dewey et

al., 1992). This is done by measuring changes in the binding of

[ 11

C]raclopride induced by pharmacological interventions (i.e.

MP, amphetamine, cocaine). Because [ 11

C]raclopride binding

is highly reproducible (Nordstrom et al., 1992; Volkow et al.,

1993b) these reductions primarily ref lect changes in synaptic

DA in response to the drug. Note that for the case of MP, which

increases DA by blocking the DA transporter (Ferris et al., 1972),

the changes in DA are a function not only of the levels of

transporter blockade but also of the amount of DA that is

released. If similar levels of DA transporter blockade are induced

across two groups of subjects, then differences in the binding of

[ 11

C]raclopride are mostly due to differences in the release of

DA. Using this strategy it has been shown that with aging there is

a decrease in striatal DA release in healthy human subjects

(Volkow et al., 1994).

Comparison of the responses to MP between cocaine abusers

and controls revealed that MP-induced decrements in [ 11

C]raclo-

pride binding in the striatum in the cocaine abusers were less

than half of that seen in the controls (Volkow et al., 1997a).

In contrast, in the cocaine abusers, but not in the controls,

MP significantly decreased binding of [ 11

C]raclopride in the

thalamus (Fig. 4a). MP-induced decreases in [ 11

C]raclopride

binding in the thalamus, but not in the striatum, were associated

with MP-induced increases in self-reports of craving (Fig. 4b).

This was intriguing since DA inner vation of the thalamus is

mainly limited to the mediodorsal and paraventricular nuclei,

which are relay nuclei to the orbitofrontal cortex and cingulate

gyrus respectively (Groenewegen, 1988), and since there is

significant binding of cocaine and MP in the thalamus (Wang et

al., 1993; Madras and Kaufman, 1994). It was also intriguing

in that the normal controls did not show a response in the

thalamus, which if anything would point to an abnormally

enhanced thalamic DA pathway in the addicted subjects. Thus,

one could speculate that in the addicted subject abnormal

activation of the DA thalamic pathway (presumably mediodorsal

nucleus) could be one of the mechanisms that enables the

activation of the orbitofrontal cortex.

Summary of Imaging Studies in Cocaine Abusers

Imaging studies have provided evidence of abnormalities in the

striatum, thalamus and orbitofrontal cortex in cocaine abusers.

Figure 4. (A) Effects of methylphenidate (MP) on binding of [11C]raclopride in thalamus (Bmax/Kd) in controls and in cocaine abusers. (B) Relationship between MP-induced changes in Bmax/Kd in thalamus and MP-induced changes in self-reports of craving in the cocaine abusers (r = 61, df, 19, P < 0.005).

Cerebral Cortex Mar 2000, V 10 N 3 321

In the striatum, cocaine abusers show both a decrease in the

levels of DA D2 receptors as well as a blunted release of DA. In

the thalamus, cocaine abusers show an enhanced responsivity of

the DA thalamic pathway. In the orbitofrontal cortex, cocaine

abusers show hyperactivity shortly after the last use of cocaine

and also during experimentally induced drug craving and

hypoactivity during withdrawal, which is associated with

reductions in striatal DA D2 receptors. We speculate that the

striatal reduction in DA release and in DA D2 receptors results in

a decreased activation of reward circuits that leads to hypo-

activity of the cingulate gyrus and may contribute to that of the

orbitofrontal cortex.

Imaging Studies in Alcoholism

Activity of the Orbitofrontal Cortex during

Detoxification

Multiple studies have been carried out to assess metabolic

changes in alcoholic subjects during detoxification. Most studies

have consistently shown a reduction in frontal metabolism,

including the anterior cingulate gyrus and orbitofrontal cortex,

in alcoholic subjects. Though studies have shown a significant

recovery on the baseline measures of metabolism with alcohol

detoxification, when compared with controls, alcoholics still

had significantly lower metabolism in orbitofrontal cortex and in

anterior cingulate gyrus (Volkow et al., 1997b). Similarly studies

performed with single photon emission computed tomography

have shown significant decreases in CBF in orbitofrontal cortex

in alcoholics subjects during detoxification (Catafau et al.,

1999). The fact that the orbitofrontal cortex changes were

present 2–3 months after detoxification (Volkow et al., 1997b)

indicates that they are not a function of withdrawal from alcohol

but represent longer lasting changes. Moreover, the fact that

in rats repeated intoxication with alcohol leads to neuronal

degeneration in the orbital frontal cortex (Corso et al., 1998)

brings up the possibility that the persistent hypometabolism in

the orbitofrontal cortex in the alcoholics may ref lect alcohol’s

neurotoxic effects.

Dopamine and the Activity of the Orbitofrontal Cortex

Disruption of the striato-thalamo-orbitofrontal has also been

proposed to participate in the craving and loss of control in

alcoholism (Modell et al., 1990). While PET studies have

documented significant reductions in DA D2 receptors in

alcoholics when compared with controls (Volkow et al., 1996b),

no study has been done to determine if there is a relation

between the decrements in D2 receptors and the changes in

metabolic activity in the orbitofrontal cortex in alcoholic

subjects.

Though DA is of relevance in the reinforcing effects of alcohol

(El-Ghundi et al., 1998), its effects in other neurotransmitters

(opiates, NMDA, serotonin, GABA) have also been implicated in

its reinforcing and addictive effects (Lewis, 1996).

GABA and the Activity of the Orbitofrontal Cortex

The effect of alcohol on GABA neurotransmission is of particular

interest in that at the doses abused by humans, alcohol facilitates

GA BA neurotransmission. It has also been hypothesized that

alcohol addiction is the result of decreased GABA brain function

(Coffman and Petty, 1985). However, it is unclear how changes

in GABA brain function could contribute to addictive behaviors

in alcoholic subjects. PET has been used to study the brain GABA

system by measuring the regional brain metabolic changes

induced by an acute challenge with a benzodiazepine drug —

since benzodiazepines, like alcohol, also facilitate GABA neuro-

transmission in brain (Hunt, 1983) — and by directly measuring

the concentration of benzodiazepine receptors in the human

brain.

The regional brain metabolic response to lorazepam in

recently detoxified alcoholic subjects has been compared

with that in healthy controls. Lorazepan decreases whole-brain

glucose metabolism to the same extent in normal and alcoholic

subjects (Volkow et al., 1993c). However, alcoholic subjects

showed significantly less of a response than controls in thal-

amus, striatum and orbitofrontal cortex. These findings were

interpreted as ref lecting a decreased sensitivity to inhibitory

neurotransmission in the striato-thalamo-orbitofrontal circuit in

alcoholics during early detoxification (2–4 weeks af ter last

alcohol use). A subsequent study assessed the extent to which

these blunted responses normalized with protracted detoxifica-

tion. This study showed that even after protracted detoxification

(8–10 weeks after detoxification) alcoholics had a blunted

response in the orbitofrontal cortex when compared with

controls (Volkow et al., 1997b). This suggests that the hypo-

responsivity of the orbitofrontal cortex is not just a function of

alcohol withdrawal but could ref lect a regionally specific

decrease in sensitivity to inhibitor y neurotransmission in

alcoholics.

Further evidence of the involvement of GA BA in the long-

lasting functional changes in the orbitofrontal cortex of

alcoholics is also provided by a study that measured levels of

benzodiazepine receptors in the brains of detoxified alcohol

abusers (>3 months detoxification) using [ 123

I]Iomazenil. This

study showed that detoxified alcoholics had significant reduc-

tions in the levels of benzodiazepine receptors in the orbito-

frontal cortex when compared with controls (Lingford-Hughes et

al., 1998). A reduction in the levels of benzodiazepine receptors

in the orbitofrontal cortex could explain the blunted regional

brain metabolic responses to lorazepam administration in this

brain region in the alcoholic subjects. One could postulate that

a consequence of the reduced sensitivity to GABA neurotrans-

mission could be a defect in the ability of inhibitor y signals

to terminate the activation of the orbitofrontal cortex in these

subjects.

Serotonin and the Activity of the Orbitofrontal Cortex

The orbitofrontal cortex receives significant serotonergic

inner vation (Dringenberg and Vanderwolf, 1997) and thus

serotonin abnormalities could also contribute to the abnormal

function of this brain region. Evidence that this may be the case

was provided by a study that measured changes in regional brain

metabolism in response to m-chlorophenylpiperazine (mCPP),

a mixed serotonin agonist/antagonist drug, in alcoholics and

controls. This study showed that mCPP-induced activation in

thalamus, orbitofrontal cortex, caudate and middle frontal

gyrus was significantly blunted in alcoholics when compared

with controls (Hommer et al., 1997). This was interpreted as

ref lecting a hyporesponsive striato-thalamo-orbitofrontal circuit

in alcoholics. The abnormal response to mCPP suggests an

involvement of the serotonin system in the abnormalities seen in

this circuit in alcoholic patients. In support of this is a study

showing reductions in serotonin transporters, which serve as

markers for the serotonin terminals, in the mesencephalon of

alcoholic subjects (Heinz et al., 1998). In this respect it is also

interesting to note that serotonin reuptake inhibitor drugs have

322 The Orbitofrontal Cortex and Drug Addiction • Volkow and Fowler

been shown to be effective in decreasing alcohol intake in

alcoholic subjects (Balldin et al., 1994).

Summary of Imaging Studies in Alcoholics

Imaging studies have provided evidence of abnormalities in the

striatum, thalamus and orbitofrontal cortex in alcoholics. In the

striatum, thalamus and orbitofrontal cortex alcoholics have a

blunted regional brain metabolic response to either GABAergic

or serotonergic stimulation suggestive of hyporesponsiveness in

this circuit. In addition detoxified alcoholics also showed

decreases in metabolism, f low and benzodiazepine receptors in

the orbitofrontal cortex. These abnormalities are therefore likely

to ref lect in part changes in GA BAergic and serotonergic

activity.

Drug Addiction as a Disease of Drive and Compulsive Behavior Here we postulate that repeated exposure to drugs of abuse

disrupts the function of the striato-thalamo-orbitofrontal circuit.

As a consequence of this dysfunction a conditioned response

occurs when the addicted subject is exposed to the drug and/or

drug-related stimuli that activates this circuit and results in the

intense drive to get the drug (consciously perceived as craving)

and compulsive self-administration of the drug (consciously

perceived as loss of control). This model of addiction postulates

that the drug-induced perception of pleasure is particularly

important for the initial stage of drug self-administration but that

with chronic administration pleasure per se cannot account for

the compulsive drug intake. Rather, dysfunction of the striato-

thalamo-orbitofrontal circuit, which is known to be involved

with perseverative behaviors, accounts for the compulsive

intake. We postulate that the pleasurable response is required to

form the conditioned association for the drug to elicit an

activation of the orbitofrontal cortex on subsequent exposure.

The orbitofrontal cortex, once activated, will cause what is

consciously perceived as an intense urge or drive to take the drug

even when the subject may have conf licting cognitive signals

telling him/her not to do it. Once he/she takes the drug the DA

activation that ensues during the intoxication maintains the

activation of the striato-thalamo-orbitofrontal circuit, which sets

a pattern of activation that results in perseveration of

the behavior (drug administration) and which is consciously

perceived as loss of control. An analogy that may be useful

to explain the dissociation of pleasure from drug intake in the

addicted subject could be that occurring during prolonged food

deprivation when a subject will eat any food regardless of its

taste, even when it is repulsive. Under these circumstances the

urge to eat is not driven by the pleasure of the food but by the

intense drive from the hunger. It would therefore appear that

during addiction the chronic drug administration has resulted in

brain changes that are perceived as a state of urgency not

dissimilar to that obser ved on states of severe food or water

deprivation. However, different from a state of physiological

urgency for which the execution of the behavior will result in

satiation and termination of the behavior, in the case of the

addicted subject the disruption of the orbitofrontal cortex

coupled with the increases in DA elicited by the administration

of the drug set a pattern of compulsive drug intake that is not

terminated by satiety and/or competing stimuli.

During withdrawal and without drug stimulation, the

striato-thalamo-orbitofrontal circuit becomes hypofunctional,

resulting in a decrease drive for goal-motivated behaviors.

The pattern of derangements in activity in this circuit, hypo-

active when there is no drug and/or drug-related stimuli and

hyperactive during intoxication, is similar to the derangement

seen with epilepsy, which is characterized by an increase in

activity of the abnormal foci during the ictal period and by

decreased activity during the interictal state (Saha et al., 1994).

The long-lasting abnormalities in the orbitofrontal cortex could

lead one to predict that reactivation of compulsive drug intake

could occur even after prolonged periods of drug abstinence as

a result of activation of rewards circuits (nucleus accumbens,

amygdala) by exposure either to the drug or to drug-conditioned

stimuli. In fact studies in laborator y animals have shown re-

instatement of compulsive drug intake after protracted drug

withdrawal upon re-exposure to the drug (A hmed and Koob,

1998).

An interesting question that results from this model is the

extent to which the abnormalities in the orbitofrontal cortex

are specific to disruptions related to drug intake or whether

they result in other compulsive behaviors. Though there is not

much data on the prevalence of other compulsive behaviors

in addicted subjects, there is some evidence from studies that

substance abusers report having higher scores in Compulsive

Personality scales than non-drug abusers (Yeager et al., 1992).

Moreover studies have shown that in pathological gambling,

which is another disorder of compulsive behavior, there is an

association with high alcohol and/or drug abuse (Ramirez et al.,

1983).

This model of addiction has therapeutic implications for it

would imply that drugs that could either decrease the threshold

for its activation or increase the threshold for its inhibition could

be therapeutically beneficial. In this respect it is interesting that

the anticonvulsant drug gamma vinyl GA BA (GVG), which

decreases neuronal excitability by increasing GA BA concen-

tration in brain, has been shown to be effective in blocking drug

self-administration and place preference irrespective of the drug

of abuse tested (Dewey et al., 1998, 1999). Though the ability of

GVG to block drug-induced increases in DA in the nucleus

accumbens has been postulated to be responsible for its efficacy

in inhibiting conditioned place preference and self-administra-

tion, here we postulate that GVG’s ability to decrease neuronal

excitability may also be involved via its interference with

the activation of the striato-thalamo-orbitofrontal circuit. A lso,

because the striato-thalamo-orbitofrontal circuit is regulated by

multiple neurotransmitters (Modell et al., 1990), non-dopamin-

ergic drugs that modulate this pathway could also be beneficial

in treating drug addiction. In this respect it is interesting to note

that drugs that increase serotonin concentration in the brain

decrease cocaine self-administration (Glowa et al., 1997)

whereas procedures that decrease serotonin increase breaking

points for cocaine administration (Loh and Roberts, 1990), a

finding which was interpreted as serotonin interfering with the

drive for drug self-administration.

Though imaging studies seem to implicate the striato-thalamo-

orbitofrontal circuit in drug addiction, other brain regions, such

as the anterior cingulate gyrus, medial temporal structures

(amygdala and hippocampus) and insular cortex, also appear

to be involved. While imaging studies have identified the

orbitofrontal cortex in addiction, more research is needed to

identif y the areas within the orbitofrontal cortex and the

thalamus that are involved.

Notes This research was supported in part by the US Department of Energy

(Office of Health and Environmental Research) under Contract

DE-ACO2-98CH10886, the Institute of Drug Abuse under Grant no.

Cerebral Cortex Mar 2000, V 10 N 3 323

DA 06891 and the Institute of A lcohol Abuse and A lcoholism under Grant

no. A A 09481.

Address correspondence to Nora D. Volkow, MD, Medical Depart-

ment, Bldg 490, Upton, N Y 11973, USA. Email: [email protected].

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