0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
Reviews and Overviews   |    
PET Imaging of Dopamine D2 Receptors in Monkey Models of Cocaine Abuse: Genetic Predisposition Versus Environmental Modulation
Michael A. Nader, Ph.D.; Paul W. Czoty, Ph.D.
Am J Psychiatry 2005;162:1473-1482. doi:10.1176/appi.ajp.162.8.1473

OBJECTIVE: Animals self-administer many of the drugs that humans abuse, including cocaine. This article describes studies using preclinical animal models to differentiate the influences of neurobiological predisposition from environmental modulation of cocaine addiction, including studies from the authors’ laboratory using nonhuman primates. METHOD: Addiction is described in terms of vulnerability, maintenance, and abstinence. This review focuses on dopamine receptor function, in particular that of the D2-like receptors, as measured by the noninvasive imaging procedure positron emission tomography. Findings from human studies of addiction and animal models are reviewed. RESULTS: There appears to be an inverse relationship between D2 receptor availability and vulnerability to the reinforcing effects of cocaine. Environmental variables can increase or decrease D2 receptor binding in an orderly fashion, and the resulting changes in D2 function influence the vulnerability to abuse cocaine. In maintenance, chronic cocaine exposure produces decreases in D2 receptor binding, which may be a mechanism that contributes to continued drug use. Finally, during abstinence there are individual differences in rates of recovery of D2 receptor availability. CONCLUSIONS: The goal of the preclinical research described in this review is to achieve a better understanding of individual differences in susceptibility and vulnerability to the reinforcing effects of cocaine. It is clear that the development of novel animal models will extend our understanding of the neurobiological basis of drug addiction to include a greater appreciation of the role of environmental factors in affecting predisposition, mediating continued drug use, and triggering relapse.

Abstract Teaser
Figures in this Article

Recent estimates indicate that the number of new cocaine users per year more than doubled from 1992 (0.5 million) to 2002 (1.1 million) (1). From 1994 to 2001, visits to hospital emergency rooms that involved cocaine increased by 22% (2). Despite more than three decades of research into the molecular, cellular, and behavioral effects of cocaine, no pharmacotherapy for cocaine abuse has demonstrated sufficient safety and effectiveness for widespread clinical use (3, 4). As astutely pointed out by Leshner (5), most people see drug abuse and addiction as a social problem, and as such, the problem is frequently handled only with social solutions, in particular through the criminal justice system. Recent reports indicate that the 40%–60% of people seeking treatment are ordered to do so by the courts or corrections system (see reference 6), suggesting that treatment does not occur until drug use has led to substantial adverse consequences to the individual. However, if drug addiction is viewed as a brain disease, then addiction should be amenable to treatments, just as depression, schizophrenia, and anxiety are treatable. As Leshner stated,

Understanding addiction as a brain disease explains in part why historic policy strategies focusing solely on the social or criminal justice aspects of drug use and addiction have been unsuccessful. They are missing at least half of the issue. If the brain is the core of the problem, attending to the brain needs to be a core part of the solution. (5, p. 47)

In response to growing evidence, the World Health Organization recently issued a report focusing on the role of the brain in mediating drug dependence (7). The goal of the present review is to highlight some of the brain imaging studies of cocaine abuse with a special emphasis on the use of animal models to help us understand the human condition.

Cocaine is an indirectly acting monoamine agonist, binding to the dopamine, serotonin, and norepinephrine transporters (8, 9). The majority of research on cocaine has involved the dopamine system, which will be the focus of this review. Cocaine binds to the dopamine transporter and blocks uptake of dopamine from the synapse. The elevated levels of dopamine activate two superfamilies of dopamine receptors, D1- and D2-like. This review will focus on D2-like receptors, which have been intimately linked to drug abuse (for instance, see references 10–12). The positron emission tomography (PET) studies that we will describe involve radiotracers that do not differentiate among subtypes of the D2 superfamily (i.e., D2, D3, and D4 receptor subtypes).

To study the brain, powerful imaging techniques have been developed that allow for the noninvasive exploration of brain function in humans and in animals. In this review, we will highlight studies utilizing PET. A clear strength of PET is the ability to examine the brain repeatedly in longitudinal studies. PET has been described as a functional measure of brain activity because it records the uptake and washout of a radioactive marker that competes with endogenous neurotransmitters (13). For example, the radiotracers [11C]raclopride and [18F]fluoroclebopride bind to D2-like receptors with similar affinities. The primary dependent variable in PET imaging studies is the ratio of the distribution of radioligand in the region of interest compared to its distribution in a region devoid of receptors. This ratio, termed the distribution volume ratio, provides a unitless number representing the ratio of receptor density (Bmax) to receptor affinity. In theory, changes in the distribution volume ratio noted in longitudinal studies reflect changes in Bmax. However, changes in the distribution volume ratio may also reflect changes in extracellular dopamine levels. Increases in extracellular dopamine will decrease radioligand binding, whereas decreases in extracellular dopamine will increase radioligand binding (for example, see references 13–15). Thus, in addition to being affected by the actual number of receptors in the tissue, the binding of these radioligands is influenced by the amount of dopamine present in the synapse. As a result, when we describe PET data, we use interchangeably "binding" and "availability," since both are being assessed.

In contrast to PET imaging studies, in vitro receptor autoradiography provides a measure of receptor density in a particular brain structure that is not influenced by the levels of a neurotransmitter. The limitation, however, is that the procedures are terminal and, consequently, only one time point can be studied. These are important considerations for longitudinal PET studies because the possibility that changes in PET measures are due to changes in neurotransmitter levels rather than the density of receptors cannot be ruled out unless additional studies are conducted. In this review, we attempt to address this issue by also describing in vitro studies using receptor autoradiography procedures in which circulating dopamine levels are not influencing receptor density assessments.

One strategy implemented by the National Institute on Drug Abuse is the development of novel animal models to better understand the neurochemical mechanisms mediating the high abuse potential of cocaine. A greater understanding of the neuropharmacology of cocaine will ultimately lead to improved treatment for cocaine dependence. Animal models of drug self-administration have proven to be valid predictors of human drug abuse (3, 16–20). Animals will self-administer most of the drugs that humans abuse, including cocaine, alcohol, nicotine, and heroin, by the routes (intravenous, inhaled, and oral) used by humans (17). More recently, these models have been extended to examine behavioral and physiological responsiveness to environmental variables as indicators of vulnerability to drug use (21). In one of the earliest studies on individual differences and vulnerability to drug abuse, Piazza et al. (22) initially characterized rats’ behavior in an open-field apparatus on the basis of how much locomotor activity was observed prior to any drug exposure. They found that rats characterized as "high responders" in an open field had higher basal corticosterone levels and were more likely to self-administer d-amphetamine than rats characterized as "low responders." Consistent with this characterization, noncontingent electric foot shock, which increased corticosterone levels in rats, facilitated acquisition of cocaine self-administration (23). In other experiments, bilateral adrenalectomy or administration of metyrapone, which blocks corticosterone synthesis, completely abolished the acquisition of cocaine self-administration (24). Thus, it appears that individual differences in vulnerability to drug abuse can be observed in animal models and that these differences may be due, in part, to stress-hormone responsiveness.

In addition, animal models of drug abuse have begun to incorporate more sophisticated designs, including the inclusion of alternative reinforcers and the study of cocaine choice, that may provide greater validity than models that simply examine the reinforcing effects of drugs (see references 25–27). For example, when monkeys are given a choice between food and cocaine, there is a dose-dependent relationship between drug dose and preference (see, for instance, references 26–28). That is, when low cocaine doses are the alternative to food, monkeys choose food; at higher cocaine doses, a monkey’s preference shifts to almost exclusively cocaine choices. Manipulations of environmental variables can increase or decrease cocaine choice. For example, increases in the magnitude of the nondrug alternative (i.e., food reinforcement) decrease cocaine choice. Similarly, increases in the response requirement for cocaine (analogous to increases in the cost of the drug) decrease cocaine choice (26, 27, 29). The converse is also true: increases in the cost of the preferred nondrug alternative increase the frequency with which cocaine is chosen (26, 27, 29).

These results emphasize that drug reinforcement is not simply mediated by actions in the brain but that the environment can alter drug reinforcement and, as we will show, brain function. A growing body of preclinical research supports the hypothesis that environmental stressors can enhance and environmental enrichment can attenuate the reinforcing effects of drugs. This hypothesis has clear implications for clinical outcomes. As we will discuss, these environmental stimuli affect brain function, including processes mediated by dopamine receptors. Compared to enrichment, more work has focused on the role of stress in drug abuse (see reference 30), with stressors including foot shock or more ethologically relevant variables such as social stress and social defeat. We will describe studies that utilize a novel animal model of drug abuse in which male monkeys live in social groups and have access to cocaine daily.

To relate the preclinical findings to a more global goal of translational research, it is important to point out several advantages of the animal models highlighted in this article. First, drugs can have different effects on brain function depending on whether they are administered by the investigator or self-administered by the animal (31, 32). Because we are interested in studying addictive behavior, drug self-administration has face validity as an animal model of a human condition. Second, in our studies of nonhuman primates we also examine complex social behaviors and stable individual behavioral characteristics (e.g., aggressive and affiliative behaviors in particular) that closely model human social interactions (see reference 33). In macaque monkeys, the formation of social hierarchies is determined by the outcome of physical confrontations (i.e., fights). The monkey that wins all of the fights in the social group is the most dominant, the monkey that wins all encounters except with the most dominant animal is the monkey ranked number 2, and so forth. This hierarchy is transitory and linear, such that if number 2 wins a battle with number 3 and number 3 is ranked above number 4, then number 2 is above number 4. We view the linear hierarchy that forms, with the dominant monkeys at the top and the subordinate animals at the bottom, as a continuum from environmental enrichment at one end to high levels of stress at the other. Socially derived stressors have high ethological validity with regard to the study of human drug abuse. Finally, nonhuman primates have many advantages over other animal species. There is abundant evidence that rodent and primate brains differ in the anatomy, physiology, and neurochemistry of brain dopamine systems (3437). Furthermore, the nonhuman primate brain differs substantially from the rodent brain in terms of cocaine-induced changes in brain metabolism (38, 39). Nonhuman primates can be studied in long-term experiments with cocaine self-administration (over years) that use within-subject designs, and they are capable of learning complex behaviors in order to obtain drugs. The use of PET imaging to examine neuroadaptations allows for longitudinal examination of brain changes due to environmental and/or pharmacological manipulations (e.g., references 40–42). The studies described in the following sections will focus on three phases of drug addiction: vulnerability, maintenance, and abstinence/relapse.

Perhaps one of the most challenging issues in drug abuse research involves understanding the etiology of addiction. Epidemiological studies suggest that approximately 17% of the people who use cocaine become dependent on the drug (43, 44). Studies in humans can generate hypotheses about potential brain markers that may indicate a predisposition to become addicted. For example, Volkow et al. (45) studied 23 non-drug-abusing male subjects and used the dopamine transport inhibitor methylphenidate as a tool to study stimulant abuse. First, each subject was scanned with the D2 receptor ligand [11C]raclopride. On another day, they were administered 0.5 mg/kg of methylphenidate and asked to complete an analogue self-rating scale for pleasant drug effects. Approximately one-half (N=12) of the 23 subjects reported liking the dose of methylphenidate, while nine of them described it as "unpleasant" (two were indifferent to the drug effect). Subjects who found methylphenidate "pleasant" had significantly lower levels of D2 receptor binding than subjects who reported the drug as "unpleasant." While these findings suggest an inverse relationship between D2 receptor availability and "vulnerability" to stimulant reinforcement, because of ethical concerns humans cannot be studied prior to drug exposure and then allowed to self-administer the drug for an extended period of time. Animal models, however, can be used to test hypotheses generated from studies of human drug abusers.

We explored further the relationship between D2 receptors and sensitivity to psychostimulants in a novel model of drug abuse in monkeys housed together (40). Previous work from our group had shown a relationship between D2 receptor availability, as measured with PET, and the social rank of female monkeys (46). Subordinate monkeys had significantly lower levels of D2 receptor binding than dominant monkeys. This relationship between social rank and D2 receptors generated an interesting series of questions related not only to drug abuse but also to trait theory. Our first question was whether D2 receptor availability influenced social rank. That is, were monkeys genetically predisposed to a particular position in the social hierarchy according to basal D2 receptor availability? To answer this question, we studied 20 individually housed male monkeys by using the D2 receptor ligand [18F]fluoroclebopride (47) before the monkeys were housed together. The level of D2 receptor binding determined during individual housing did not predict eventual social rank. That is, D2 availability was not a trait variable influencing dominance hierarchies (40).

The next question was whether formation of the social hierarchies influenced D2 receptor availability. When these animals were rescanned after 3 months of social housing, there were significant differences between groups, with the subordinate monkeys having significantly lower D2 receptor binding than the dominant monkeys (40). This finding replicated our earlier work with female monkeys (46) and extended it to males. However, when we compared each monkey’s [18F]fluoroclebopride distribution volume ratio when they were individually housed to the new ratio after social group formation, a profound effect was noted: the average distribution volume ratios for dominant monkeys increased by over 20%, while those for the subordinate animals were nearly unchanged from their original baselines (t1). These results suggest that becoming the dominant monkey in the social group produced large changes in dopamine receptor function.

One hypothesis that could account for the observed changes is that being the dominant monkey is analogous to living in an enriched environment. Dominant animals have access to treats in the pen, they are groomed more often than subordinate monkeys, and they move about freely (33). Enrichment could affect the PET signal (i.e., produce increases in the distribution volume ratio) by increasing D2 receptor densities and/or decreasing levels of extracellular dopamine in dominant monkeys. Studies using rodents have clearly shown that environmental enrichment can affect dopamine neurotransmission in an orderly and reliable fashion consistent with both potential mechanisms. For example, Bowling et al. (48)) examined the effects of different rearing environments on dopamine synthesis and metabolism in rats. The group in the "enriched" condition lived together, with 12 or 13 rats per cage, and was exposed to novel toys. Another group lived under "impoverished" conditions consisting of individual housing without toys in the cage. In vitro studies indicated that the rats in the enriched condition had lower striatal concentrations of dopamine than the rats in the impoverished condition. In another study, Hall et al. (49) used in vivo microdialysis to compare rats reared in isolation with socially reared rats, and they found that dopamine levels in the nucleus accumbens were higher in the isolation-reared rats than in the socially reared rats. Furthermore, D2 receptor densities were lower in the isolation-reared rats than in the socially reared rats (49). These findings clearly show that environmental variables as seemingly subtle as housing conditions can produce profound changes in the functional status of dopamine systems. Overall, the findings in rodents are in the same direction as the effects we observed after formation of social groups by monkeys.

An important question is whether these environmentally induced brain changes have behavioral consequences. In particular, how do these variables influence vulnerability to drug abuse? If, as previously noted in humans, there is a relationship between D2 receptor availability and stimulant reinforcement, then there should be differences in drug reinforcement between dominant and subordinate monkeys and subordinate animals should be more sensitive to the effects of cocaine. This is, in fact, what we found (40). When subsequently allowed access to cocaine, subordinate animals self-administered cocaine at higher rates and had larger intakes than those for dominant monkeys (F1). Overall, these findings confirmed an inverse relationship between D2 receptor availability and cocaine reinforcement and suggested that environmental variables could affect brain function and vulnerability to cocaine abuse.

Human PET imaging studies have shown lower D2 receptor availability in cocaine abusers than in age-matched comparison subjects (11). However, as already described, it is not clear whether the lower D2 receptor binding was a predisposing trait or a consequence of cocaine exposure (see reference 11). Understanding how long-term cocaine exposure affects dopamine receptor function could ultimately lead to better treatment strategies. One hypothesis is that D2 receptor down-regulation occurs as an adaptation to the chronic elevation in extracellular dopamine due to chronic blockade of dopamine uptake. A strength of using animal subjects is the ability to study drug-naive subjects and to observe changes in receptor availability with exposure to a drug by means of a within-subjects, longitudinal design (see reference 50, for example).

We recently extended our studies of socially housed monkeys to examine the effects of chronic cocaine exposure in dominant and subordinate monkeys (51). Whereas dominant monkeys were initially protected from the reinforcing effects of cocaine by elevated D2 availability, chronic exposure to self-administered cocaine resulted in D2 measures that were no longer different from those of subordinate monkeys (F2). These findings suggested that exposure to cocaine attenuated or reversed the powerful effects of environmental context on dopamine receptor availability. Studies utilizing in vitro receptor autoradiography of D2 receptors have consistently shown lower receptor densities in monkeys with long-term histories of cocaine self-administration; many of these effects were directly related to dose and duration of exposure (5254).

A central issue for this phase of addiction is one that was raised for the first phase, namely individual differences. For example, one issue to consider in addition to the dose of a drug taken in the lifetime of the individual is the pattern and duration of drug use. Volkow et al. (11) noted that there was not a relationship between D2 receptor binding and the dose of cocaine used, but there was a significant correlation between D2 binding and duration of cocaine use. The effects of duration and cocaine intake can be addressed with animal models in which cocaine availability is the primary independent variable. The question could be phrased as, Does administering a large amount of cocaine over a short period of time produce greater long-term effects on dopamine receptor function than does administering moderate doses over longer periods? In a study not utilizing cocaine self-administration, in vitro receptor autoradiography was used to assess the consequences of chronic cocaine use and abstinence on D2 receptor levels (55). Monkeys were treated four times per day with cocaine for 2 consecutive weeks, followed by a 2-week withdrawal period. The investigators found no differences between cocaine-treated and control monkeys in D2 receptor densities in the caudate nucleus, prefrontal cortex, substantia nigra, and nucleus accumbens. However, this amount of cocaine administered has since been shown to produce robust decreases in D2 receptor densities when self-administered over longer periods of time (see, for instance, references 52 and 53). Such findings suggest that the duration of exposure is as important as the actual dose of drug administered and reinforce the importance of using contingent drug administration in animal models of addiction. Future studies using in vivo imaging techniques will better address this extremely important question.

As we discussed for the vulnerability phase, an important question is whether there are functional consequences to cocaine-induced changes in D2 receptor binding. Of particular interest are issues related to cognitive function, decision making, and choice behavior. For example, Grant et al. (56) compared a group of drug abusers (opiate and/or stimulant) and non-drug-abusing comparison subjects on a series of neuropsychological tests to examine the long-term consequences of drug use on decision making. In one set of studies, subjects were exposed to the "gambling task" (57), which has strong face validity for evaluating cognitive deficits (56). The task involved four different decks of cards that differed along three dimensions: immediate gain, long-term expected gain, and schedule of penalties. Two of the four decks had smaller gains and punishers but higher overall "yields"; the comparison subjects chose from those decks most often. In contrast, the majority of the drug abusers chose from the low-yield decks, indicating poor decision making. To control for possible differences in IQ, Grant et al. (56) also used the Wisconsin Card Sorting Test and found no differences between the groups. The authors concluded that impairments in decision making could certainly account for continued use of drugs in the presence of adverse social and personal consequences.

Studies with cocaine abusers cannot clarify whether such cognitive impairments are a consequence of excessive cocaine use or reflect preexisting decrements that predispose certain individuals to drug abuse. Animal studies can address this issue. Using our model with group-housed monkeys, we studied choice behavior involving cocaine and a nondrug reinforcer—banana-flavored pellets (27). Subordinate monkeys were more sensitive to the reinforcing effects of cocaine than were dominant monkeys. That is, subordinate monkeys chose cocaine over food at a lower cocaine dose than that for dominant monkeys. Such findings suggest that environmental context can substantially influence the preference to choose drug over nondrug alternatives even when D2 binding does not differ between groups.

The final phase of drug addiction to be discussed is abstinence and the variables that influence relapse. As with vulnerability and maintenance, we will focus on dopamine D2 receptor availability. From a clinician’s viewpoint, abstinence is the critical phase because the population seeking professional guidance and treatment are in this phase; it is worth pointing out that this is the phase of drug addiction about which we know and understand the least. The preceding issues related to vulnerability (predisposition) and maintenance (i.e., changes in brain function due to chronic drug exposure) are critical in understanding brain changes associated with abstinence. However, understanding these variables may provide only a glimpse of the complexity involved in brain changes during abstinence. Perhaps Childress et al. stated it best: "This search [for a cocaine medication] has been complicated by the heterogenous target: drug desire that emerges during cocaine cessation…may well have a different brain substrate than desire induced by cocaine itself…and the cues that signal it" (58, p. 11).

Over a decade ago, Volkow and colleagues (59) reported significantly lower D2 receptor binding in cocaine abusers abstinent from cocaine for up to 4 months. These reductions in D2 receptor binding were associated with decreased glucose utilization in the orbitofrontal cortex and with self-ratings of dysphoria (11). Thus, there was an association between dopamine receptor availability and negative subjective effects during abstinence. The study ended 4 months after the start of abstinence because all subjects had relapsed. Animal models, on the other hand, can provide valuable insight into the neuropharmacology of abstinence and relapse because abstinence can be studied for years.

Our first efforts to study D2 receptor function during abstinence involved using PET imaging to compare D2 receptor binding in monkeys with extensive histories of cocaine self-administration and cocaine-naive comparison monkeys (i.e., a group design). For example, the first monkey we studied had self-administered cocaine for over 3 years and had a lifetime cocaine intake of approximately 20 g. PET scans were conducted at various time points during abstinence. Differences in [18F]fluoroclebopride binding between this cocaine-experienced monkey and a cocaine-naive monkey were apparent at all time points and, as shown in F3, did not dissipate even after 7 months of abstinence. The image from a comparison monkey shows excellent uptake of [18F]fluoroclebopride into D2-rich regions of the basal ganglia. In the abstinent cocaine-experienced monkey, D2 receptor binding was more than 20% lower. While it is possible that the lower D2 signal in the cocaine-experienced monkey was due to elevated levels of dopamine, it is unlikely that such an effect would persist for 7 months. The other possibility is that chronic cocaine exposure resulted in persistent reductions in D2 receptor densities. This hypothesis has been confirmed by means of in vitro receptor autoradiography (52, 53; see reference 54 for further discussion).

It is necessary to comment on animal models and "craving." As defined by Hommer, craving "is a term derived from popular psychology that is used to describe one of the mental states—namely, the intense desire for a certain object or experience" (60, p. 187). Assessing a mental state in an animal is not a realistic undertaking. However, we can measure behavior and hypothesize about mental states. Describing the multitude of animal models of craving is beyond the scope of this review. In brief, the strategies can involve persistence of drug seeking in the presence of stimuli that signal no drug is available (61), escalation of drug seeking with changes in drug availability (62), responding in the presence of conditioned stimuli (63), or a return of responding that had been previously extinguished (i.e., reinstatement) (64).

The reinstatement procedure has been widely used as a model of the ability of priming injections of drugs, drug-related cues, and stress to precipitate relapse into drug taking (reviewed in reference 65). Although the predictive and construct validity of the procedure remain to be firmly established (66), the ability of noncontingent administration of cocaine to reinstate extinguished responding previously maintained by cocaine has been well established (65). Furthermore, it has been demonstrated that drugs that directly or indirectly activate the dopamine system can reinstate cocaine seeking under a food-drug choice procedure (67). Thus, the reinstatement procedure allowed us another means to assess potential differences in dopamine receptor function between dominant and subordinate monkeys. Socially housed monkeys were allowed to self-administer cocaine under conditions in which they also could choose food reinforcement. Under these conditions, as the cocaine dose increased, the percentage of total responses involving the cocaine-associated lever increased (27). When saline was substituted for cocaine, the monkeys shifted their responses to the food-associated lever (F4). We next examined the ability of noncontingent cocaine to reinstate responses on the cocaine-associated lever, although these responses continued to produce saline injections. Noncontingent cocaine produced dose-related increases in responses on the cocaine-associated lever at doses up to 0.30 mg/kg in all monkeys (data not shown). However, dominant and subordinate monkeys differed in their responses to a higher cocaine dose (0.56 mg/kg). All four subordinate monkeys responded primarily on the injection lever following this dose of cocaine (F4). Greater variability was observed in the dominant monkeys’ responses to this dose. These data are consistent with our earlier results demonstrating that subordinate monkeys are, on average, more sensitive to the reinforcing strength of cocaine and/or less sensitive to the aversive effects of cocaine than are dominant monkeys.

In this review we have attempted to briefly highlight the use of animal models and brain imaging procedures (PET and in vitro receptor autoradiography) to convey a better understanding of the neuropharmacology of drug addiction. The focus on dopamine D2 receptors can be viewed as a strength as well as a limitation. The strength of this focus is the understanding of how the level of this receptor superfamily serves as a trait influencing vulnerability to drug abuse and how it serves as a potential state variable showing malleability as a result of environmental or pharmacological manipulations. The weakness of this focus on D2 receptors is the fact that drug addiction is not mediated by one receptor subtype. Future studies must examine how other neurotransmitter and neurohormone systems change in concert with brain dopamine systems, as well as the development of novel radioligands for specific receptor subtypes (e.g., D3 receptors). In addition, increased anatomical selectivity with higher-resolution PET cameras will better address the contribution of particular brain circuitry to behavioral effects.

The use of animal models to study human disease is an extremely important tool. We have described models that could be characterized as predictive, isomorphic, and homologous of the human condition. In particular, the use of socially housed nonhuman primates to better understand the neuropharmacology and the behavioral and social consequences of drug abuse and to evaluate potential treatment strategies has unequivocal potential. It is our hope that clinicians reading this review will gain a better understanding of the research questions being asked and the potential importance of the results for the development of therapies (behavioral and pharmacological) for drug addiction.

Finally, this review has provided evidence that the environment can profoundly affect drug abuse vulnerability, maintenance, and relapse. Environmental stress and enrichment can influence brain function and vulnerability to drug abuse. Furthermore, even following long-term drug use, environmental variables can affect the behavioral effects of cocaine. The research described in this review represents the growing number of studies documenting the benefits of environmental enrichment, irrespective of genetic predispositions to abuse drugs. Such preclinical findings suggest that outcome measures will be enhanced not only by taking individuals out of a stressful environment but also by providing alternative reinforcers—whether these are better living conditions, jobs, or other activities (68).

 

Presented at the 157th annual meeting of the American Psychiatric Association, New York, May 1–6, 2004. Received Sept. 15, 2004; revision received Feb. 14, 2005; accepted Feb. 22, 2005. From the Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology and Department of Radiology, Wake Forest University School of Medicine. Address correspondence and reprint requests to Dr. Nader, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157; mnader@wfubmc.edu (e-mail). Supported by National Institute on Drug Abuse grants DA-10584, DA-14637, DA-09085, and P50 DA-06634.

 
Anchor for JumpAnchor for JumpAnchor for Jump
Figure 1.

Relationship of Cocaine Self-Administration to Social Rank in Monkeysa

aThe values are averages from the last 3 days that each dose was available for self-administration. The data are adapted from an article by Morgan et al. (40) in Nature Neuroscience (http://www.nature.com/neuro) and are reprinted with permission of Nature Publishing Group.

bSignificantly different from value for dominant group (p<0.05).

 
Anchor for JumpAnchor for JumpAnchor for Jump
Figure 2.

PET Images of [18F]Fluoroclebopride in Dominant and Subordinate Monkeys With Extensive Histories of Cocaine Self-Administrationa

aThe images were coregistered with MRIs from the same monkeys and are shown at the level of the striatum (caudate and putamen). From experiments described by Czoty et al. (51).

 
Anchor for JumpAnchor for JumpAnchor for Jump
Figure 3.

PET Images of [18F]Fluoroclebopride in Cocaine-Naive and Cocaine-Experienced Monkeysa

aImages are shown at the level of the basal ganglia. From an unpublished study by M.A. Nader and R.H. Mach.

 
Anchor for JumpAnchor for JumpAnchor for Jump
Figure 4.

Effect of a Noncontingent Cocaine Injection on Individual Dominant (D1–D4) and Subordinate (S1–S4) Monkeys’ Responses on a Lever Previously Associated With Cocaine but Currently Producing Saline Injectionsa

aThe first bar for each group represents the average injection-lever responding following noncontingent saline injection. A significant difference was observed after noncontingent injection of 0.56 mg/kg cocaine between the dominant and subordinate monkeys. The data are from an unpublished study by P.W. Czoty, C. McCabe, and M.A. Nader.

2003 National Survey on Drug Use and Health (NSDUH). Rockville, Md, US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, National Institute on Drug Abuse, 2004
 
Emergency Department Trends From the Drug Abuse Warning Network, Final Estimates 1994–2001. Rockville, Md, US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, National Institute on Drug Abuse, 2002
 
Mello NK, Negus SS: Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology  1996; 14:375–424
[PubMed]
[CrossRef]
 
Platt DM, Rowlett JK, Spealman RD: Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development. Psychopharmacology (Berl)  2002; 163:265–282
[PubMed]
[CrossRef]
 
Leshner AI: Addiction is a brain disease, and it matters. Science  1997; 278:45–47
[PubMed]
[CrossRef]
 
McLellan AT: Crime and punishment and treatment: latest findings in the treatment of drug-related offenders (editorial). J Subst Abuse Treat  2003; 25:187–188
[PubMed]
[CrossRef]
 
World Health Organization: Neuroscience of Psychoactive Substance Use and Dependence. Geneva, WHO, 2004
 
Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman RD: Effects of cocaine and related drugs in nonhuman primates, I: [3H]cocaine binding sites in caudate-putamen. J Pharmacol Exp Ther  1989; 251:131–141
[PubMed]
 
Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ: Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science  1987; 237:1219–1223
[PubMed]
[CrossRef]
 
Blum K, Cull JC, Braverman ER, Comings DE: Reward deficiency syndrome. Am Sci  1996; 84:132–145
 
Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP: Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse  1993; 14:169–177
[PubMed]
[CrossRef]
 
Young RM, Lawford BR, Nutting A, Noble EP: Advances in molecular genetics and the prevention and treatment of substance misuse: implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav  2004; 29:1275–1294
[PubMed]
[CrossRef]
 
Laruelle M: Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab  2000; 20:423–451
[PubMed]
 
Dewey SL, Smith GS, Logan J, Brodie JD, Yu DW, Ferrieri RA, King PT, MacGregor RR, Martin TP, Wolf AP, Volkow ND, Fowler JS, Meller E: GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci  1992; 12:3773–3780
[PubMed]
 
Mach RH, Nader MA, Ehrenkaufer RL, Line SW, Smith CR, Gage HD, Morton TE: Use of positron emission tomography to study the dynamics of psychostimulant-induced dopamine release. Pharmacol Biochem Behav  1997; 57:477–486
[PubMed]
[CrossRef]
 
Spealman RD, Goldberg SR: Drug self-administration by laboratory animals: control by schedules of reinforcement. Annu Rev Pharmacol Toxicol  1978; 18:313–339
[PubMed]
[CrossRef]
 
Griffiths RR, Bigelow GE, Henningfield JE: Similarities in animal and human drug-taking behavior, in Advances in Substance Abuse, vol 1. Edited by Mello NK. Greenwich, Conn, JAI Press, 1980, pp 1–90
 
Johanson CE, Fischman MW: The pharmacology of cocaine related to its abuse. Pharmacol Rev  1989; 41:3–52
[PubMed]
 
Woolverton WL, Nader MA: Experimental evaluation of the reinforcing effects of drugs, in Testing and Evaluation of Drugs of Abuse. Edited by Adler MW, Cowan A. New York, Wiley-Liss, 1990, pp 165–192
 
Koob GF, Sanna PP, Bloom FE: Neuroscience of addiction. Neuron  1998; 21:467–476
[PubMed]
[CrossRef]
 
Koob GF, Le Moal M: Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology  2001; 24:97–129
[PubMed]
[CrossRef]
 
Piazza PV, Deminiere JM, Le Moal M, Simon H: Factors that predict individual vulnerability to amphetamine self-administration. Science  1989; 245:1511–1513
[PubMed]
[CrossRef]
 
Goeders NE, Guerin GF: Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Psychopharmacology  1994; 114:63–70
[PubMed]
[CrossRef]
 
Goeders NE, Guerin GF: Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats. Brain Res  1996; 722:145–152
[PubMed]
[CrossRef]
 
Paronis CA, Gasior M, Bergman J: Effects of cocaine under concurrent fixed ratio schedules of food and IV drug availability: a novel choice procedure in monkeys. Psychopharmacology (Berl)  2002; 163:283–291
[PubMed]
[CrossRef]
 
Negus SS: Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d–amphetamine and flupenthixol. Neuropsychopharmacology  2003; 28:919–931
[PubMed]
 
Czoty PW, McCabe C, Nader MA: Assessment of the relative reinforcing strength of cocaine in socially housed monkeys using a choice procedure. J Pharmacol Exp Ther  2005; 312:96–102
[PubMed]
 
Nader MA, Wolverton WL: Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology (Berl)  1991; 105:169–174
[PubMed]
[CrossRef]
 
Nader MA, Woolverton WL: Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys. Psychopharmacology (Berl)  1992; 108:295–300
[PubMed]
[CrossRef]
 
Goeders NE: Stress, the hypothalamic-pituitary-adrenal axis, and vulnerability to drug abuse. NIDA Res Monogr  1998; 169:83–104
[PubMed]
 
Dworkin SI, Mirkis S, Smith JE: Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology (Berl)  1995; 117:262–266
[PubMed]
[CrossRef]
 
Bradberry CW: Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine abuse. J Neurosci  2000; 20:7109–7115
[PubMed]
 
Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM: Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis  1982; 2:359–368
[PubMed]
[CrossRef]
 
Berger B, Gaspar P, Verney C: Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci  1991; 14:21–27
[PubMed]
[CrossRef]
 
Haber SN, McFarland NR: The concept of the ventral striatum in nonhuman primates. Ann NY Acad Sci  1999; 877:33–48
[PubMed]
[CrossRef]
 
Joel D, Weiner I: The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience  2000; 96:451–474
[PubMed]
[CrossRef]
 
Cragg SJ, Hille CJ, Greenfield SA: Dopamine release and uptake dynamics within nonhuman primate striatum in vitro. J Neurosci  2000; 20:8209–8217
[PubMed]
 
Lyons D, Friedman DP, Nader MA, Porrino LJ: Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J Neurosci  1996; 16:1230–1238
[PubMed]
 
Porrino LJ, Lyons D, Miller MD, Smith HR, Friedman DP, Daunais JB, Nader MA: Metabolic mapping of the effects of cocaine during the initial phases of self-administration in the nonhuman primate. J Neurosci  2002; 22:7687–7694
[PubMed]
 
Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, Nader SH, Buchheimer N, Ehrenkaufer RL, Nader MA: Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci  2002; 5:169–174
[PubMed]
[CrossRef]
 
Howell LL, Hoffman JM, Votak JR, Landrum AM, Wilcox KM, Lindsey KP: Cocaine-induced brain activation determined by positron emission tomography neuroimaging in conscious rhesus monkeys. Psychopharmacology (Berl)  2002; 159:154–160
[PubMed]
[CrossRef]
 
Lindsey KP, Wilcox KM, Votak JR, Goodman MM, Plisson C, Carroll FI, Rice KC, Howell LL: Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. J Pharmacol Exp Ther  2004; 309:959–969
[PubMed]
[CrossRef]
 
Anthony JC, Warner LA, Kessler RC: Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol  1994; 2:244–268
[CrossRef]
 
Wagner FA, Anthony JC: From first drug use to drug dependence: developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology  2002; 26:479–488
[PubMed]
[CrossRef]
 
Volkow ND, Wang G-J, Fowler JS, Logan J, Gatley SJ, Gifford A, Hitzemann R, Ding Y-S, Pappas N: Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry  1999; 156:1440–1443
[PubMed]
 
Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, Gage HD, Mach RH: The effect of social status on striatal dopamine D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse  1998; 29:80–83
[PubMed]
[CrossRef]
 
Mach RH, Luedtke RR, Unsworth CD, Boundy VA, Nowak PA, Scripko JG, Elder ST, Jackson JR, Hoffman PL, Evora PH, Rao AV, Moilinoff PB, Childers SR, Ehrenkaufer RLE: 18F-Labeled radioligands for studying the dopamine D2 receptor with positron emission tomography. J Med Chem  1993; 36:3707–3720
[PubMed]
[CrossRef]
 
Bowling SL, Rowlett JK, Bardo MT: The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release. Neuropharmacology  1993; 32:885–893
[PubMed]
[CrossRef]
 
Hall FS, Wilkinson LS, Humby T, Inglis W, Kendall DA, Marsden CA, Robbins TW: Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems. Pharmacol Biochem Behav  1998; 59:859–872
[PubMed]
[CrossRef]
 
Thanos PK, Volkow ND, Freimuth P, Umegaki H, Ikari H, Roth G, Ingram DK, Hitzemann R: Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem  2001; 78:1094–1103
[PubMed]
[CrossRef]
 
Czoty PW, Morgan D, Shannon EA, Gage HD, Nader MA: Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine. Psychopharmacology (Berl)  2004; 174:381–388
[PubMed]
 
Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP: Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse  1998; 30:88–96
[PubMed]
[CrossRef]
 
Nader MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR, Friedman DP, Porrino LJ: Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology  2002; 27:35–46
[PubMed]
[CrossRef]
 
Porrino LJ, Lyons D, Letchworth SR, Freedland CS, Nader MA: Structural and functional neuroimaging of the effects of cocaine in human and nonhuman primates, in Handbook of Neurotoxicology, vol 2. Edited by Massaro EJ. Totowa, NJ, Humana Press, 2002, pp 413–435
 
Farfel GM, Kleven MS, Woolverton WL, Seiden LS, Perry BD: Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkeys. Brain Res  1992; 578:235–243
[PubMed]
[CrossRef]
 
Grant S, Contoreggi C, London ED: Drug abusers show impaired performance in a laboratory test of decision making. Neuropsychologia  2000; 38:1180–1187
[PubMed]
[CrossRef]
 
Bechara A, Damasio AR, Damasio H, Anderson SW: Insensitivity to future consequences following damage to human prefrontal cortex. Cognition  1994; 50:7–15
[PubMed]
[CrossRef]
 
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP: Limbic activation during cue-induced cocaine craving. Am J Psychiatry  1999; 156:11–18
[PubMed]
 
Volkow ND, Fowler JS, Wolf AP, Schlyer D, Shiue C-Y, Alpert R, Dewey SL, Logan J, Bendriem B, Christman D, Hitzemann R, Henn F: Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry  1990; 147:719–724
[PubMed]
 
Hommer DM: Functional imaging of craving. Alcohol Res Health  1999; 23:187–196
[PubMed]
 
Deroche-Gamonet V, Belin D, Piazza PV: Evidence for addiction-like behavior in the rat. Science  2004; 305:1014–1017
[PubMed]
[CrossRef]
 
Ahmed SH, Koob GF: Transition from moderate to excessive drug intake: change in hedonic set point. Science  1998; 282:298–300
[PubMed]
[CrossRef]
 
Vanderschuren LJMJ, Everitt BJ: Drug seeking becomes compulsive after prolonged cocaine self-administration. Science  2004; 305:1017–1019
[PubMed]
[CrossRef]
 
de Wit H, Stewart J: Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl)  1981; 75:134–143
[PubMed]
[CrossRef]
 
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J: The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl)  2003; 168:3–20
[PubMed]
[CrossRef]
 
Katz JL, Higgins ST: The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology (Berl)  2003; 168:21–30
[PubMed]
[CrossRef]
 
Gasior M, Paronis CA, Bergman J: Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys. J Pharmacol Exp Ther  2004; 308:249–259
[PubMed]
 
Higgins ST: The influence of alternative reinforcers on cocaine use and abuse: a brief review. Pharmacol Biochem Behav  1997; 57:419–427
[PubMed]
[CrossRef]
 

Figure 1.

Relationship of Cocaine Self-Administration to Social Rank in Monkeysa

aThe values are averages from the last 3 days that each dose was available for self-administration. The data are adapted from an article by Morgan et al. (40) in Nature Neuroscience (http://www.nature.com/neuro) and are reprinted with permission of Nature Publishing Group.

bSignificantly different from value for dominant group (p<0.05).

Figure 2.

PET Images of [18F]Fluoroclebopride in Dominant and Subordinate Monkeys With Extensive Histories of Cocaine Self-Administrationa

aThe images were coregistered with MRIs from the same monkeys and are shown at the level of the striatum (caudate and putamen). From experiments described by Czoty et al. (51).

Figure 3.

PET Images of [18F]Fluoroclebopride in Cocaine-Naive and Cocaine-Experienced Monkeysa

aImages are shown at the level of the basal ganglia. From an unpublished study by M.A. Nader and R.H. Mach.

Figure 4.

Effect of a Noncontingent Cocaine Injection on Individual Dominant (D1–D4) and Subordinate (S1–S4) Monkeys’ Responses on a Lever Previously Associated With Cocaine but Currently Producing Saline Injectionsa

aThe first bar for each group represents the average injection-lever responding following noncontingent saline injection. A significant difference was observed after noncontingent injection of 0.56 mg/kg cocaine between the dominant and subordinate monkeys. The data are from an unpublished study by P.W. Czoty, C. McCabe, and M.A. Nader.

+

References

2003 National Survey on Drug Use and Health (NSDUH). Rockville, Md, US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, National Institute on Drug Abuse, 2004
 
Emergency Department Trends From the Drug Abuse Warning Network, Final Estimates 1994–2001. Rockville, Md, US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, National Institute on Drug Abuse, 2002
 
Mello NK, Negus SS: Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology  1996; 14:375–424
[PubMed]
[CrossRef]
 
Platt DM, Rowlett JK, Spealman RD: Behavioral effects of cocaine and dopaminergic strategies for preclinical medication development. Psychopharmacology (Berl)  2002; 163:265–282
[PubMed]
[CrossRef]
 
Leshner AI: Addiction is a brain disease, and it matters. Science  1997; 278:45–47
[PubMed]
[CrossRef]
 
McLellan AT: Crime and punishment and treatment: latest findings in the treatment of drug-related offenders (editorial). J Subst Abuse Treat  2003; 25:187–188
[PubMed]
[CrossRef]
 
World Health Organization: Neuroscience of Psychoactive Substance Use and Dependence. Geneva, WHO, 2004
 
Madras BK, Fahey MA, Bergman J, Canfield DR, Spealman RD: Effects of cocaine and related drugs in nonhuman primates, I: [3H]cocaine binding sites in caudate-putamen. J Pharmacol Exp Ther  1989; 251:131–141
[PubMed]
 
Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ: Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science  1987; 237:1219–1223
[PubMed]
[CrossRef]
 
Blum K, Cull JC, Braverman ER, Comings DE: Reward deficiency syndrome. Am Sci  1996; 84:132–145
 
Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ, Dewey SL, Wolf AP: Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse  1993; 14:169–177
[PubMed]
[CrossRef]
 
Young RM, Lawford BR, Nutting A, Noble EP: Advances in molecular genetics and the prevention and treatment of substance misuse: implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav  2004; 29:1275–1294
[PubMed]
[CrossRef]
 
Laruelle M: Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab  2000; 20:423–451
[PubMed]
 
Dewey SL, Smith GS, Logan J, Brodie JD, Yu DW, Ferrieri RA, King PT, MacGregor RR, Martin TP, Wolf AP, Volkow ND, Fowler JS, Meller E: GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci  1992; 12:3773–3780
[PubMed]
 
Mach RH, Nader MA, Ehrenkaufer RL, Line SW, Smith CR, Gage HD, Morton TE: Use of positron emission tomography to study the dynamics of psychostimulant-induced dopamine release. Pharmacol Biochem Behav  1997; 57:477–486
[PubMed]
[CrossRef]
 
Spealman RD, Goldberg SR: Drug self-administration by laboratory animals: control by schedules of reinforcement. Annu Rev Pharmacol Toxicol  1978; 18:313–339
[PubMed]
[CrossRef]
 
Griffiths RR, Bigelow GE, Henningfield JE: Similarities in animal and human drug-taking behavior, in Advances in Substance Abuse, vol 1. Edited by Mello NK. Greenwich, Conn, JAI Press, 1980, pp 1–90
 
Johanson CE, Fischman MW: The pharmacology of cocaine related to its abuse. Pharmacol Rev  1989; 41:3–52
[PubMed]
 
Woolverton WL, Nader MA: Experimental evaluation of the reinforcing effects of drugs, in Testing and Evaluation of Drugs of Abuse. Edited by Adler MW, Cowan A. New York, Wiley-Liss, 1990, pp 165–192
 
Koob GF, Sanna PP, Bloom FE: Neuroscience of addiction. Neuron  1998; 21:467–476
[PubMed]
[CrossRef]
 
Koob GF, Le Moal M: Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology  2001; 24:97–129
[PubMed]
[CrossRef]
 
Piazza PV, Deminiere JM, Le Moal M, Simon H: Factors that predict individual vulnerability to amphetamine self-administration. Science  1989; 245:1511–1513
[PubMed]
[CrossRef]
 
Goeders NE, Guerin GF: Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Psychopharmacology  1994; 114:63–70
[PubMed]
[CrossRef]
 
Goeders NE, Guerin GF: Effects of surgical and pharmacological adrenalectomy on the initiation and maintenance of intravenous cocaine self-administration in rats. Brain Res  1996; 722:145–152
[PubMed]
[CrossRef]
 
Paronis CA, Gasior M, Bergman J: Effects of cocaine under concurrent fixed ratio schedules of food and IV drug availability: a novel choice procedure in monkeys. Psychopharmacology (Berl)  2002; 163:283–291
[PubMed]
[CrossRef]
 
Negus SS: Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d–amphetamine and flupenthixol. Neuropsychopharmacology  2003; 28:919–931
[PubMed]
 
Czoty PW, McCabe C, Nader MA: Assessment of the relative reinforcing strength of cocaine in socially housed monkeys using a choice procedure. J Pharmacol Exp Ther  2005; 312:96–102
[PubMed]
 
Nader MA, Wolverton WL: Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure. Psychopharmacology (Berl)  1991; 105:169–174
[PubMed]
[CrossRef]
 
Nader MA, Woolverton WL: Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys. Psychopharmacology (Berl)  1992; 108:295–300
[PubMed]
[CrossRef]
 
Goeders NE: Stress, the hypothalamic-pituitary-adrenal axis, and vulnerability to drug abuse. NIDA Res Monogr  1998; 169:83–104
[PubMed]
 
Dworkin SI, Mirkis S, Smith JE: Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology (Berl)  1995; 117:262–266
[PubMed]
[CrossRef]
 
Bradberry CW: Acute and chronic dopamine dynamics in a nonhuman primate model of recreational cocaine abuse. J Neurosci  2000; 20:7109–7115
[PubMed]
 
Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM: Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis  1982; 2:359–368
[PubMed]
[CrossRef]
 
Berger B, Gaspar P, Verney C: Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents and primates. Trends Neurosci  1991; 14:21–27
[PubMed]
[CrossRef]
 
Haber SN, McFarland NR: The concept of the ventral striatum in nonhuman primates. Ann NY Acad Sci  1999; 877:33–48
[PubMed]
[CrossRef]
 
Joel D, Weiner I: The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience  2000; 96:451–474
[PubMed]
[CrossRef]
 
Cragg SJ, Hille CJ, Greenfield SA: Dopamine release and uptake dynamics within nonhuman primate striatum in vitro. J Neurosci  2000; 20:8209–8217
[PubMed]
 
Lyons D, Friedman DP, Nader MA, Porrino LJ: Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J Neurosci  1996; 16:1230–1238
[PubMed]
 
Porrino LJ, Lyons D, Miller MD, Smith HR, Friedman DP, Daunais JB, Nader MA: Metabolic mapping of the effects of cocaine during the initial phases of self-administration in the nonhuman primate. J Neurosci  2002; 22:7687–7694
[PubMed]
 
Morgan D, Grant KA, Gage HD, Mach RH, Kaplan JR, Prioleau O, Nader SH, Buchheimer N, Ehrenkaufer RL, Nader MA: Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat Neurosci  2002; 5:169–174
[PubMed]
[CrossRef]
 
Howell LL, Hoffman JM, Votak JR, Landrum AM, Wilcox KM, Lindsey KP: Cocaine-induced brain activation determined by positron emission tomography neuroimaging in conscious rhesus monkeys. Psychopharmacology (Berl)  2002; 159:154–160
[PubMed]
[CrossRef]
 
Lindsey KP, Wilcox KM, Votak JR, Goodman MM, Plisson C, Carroll FI, Rice KC, Howell LL: Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. J Pharmacol Exp Ther  2004; 309:959–969
[PubMed]
[CrossRef]
 
Anthony JC, Warner LA, Kessler RC: Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol  1994; 2:244–268
[CrossRef]
 
Wagner FA, Anthony JC: From first drug use to drug dependence: developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology  2002; 26:479–488
[PubMed]
[CrossRef]
 
Volkow ND, Wang G-J, Fowler JS, Logan J, Gatley SJ, Gifford A, Hitzemann R, Ding Y-S, Pappas N: Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry  1999; 156:1440–1443
[PubMed]
 
Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, Gage HD, Mach RH: The effect of social status on striatal dopamine D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse  1998; 29:80–83
[PubMed]
[CrossRef]
 
Mach RH, Luedtke RR, Unsworth CD, Boundy VA, Nowak PA, Scripko JG, Elder ST, Jackson JR, Hoffman PL, Evora PH, Rao AV, Moilinoff PB, Childers SR, Ehrenkaufer RLE: 18F-Labeled radioligands for studying the dopamine D2 receptor with positron emission tomography. J Med Chem  1993; 36:3707–3720
[PubMed]
[CrossRef]
 
Bowling SL, Rowlett JK, Bardo MT: The effect of environmental enrichment on amphetamine-stimulated locomotor activity, dopamine synthesis and dopamine release. Neuropharmacology  1993; 32:885–893
[PubMed]
[CrossRef]
 
Hall FS, Wilkinson LS, Humby T, Inglis W, Kendall DA, Marsden CA, Robbins TW: Isolation rearing in rats: pre- and postsynaptic changes in striatal dopaminergic systems. Pharmacol Biochem Behav  1998; 59:859–872
[PubMed]
[CrossRef]
 
Thanos PK, Volkow ND, Freimuth P, Umegaki H, Ikari H, Roth G, Ingram DK, Hitzemann R: Overexpression of dopamine D2 receptors reduces alcohol self-administration. J Neurochem  2001; 78:1094–1103
[PubMed]
[CrossRef]
 
Czoty PW, Morgan D, Shannon EA, Gage HD, Nader MA: Characterization of dopamine D1 and D2 receptor function in socially housed cynomolgus monkeys self-administering cocaine. Psychopharmacology (Berl)  2004; 174:381–388
[PubMed]
 
Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP: Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse  1998; 30:88–96
[PubMed]
[CrossRef]
 
Nader MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR, Friedman DP, Porrino LJ: Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology  2002; 27:35–46
[PubMed]
[CrossRef]
 
Porrino LJ, Lyons D, Letchworth SR, Freedland CS, Nader MA: Structural and functional neuroimaging of the effects of cocaine in human and nonhuman primates, in Handbook of Neurotoxicology, vol 2. Edited by Massaro EJ. Totowa, NJ, Humana Press, 2002, pp 413–435
 
Farfel GM, Kleven MS, Woolverton WL, Seiden LS, Perry BD: Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkeys. Brain Res  1992; 578:235–243
[PubMed]
[CrossRef]
 
Grant S, Contoreggi C, London ED: Drug abusers show impaired performance in a laboratory test of decision making. Neuropsychologia  2000; 38:1180–1187
[PubMed]
[CrossRef]
 
Bechara A, Damasio AR, Damasio H, Anderson SW: Insensitivity to future consequences following damage to human prefrontal cortex. Cognition  1994; 50:7–15
[PubMed]
[CrossRef]
 
Childress AR, Mozley PD, McElgin W, Fitzgerald J, Reivich M, O’Brien CP: Limbic activation during cue-induced cocaine craving. Am J Psychiatry  1999; 156:11–18
[PubMed]
 
Volkow ND, Fowler JS, Wolf AP, Schlyer D, Shiue C-Y, Alpert R, Dewey SL, Logan J, Bendriem B, Christman D, Hitzemann R, Henn F: Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry  1990; 147:719–724
[PubMed]
 
Hommer DM: Functional imaging of craving. Alcohol Res Health  1999; 23:187–196
[PubMed]
 
Deroche-Gamonet V, Belin D, Piazza PV: Evidence for addiction-like behavior in the rat. Science  2004; 305:1014–1017
[PubMed]
[CrossRef]
 
Ahmed SH, Koob GF: Transition from moderate to excessive drug intake: change in hedonic set point. Science  1998; 282:298–300
[PubMed]
[CrossRef]
 
Vanderschuren LJMJ, Everitt BJ: Drug seeking becomes compulsive after prolonged cocaine self-administration. Science  2004; 305:1017–1019
[PubMed]
[CrossRef]
 
de Wit H, Stewart J: Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology (Berl)  1981; 75:134–143
[PubMed]
[CrossRef]
 
Shaham Y, Shalev U, Lu L, De Wit H, Stewart J: The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl)  2003; 168:3–20
[PubMed]
[CrossRef]
 
Katz JL, Higgins ST: The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology (Berl)  2003; 168:21–30
[PubMed]
[CrossRef]
 
Gasior M, Paronis CA, Bergman J: Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys. J Pharmacol Exp Ther  2004; 308:249–259
[PubMed]
 
Higgins ST: The influence of alternative reinforcers on cocaine use and abuse: a brief review. Pharmacol Biochem Behav  1997; 57:419–427
[PubMed]
[CrossRef]
 
+
+

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Web of Science® Times Cited: 65

Related Content
Articles
Books
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 49.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 49.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 58.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 10.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 49.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles