Addiction: A Disease of Compulsion and Drive Involvement of the Orbitofrontal Cortex (2000)

COMMENTS: This an overview of the frontal cortex’s involvement in addiction. This part of the brain is all about executive control, planning and achieving goals, along with impulse control.

FULL STUDY: Addiction: A Disease of Compulsion and Drive Involvement of the Orbitofrontal Cortex

Cereb. Cortex (2000) 10 (3): 318-325. doi: 10.1093/cercor/10.3.318

Nora D. Volkow1,3 and Joanna S. Fowler2

+ Author Affiliations

1Medical and

2Chemistry Departments, Brookhaven National Laboratory, Upton, NY 11973 and

3Department of Psychiatry, SUNY-Stony Brook, Stony Brook, NY 11794, USA


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 hypermetabolic 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 drugaddicted 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 particular 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; EppingJordan 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 Association, 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 description 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 (conditioned expectation, compulsivity, impulsivity, obsessiveness) which result from dysfunction of the striato-thalamo-orbitofrontal 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 orbitofrontal 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).

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.

Among the various functions of the orbitofrontal cortex, its role in reward-related behaviors are of most relevance when 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 subserve a similar role for pharmacological reinforcers.

In laboratory animals damage of the orbital frontal cortex results in impairment of reversal of stimulus–reinforcement associations, and leads to perseveration and resistance to extinction 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 involvement 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 secondary 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). Also 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 Alona 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 selfadministration 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 importance of the orbitofrontal cortex in maintaining drug self-administration 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 orbitofrontal 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 monetary 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 behavior. 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). Also 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 incarceration 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 selfstimulation 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 2deoxy-2-[18F]fluoro-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.

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 significantly 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 significantly 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).

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.

The association of metabolism in the orbitofrontal cortex and cingulate gyrus with striatal DA D2 receptors was interpreted as reflecting 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 psychostimulant drug methylphenidate) on regional brain glucose metabolism in detoxified cocaine abusers. Methylphenidate (MP) increased metabolism in the anterior cingulate gyrus, 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).

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.

The increase in metabolic activity in the cingulate gyrus after MP administration suggests that its hypometabolism in cocaine abusers reflects 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 necessary 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 reflect 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 reflect 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 reflects its neuroanatomical connections with the orbitofrontal cortex via the striato-thalamoorbitofrontal circuit (Johnson et al., 1968).

Activation of the orbitofrontal cortex by MP, a drug pharmacologically similar to cocaine (Volkow et al., 1995), may be one of the mechanisms by which cocaine elicits craving and the subsequent compulsive drug 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 demonstrated 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 interview 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 flow (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 [11C]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 [11C]raclopride induced by pharmacological interventions (i.e. MP, amphetamine, cocaine). Because [11C]raclopride binding is highly reproducible (Nordstrom et al., 1992; Volkow et al., 1993b) these reductions primarily reflect 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 [11C]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 [11C]raclopride 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 [11C]raclopride in the thalamus (Fig. 4a). MP-induced decreases in [11C]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 innervation 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.

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).

Summary of Imaging Studies in Cocaine Abusers

Imaging studies have provided evidence of abnormalities in the striatum, thalamus and orbitofrontal cortex in cocaine abusers. 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 hypoactivity 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 reflect 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 GABA 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 neurotransmission 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 thalamus, striatum and orbitofrontal cortex. These findings were interpreted as reflecting a decreased sensitivity to inhibitory neurotransmission in the striato-thalamo-orbitofrontal circuit in alcoholics during early detoxification (2–4 weeks after last alcohol use). A subsequent study assessed the extent to which these blunted responses normalized with protracted detoxification. 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 hyporesponsivity of the orbitofrontal cortex is not just a function of alcohol withdrawal but could reflect a regionally specific decrease in sensitivity to inhibitory neurotransmission in alcoholics.

Further evidence of the involvement of GABA in the longlasting 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 [123I]Iomazenil. This study showed that detoxified alcoholics had significant reductions in the levels of benzodiazepine receptors in the orbitofrontal 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 neurotransmission could be a defect in the ability of inhibitory 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 innervation (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 reflecting 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 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, flow and benzodiazepine receptors in the orbitofrontal cortex. These abnormalities are therefore likely to reflect in part changes in GABAergic 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 striatothalamo-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 conflicting 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 observed 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, hypoactive 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 laboratory animals have shown reinstatement of compulsive drug intake after protracted drug withdrawal upon re-exposure to the drug (Ahmed 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 GABA (GVG), which decreases neuronal excitability by increasing GABA concentration 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-administration, 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. Also, because the striato-thalamo-orbitofrontal circuit is regulated by multiple neurotransmitters (Modell et al., 1990), non-dopaminergic 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-thalamoorbitofrontal 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 identify the areas within the orbitofrontal cortex and the thalamus that are involved.


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. DA 06891 and the Institute of Alcohol Abuse and Alcoholism under Grant no. AA 09481.

Address correspondence to Nora D. Volkow, MD, Medical Department, Bldg 490, Upton, NY 11973, USA. Email: [email protected].


1. ↵

Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300.

Abstract/FREE Full Text

2. ↵

American Psychiatric Association (1994) Diagnostic and statistical manual for mental disorders. Washington, DC: American Psychiatric Association.

3. ↵

Aou S, Oomura Y, Nishino H, Inokuchi A, Mizuno Y (1983) Influence of catecholamines on reward-related neuronal activity in monkey orbitofrontal cortex. Brain Res 267:165–170.

CrossRefMedlineWeb of Science

4. ↵

Balldin J, Berggren U, Bokstrom K, Eriksson M, Gottfries CG, Karlsson I, Walinder J (1994) Six-month open trial with Zimelidine in alcoholdependent patients: reduction in days of alcohol intake. Drug Alcohol Depend 35:245–248.

CrossRefMedlineWeb of Science

5. ↵

Baxter LR, Phelps ME, Mazziotta J (1987) Local cerebral glucose metabolic rates in obsessive compulsive disorder: a comparison with rates in unipolar depression and normal controls. Arch Gen Psychiat 44:211–218.

Abstract/FREE Full Text

6. ↵

Braun AR, Randolph C, Stoetter B, Mohr E, Cox C, Vladar K, Sexton R, Carson RE, Herscovitch P, Chase TN (1995) The functional neuroanatomy of Tourette’s syndrome: an FDG–PET study. II: Relationships between regional cerebral metabolism and associated behavioral and cognitive features of the illness. Neuropsychopharmacology 13:151–168.

CrossRefMedlineWeb of Science

7. ↵

Brown EE, Robertson GS, Fibiger HC (1992) Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures. Neuroscience 12: 4112–4121.


8. ↵

Butter CM, Mishkin M, Rosvold HE (1963) Conditioning and extinction of a food rewarded response after selective ablations of frontal cortex in rhesus monkeys. Exp Neurol 7:65–67.

9. Carmichael ST, Price JL (1995) Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys. Comp Neurol 363:615–641.

CrossRefMedlineWeb of Science

10. ↵

Catafau AM, Etcheberrigaray A, Perez de los Cobos J, Estorch M, Guardia J, Flotats A, Berna L, Mari C, Casas M, Carrio I (1999) Regional cerebral blood flow changes in chronic alcoholic patients induced by naltrexone challenge during detoxification. J Nucl Med 40:19–24.

Abstract/FREE Full Text

11. ↵

Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiat 156:11–18.

Abstract/FREE Full Text

12. ↵

Coffman, JA, Petty F (1985) Plasma GABA levels in chronic alcoholics. Am J Psychiat 142:1204–1205.

Abstract/FREE Full Text

13. ↵

Cohen L, Angladette L, Benoit N, Pierrot-Deseilligny C (1999) A man who borrowed cars. Lancet 353:34.

CrossRefMedlineWeb of Science

14. ↵

Corso TD, Mostafa HM, Collins MA, Neafsey EJ (1998) Brain neuronal degeneration caused by episodic alcohol intoxication in rats: effects of nimodipine, 6,7-dinitro-quinoxaline-2,3-dione, and MK-801. Alcohol Clin Exp Res 22:217–224.

CrossRefMedlineWeb of Science

15. ↵

Dackis CA, Gold MS (1985) New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev 9:469–477.

CrossRefMedlineWeb of Science

16. ↵

Dewey SL, Smith GW, Logan J, Brodie JD, Wei Y-D, Ferrieri RA, King P, MacGregor R, Martin PT, Wolf AP, Volkow ND, Fowler JS (1992) GABAergic inhibition of endogeneous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci 12:3773–3780.


17. ↵

Dewey SL, Morgan AE, Ashby CR Jr, Horan B, Kushner SA, Logan J, Volkow ND, Fowler JS, Gardner EL, Brodie JD (1998) A novel strategy for the treatment of cocaine addiction. Synapse 30:119–129.

CrossRefMedlineWeb of Science

18. ↵

Dewey SL, Brodie JD, Gerasimov M, Horan B, Gardner EL, Ashby CR Jr (1999) A pharmacologic strategy for the treatment of nicotine addiction. Synapse 31:76–86.

CrossRefMedlineWeb of Science

19. ↵

Dringenberg HC, Vanderwolf CH (1997) Neocortical activation: modulation by multiple pathways acting on central cholinergic and serotonergic systems. Exp Brain Res 116:160–174.

CrossRefMedlineWeb of Science

20. ↵

El-Ghundi M, George SR, Drago J, Fletcher PJ, Fan T, Nguyen T, Liu C, Sibley DR, Westphal H, O’Dowd BF (1998) Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior. Eur J Pharmacol 353:149–158.

CrossRefMedlineWeb of Science

21. Epping-Jordan MP, Watkins SS, Koob GF, Markou A (1998) Dramatic decreases in brain reward function during nicotine withdrawal. Nature 393:76–79.


22. ↵

Ferris R, Tang F, Maxwell R (1972) A comparison of the capabilities of isomers of amphetamine, deoxyperadrol and methylphenidate to inhibit the uptake of catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta. J Pharmacol 14:47–59.

23. ↵

Fischman MW, Schuster CR, Javaid J, Hatano Y, Davis J (1985) Acute tolerance development to the cardiovascular and subjective effects of cocaine. J Pharmacol Exp Ther 235:677–682.

Abstract/FREE Full Text

24. ↵

Glowa JR, Rice KC, Matecka D, Rothman RB (1997) Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys. NeuroReport 8:1347–51.

MedlineWeb of Science

25. ↵

Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C, Phillips RL, Kimes AS, Margolin A (1996) Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA 93:12040–12045.

Abstract/FREE Full Text

26. ↵

Groenewegen HJ (1988) Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal– prefrontal topography. Neuroscience 24:379–431.

CrossRefMedlineWeb of Science

27. Groenewegen HJ, Berendse HW, Wolters JG, Lohman AH (1990) The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization. Prog Brain Res 85:95–116.


28. ↵

Haber SN (1986) Neurotransmitters in the human and nonhuman primate basal ganglia. Hum Neurobiol 5:159–168.

MedlineWeb of Science

29. ↵

Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E (1995) The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 15:4851–4867.


30. ↵

Heimer L, Alheid GF, Zaborzky L (1985) The basal ganglia. In: The rat nervous system (Paxinos G, ed), pp 37–74. Sidney: Academic Press.

31. ↵

Heinz A, Ragan P, Jones DW, Hommer D, Williams W, Knable MB, Gorey JG, Doty L, Geyer C, Lee KS, Coppola R, Weinberger DR, Linnoila M (1998) Reduced central serotonin transporters in alcoholism. Am J Psychiat 155:1544–1549.

Abstract/FREE Full Text

32. ↵

Hommer D, Andreasen P, Rio D, Williams W, Ruttimann U, Momenan R, Zametkin A, Rawlings R, Linnoila M (1997) Effects of m-chlorophenylpiperazine on regional brain glucose utilization: a positron emission tomographic comparison of alcoholic and control subjects. J Neurosci 17:2796–2806.

Abstract/FREE Full Text

33. ↵

Hugdahl K, Berardi A, Thompson WL, Kosslyn SM, Macy R, Baker DP, Alpert NM, LeDoux JE (1995) Brain mechanisms in human classical conditioning: a PET blood flow study. NeuroReport 6:1723–1728.

MedlineWeb of Science

34. ↵

Hunt WA (1983) The effect of ethanol on GABAergic transmission. Neurosci Biobehav Rev 7:87.

CrossRefMedlineWeb of Science

35. ↵

Insel TR (1992) Towards a neuroanatomy of obsessive-compulsive disorder. Arch Gen Psychiat 49:739–744.

Abstract/FREE Full Text

36. ↵

Isaac WL, Nonneman AJ, Neisewander J, Landers T, Bardo MT (1989) Prefrontal cortex lesions differentially disrupt cocaine-reinforced conditioned place preference but not conditioned taste aversion. Behav Neurosci 103:345–355.

CrossRefMedlineWeb of Science

37. ↵

Johnson T, Rosvold HE, Mishkin M (1968) Projections from behaviorallydefined sectors of the prefrontal cortex to the basal ganglia, septum and diencephalon of the monkey. J Exp Neurol 21:20–34.

38. ↵

Johnson TN (1971) Topographic projections in the globus pallidus and the substantia nigra of selectively placed lesions in the precommissural caudate nucleus and putamen in the monkey. Exp Neurol 33:584–596.

CrossRefMedlineWeb of Science

39. ↵

Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723.

Abstract/FREE Full Text

40. ↵

Le Moal M, Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory notes. Physiol Rev 71:155–234.

FREE Full Text

41. ↵

Lewis MJ (1996) Alcohol reinforcement and neuropharmacological therapeutics. Alcohol Alcohol Suppl 1:17–25.


42. ↵

Lingford-Hughes AR, Acton PD, Gacinovic S, Suckling J, Busatto GF, Boddington SJ, Bullmore E, Woodruff PW, Costa DC, Pilowsky LS, Ell PJ, Marshall EJ, Kerwin RW (1998) Reduced levels of GABAbenzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy. Br J Psychiat 173:116–122.

Abstract/FREE Full Text

43. ↵

Loh EA, Roberts DC (1990) Break-points on a progressive ratio schedule reinforced by intravenous cocaine increase following depletion of forebrain serotonin. Psychopharmacology (Berlin) 101:262–266.


44. ↵

Madras BK, Kaufman MJ (1994) Cocaine accumulates in dopamine rich regions of primate brain after iv administration: comparison with mazindol distribution. Synapse 18:261–275.

CrossRefMedlineWeb of Science

45. ↵

Marsden CD, Obeso JA (1994) The functions of the basal ganglia and the paradox of stereotaxic surgery in Parkinson’s disease. Brain 117: 877–897.

Abstract/FREE Full Text

46. Mc Alonan, G.M., Robbins TW, Everitt BJ (1993) Effects of medial dorsal thalamic and ventral pallidal lesions on the acquisition of a conditioned place preference: further evidence for the involvement of the ventral striatopallidal system in reward-related processes. Neuroscience 52:605–620.

CrossRefMedlineWeb of Science

47. ↵

McKay JR (1999) Studies of factors in relapse to alcohol, drug and nicotine use: a critical review of methodologies and findings. J Stud Alcohol 60:566–576.

MedlineWeb of Science

48. ↵

Modell JG, Mountz JM, Curtis G, Greden J (1989) Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive compulsive disorder. J Neuropsychiat 1:27–36.

49. ↵

Modell JG, Mountz J, Beresford TP (1990) Basal ganglia/limbic striatal and thalamocortical involvement in craving and loss of control in alcoholism. J Neuropsychiat 2:123–144.

50. Nauta WJH (1971) The problem of the frontal lobe: a reinterpretation. J Psychiat Res 8:167–189.

CrossRefMedlineWeb of Science

51. ↵

Nordstrom AL, Farde L, Pauli S, Litton JE, Halldin C (1992) PET analysis of central [11C]raclopride binding in healthy young adults and schizophrenic patients, reliability and age effects. Hum Psychopharmacol 7:157–165.

CrossRefWeb of Science

52. ↵

Oades RD, Halliday GM (1987) Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity. Brain Res 434:117–65.


53. ↵

O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? Psychopharmacology 12:15–22.

54. ↵

Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257.


55. ↵

Porrino LJ, Lyons D (2000) Orbital and medial prefrontal cortex and psychostimulant abuse: studies in animal models. Cereb Cortex 10: 326–333.

Abstract/FREE Full Text

56. ↵

Portenoy RK, Jarden JO, Sidtis JJ, Lipton RB, Foley KM, Rottenberg DA (1986) Compulsive thalamic self-stimulation: a case with metabolic, electrophysiologic and behavioral correlates. Pain 27:277–290.

CrossRefMedlineWeb of Science

57. ↵

Ramirez LF, McCormick RA, Russo AM, Taber JI (1983) Patterns of substance abuse in pathological gamblers undergoing treatment. Addict Behav 8:425–428.

CrossRefMedlineWeb of Science

58. ↵

Ray JP, Price JL (1993) The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys. Comp Neurol 337:1–31.

CrossRefMedlineWeb of Science

59. ↵

Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW, Caron MG (1998) Cocaine self-administration in dopaminetransporter knockout mice. Nature Neurosci 1:132–137.

CrossRefMedlineWeb of Science

60. ↵

Rolls ET (1996) The orbitofrontal cortex. Phil Trans R Soc Lond B Biol Sci 351:1433–1443.

MedlineWeb of Science

61. ↵

Ross SB, Jackson DM (1989) Kinetic properties of the accumulation of 3H raclopride in the mouse in vivo. Naunyn Schmiederbergs Arch Pharmacol 340:6–12.

MedlineWeb of Science

62. ↵

Saha GB, MacIntyre WJ, Go RT (1994) Radiopharmaceuticals for brain imaging. Semin Nucl Med 24:324–349.

CrossRefMedlineWeb of Science

63. ↵

Schmidt B, Richter-Rau G, Thoden U (1981) Addiction-like behavior with continuous self-stimulation of the mediothalamic system. Arch Psychiat Nervenkr 230:55–61.

CrossRefMedlineWeb of Science

64. ↵

Schoenbaum G, Chiba AA, Gallagher M (1998) Orbitofrontal cortex and basolateral amygdala encode expected outcomes during learning. Nature Neurosci 1:155–159.

CrossRefMedlineWeb of Science

65. ↵

Seeman P, Guan HC, Niznik HB (1989) Endogenous dopamine lowers the dopamine D2 receptor density as measured by 3H raclopride: implications for positron emission tomography of the human brain. Synapse 3:96–97.

CrossRefMedlineWeb of Science

66. ↵

Stuss DT, Benson DF (1986) The frontal lobes. New York: Raven Press.

67. ↵

Thorpe SJ, Rolls ET, Madison S (1983) The orbitofrontal cortex: neuronal activity in the behaving monkey. Exp Brain Res 49:93–115.

MedlineWeb of Science

68. ↵

Thut G, Schultz W, Roelcke U, Nienhusmeier M, Missimer J, Maguire RP, Leenders KL (1997) Activation of the human brain by monetary reward. NeuroReport 8:1225–1228.

MedlineWeb of Science

69. Tremblay L, Schultz W. (1999) Relative reward preference in primate orbitofrontal cortex. Nature 398:704–708.


70. ↵

Tucker DM, Luu P, Pribram KH (1995) Social and emotional selfregulation. Ann NY Acad Sci 769:213–239.

MedlineWeb of Science

71. ↵

Volkow ND, Fowler JS, Wolf AP, Hitzemann R, Dewey S, Bendriem B, Alpert R, Hoff A (1991) Changes in brain glucose metabolism in cocaine dependence and withdrawal. Am J Psychiat 148:621–626.

Abstract/FREE Full Text

72. ↵

Volkow ND, Hitzemann R, Wang G-J, Fowler JS, Wolf AP, Dewey SL (1992) Long-term frontal brain metabolic changes in cocaine abusers. Synapse 11:184–190.

CrossRefMedlineWeb of Science

73. ↵

Volkow ND, Fowler JS, Wang G-J, Hitzemann R, Logan J, Schlyer D, Dewey S, Wolf AP (1993a) Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14:169–177.

CrossRefMedlineWeb of Science

74. ↵

Volkow ND, Fowler JS, Wang G-J, Dewey SL, Schlyer D, MacGregor R, Logan J, Alexoff D, Shea C, Hitzemann R, Angrist N, Wolf AP (1993b) Reproducibility of repeated measures of 11C raclopride binding in the human brain. J Nucl Med 34:609–613.

Abstract/FREE Full Text

75. ↵

Volkow ND, Wang G-J, Hitzemann R, Fowler JS, Wolf AP, Pappas N, Biegon A, Dewey SL (1993c) Decreased cerebral response to inhibitory neurotransmission in alcoholics. Am J Psychiat 150:417–422.

Abstract/FREE Full Text

76. ↵

Volkow ND, Wang G-J, Fowler JS, Logan J, Schlyer D, Hitzemann R, Lieberman J, Angrist B, Pappas N, MacGregor R, Burr G, Cooper T, Wolf AP (1994) Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse 16:255–262.

CrossRefMedlineWeb of Science

77. ↵

Volkow ND, Ding Y-S, Fowler JS, Wang GJ, Logan J, Gatley SJ, Dewey SL, Ashby C, Lieberman J, Hitzemann R, Wolf AP (1995) Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain. Arch Gen Psychiat 52:456–463.

Abstract/FREE Full Text

78. ↵

Volkow ND, Ding Y-S, Fowler JS, Wang G-J (1996a) Cocaine addiction: hypothesis derived from imaging studies with PET. J Addict Dis 15: 55–71.

MedlineWeb of Science

79. ↵

Volkow ND, Wang G-J, Fowler JS, Logan J, Hitzemann RJ, Ding Y-S, Pappas NS, Shea C, Piscani K (1996b) Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin Exp Res 20:1594–1598.

MedlineWeb of Science

80. ↵

Volkow ND, Wang G-J, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Pappas N (1997a) Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386:830–833.


81. ↵

Volkow ND, Wang GJ, Overall JE, Hitzemann R, Fowler JS, Pappas N, Frecska E, Piscani K (1997b) Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification. Alcohol Clin Exp Res 21:1278–1284.

CrossRefMedlineWeb of Science

82. ↵

Wang G-J, Volkow ND, Fowler JS, Wolf AP, MacGregor R, Shea CE, Shyler D, Hitzemann R (1993) Comparison of two PET radioligands for imaging extrastriatal dopamine receptors in human brain. Synapse 15:246–249.

CrossRefMedlineWeb of Science

83. ↵

Wang G-J, Volkow ND, Fowler JS, Cervany P, Hitzemann RJ, Pappas N, Wong CT, Felder C (1999) Regional brain metabolic activation during craving elicited by recall of previous drug experiences. Life Sci 64: 775–784.

CrossRefMedlineWeb of Science

84. ↵

Weissenborn R, Whitelaw RB, Robbins TW, Everitt BJ (1998) Excitotoxic lesions of the mediodorsal thalamic nucleus attenuate intravenous cocaine self-administration. Psychopharmacology (Berlin) 140: 225–232.


85. ↵

Yeager RJ, DiGiuseppe R, Resweber PJ, Leaf R (1992) Comparison of million personality profiles of chronic residential substance abusers and a general outpatient population. Psychol Rep 71:71–79.

CrossRefMedlineWeb of Science

86. ↵

Young CD, Deutch AY (1998) The effects of thalamic paraventricular nucleus lesions on cocaine-induced locomotor activity and sensitization. Pharmacol Biochem Behav 60:753–758.

CrossRefMedlineWeb of Science