Orbital and Medial Prefrontal Cortex and Psychostimulant Abuse: Studies in Animal Models

Linda J. Porrino and David Lyons

Center for the Neurobiological Investigation of Abused Drugs, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA


    Abstract
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
One approach to pursuing questions about the neural substrates that support substance abuse-related behaviors involves the use of animal models. Carefully controlled animal experiments can be conducted without the confounds commonly found in studies of human addicts, such as polydrug abuse, variable drug history and premorbid psychiatric conditions. The present paper considers the orbitofrontal and related limbic prefrontal cortex in the context of such models of substance abuse. First, the importance of recognizing the heterogeneous structural and functional nature of orbitofrontal cortex in both rodents and primates is addressed, and the results of studies involving the prefrontal cortex in substance abuse-related behaviors are considered in light of this diversity. Second, data from metabolic mapping studies are described that indicate that the pattern of functional activity within medial and orbitofrontal cortex shifts as the duration of exposure to drugs such as cocaine is extended. These functional differences, in turn, may reflect progressive phases of the addictive process. In order to understand the neurobiological consequences of long-term drug use, it will be important to establish the differing roles played by distinct anatomical territories within orbital and medial prefrontal cortex during the course of chronic substance abuse.


    Introduction
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Addiction to drugs is often characterized by an inability to control substance-taking behavior with respect to onset, termination or levels of substance use, a strong sense of compulsion to take the substance, as well as a progressive neglect of alternative pleasures, and persistence of substance use despite evidence of harmful consequences. It should be noted that most drug use does not necessarily involve addiction or dependence. In fact, the use of psychoactive substances to produce pleasurable sensations dates back to the earliest days of civilization. It is commonly believed that it is this property, the capacity to elicit euphoria, that is in part responsible for their use, as well as a contributing factor in the development of addiction. Euphoria is only the starting point, however. The formation of addiction to drug use and the development of cognitive deficits that can accompany drug abuse occur after chronic repeated exposure. Rather than the acute pleasure or euphoria that appears to drive the early use of illicit drugs, it is these long-term progressive effects that are likely to underlie many of the physiological and psychological pathologies linked to substance abuse.


    Brain Reward Circuitry
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Much research has been devoted to understanding the way in which abused substances produce their pleasurable effects. For many of these substances it is the activation of dopaminergic transmission in the mesolimbic system that appears central for their reinforcing actions (Koob and Bloom, 1988Go; Wise and Rompre, 1989Go; Le Moal and Simon, 1991Go). The dopaminergic pathway extending from the ventral tegmental area to the nucleus accumbens has come to be known as the ‘brain reward circuit'.

Although the mesolimbic dopamine pathway from the ventral tegmental area to the nucleus accumbens forms a critical substrate of the positive-reinforcement brought about by abused drugs, this circuit cannot be considered in isolation. The intricacy of afferent and efferent connections of this circuit is illustrated schematically, though not exhaustively, in Figure 1Go. This figure shows that the mesolimbic pathway is embedded within a complex network of interrelated structures, each of which may influence drug-related behaviors in a unique manner. Afferent systems may convey information about both the internal and external environment, as well as provide context and emotional tone. For this reason, recent research has begun to focus on identifying the role played by those brain regions that both innervate the nucleus accumbens and receive projections from it.



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Figure 1.  Schematic representation of the connections of the ventral striatum within the limbic system of rats. The afferent and efferent projections depicted in this diagram are not intended to be an exhaustive survey, but merely to illustrate the complexity of the neuroanatomical network in which the nucleus accumbens is embedded.

 
In trying to discern the role of these brain regions, however, it is important to focus not only on the positive-reinforcing effects of drugs, but the role that these brain regions may play in other aspects of substance use and the addictive process, e.g. craving, transition to compulsive drug use, withdrawal and the deleterious consequences of chronic drug use. The recent development of new animal models, e.g. by Ahmed and Koob (Ahmed and Koob, 1998Go), may prove particularly fruitful in expanding our understanding about how the connections of the mesolimbic pathway specifically contribute to these other aspects of drug abuse. Many of these areas may not be necessary for the experience of reward, but may be central to these other aspects of drug abuse. In this article, we will explore the potential role of one of the principal sources of afferent projections to the nucleus accumbens, the prefrontal cortex, in the addictive process. Although psychostimulants are the primary focus of this discussion, many of the same issues are relevant for other abused substances. We will focus on two important considerations regarding the prefrontal cortex: the structural and functional heterogeneity of this expanse of cortex in both rodents and primates, and the effects that chronic drug use have in this brain region.


    Problems in Defining Orbitofrontal Cortex
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Nora Volkow and her colleagues (Volkow et al., 1991Go, 1992Go, 1993Go) have highlighted the importance of cortical afferents of the nucleus accumbens in investigations of human cocaine abusers studied with positron emission tomography. These researchers demonstrated that functional activity in portions of the frontal cortex of cocaine addicts was persistently reduced for up to 3 months following cessation of drug use. Although these studies indicate that the prefrontal cortex of human addicts underwent considerable functional alteration as a result of chronic drug use, comparable studies of the prefrontal cortex in animal models of substance abuse have been much more challenging to interpret. This difficulty stems from problems in identifying an homologous brain region in animals, especially in rodents. Because much of what we know about the neurobiology of substance abuse derives from studies in rodents, the question of homology is central.

Early attempts to define prefrontal cortical areas in rodents that are homologous with those of primates were based on patterns of connectivity of the cortex with the mediodorsal nucleus of the thalamus (Leonard, 1969Go). With more refined anatomical methods it became evident that cortical territories receive projections from multiple thalamic nuclei. It is difficult, therefore, to draw unambiguous conclusions based solely on thalamic connectivity patterns. Other approaches have been based largely on functional considerations (Kolb, 1984Go, 1990Go). To date, however, there has been no definitive answer as to the exact extent of cortex in rodents that is homologous to orbitofrontal cortex in primates.

Regardless of the definition that is used, the cortical territories included in such definitions contain both structurally and functionally distinct cortical subdivisions. From a cytoarchitectural standpoint, the rodent prefrontal cortex includes dorsal and ventral anterior cingulate, prelimbic, infralimbic, medial and lateral orbital, and dorsal and ventral agranular insular cortices (Zilles and Wree, 1995Go). Furthermore, these areas each have distinctive patterns of connectivity (Leonard, 1969Go; Krettek and Price, 1977Go; Van Eden, 1986Go; Groenewegen, 1988Go; Berendese et al., 1992) with which they are associated and subserve dissociable physiological and behavioral functions (Kolb, 1984Go). Most investigators, however, have not considered the anatomical diversity of the prefrontal cortex in their studies and this may account for some of the inconsistencies evident in studies relating the prefrontal cortex to substance abuse.


    Cocaine Self-administration and the Prefrontal Cortex in Rodents
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Some of the earliest evidence for the involvement of the medial prefrontal cortex (mPFC) in the reinforcing effects of psychostimulants derives from the demonstration that rats will self-administer cocaine directly into this region through intracranial cannulae. Intracranial self-administration of cocaine is dose-dependent, and is attenuated by 6-OHDA depletions of dopamine around the area of the cannulae. Furthermore, following these depletions, the substitution of dopamine for cocaine has been shown to reinstate responding for intracranial self-administration (Goeders and Smith, 1983Go, 1986Go), thus establishing the importance of cortical dopamine for this behavior.

These reports, however, are in sharp contrast to later studies that indicate a quite different role for cortical dopamine in cocaine reinforcement. Although there have been several reports that dopamine depletion of mPFC in rats does not disrupt the maintenance of responding for intravenous self-administration of either cocaine or amphetamine (Martin-Iverson et al., 1986Go; Lecceseand Lyness, 1987), more recent reports indicate that rats with similar dopamine depletions both acquired and maintained responding for lower doses of intravenous cocaine than did animals with sham lesions (Schenk et al., 1991Go; McGregor et al., 1996Go). The enhanced responsiveness to cocaine suggested by these studies is analogous to the findings of Piazza and colleagues (Piazza et al., 1991Go), who showed reduced prefrontal dopaminergic activity in rats with a predisposition to acquire self-administration of amphetamine. Thus, unlike the accumbens in which dopamine depletion interrupts IV self-administration behavior, dopamine depletion in prefrontal cortex heightens it. One interpretation of these reports is that dopamine in the prefrontal cortex is involved in behavioral inhibition and that in the absence of dopamine, responding for stimulant self-administration is released from controlling influences, potentially leading to increased drug-seeking behavior.

The role of dopaminergic activity was also addressed in experiments in which SCH23390, a selective D1 receptor antagonist, was injected directly into the mPFC (McGregor and Roberts, 1995Go). D1 blockade increased the rate of cocaine intake when fixed ratio schedules were used and decreased breakpoints when progressive ratio schedules were employed. These findings are suggestive of decreased rather than enhanced reinforcement and appear to contradict some of the studies described above. One of the difficulties in trying to establish a consistent picture of the role of mPFC in substance abuse-related behaviors is the absence of careful anatomical analysis. Since histology is not a consistent feature of many of these reports, there is little way to evaluate the consistency of lesions, depletions or cannulae placement across studies, making unequivocal interpretation exceedingly difficult.

The importance of distinguishing among the subdivisions of the prefrontal cortex is evident in a study by Weissenborn and colleagues (Weissenborn et al., 1997Go). In this study, a secondorder schedule of reinforcement for cocaine self-administration was employed, in which a light previously paired with cocaine infusion was used to maintain responding during the fixed interval components of the schedule. The effects of an excitotoxic lesion restricted to a single subdivision, the dorsal prelimbic cortex, were assessed. In normal rats, omission of the presentation of the conditioned stimulus disrupted patterns of responding and resulted in lower rates of responding in between cocaine infusions, thus establishing the ability of the conditioned stimulus to act as a reinforcer. Although rats with excitotoxic lesions of the dorsal portions of the mPFC acquired responding under this schedule at the same overall rate as controls with sham lesions, their response rates during the fixed interval, when responding should be maintained by the conditioned stimulus, were generally higher than those of controls. Furthermore, the omission of the conditioned stimulus failed to alter either the pattern or rate of responding during the fixed interval as it had for controls, suggesting that the conditioned stimulus was not controlling behavior as it did for control animals.

Although the interpretation of these results is not necessarily straightforward, one potential explanation is that dorsal prelimbic lesions cause a disruption of the incentive properties of cocaine-associated cues or conditioned stimuli. In other words, it appears that after these lesions the animals were less motivated by secondary reinforcers, those stimuli previously paired with cocaine intake. This would be consistent with the lower rates of responding for the conditioned stimulus during the fixed interval components of the second-order schedule, and the lack of response to the omission of this stimulus. Another potential explanation, however, is that lesions of the mPFC result in behavioral disinhibition. This could account for the failure of the omission of the conditioned stimulus to alter behavioral responding. It is also consistent with the more rapid acquisition of cocaine self-administration, as well as the enhanced responding for lower doses of cocaine discussed earlier. These two interpretations both indicate a loss of controlling influences on behavior following lesions of the mPFC. In the case of substance abuse, this could lead to increased or perseverative drug-seeking behavior, a cardinal characteristic of addiction.


    Cocaine Sensitization and the Prefrontal Cortex in Rodents
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Sensitization can be defined as an augmentation of the behavioral response to a drug that occurs with repeated drug exposure. Repeated cocaine administration leads to augmented locomotion and stereotypic behaviors that can persist after the termination of repeated treatment (Downs and Eddy, 1932Go; Post and Rose, 1976Go). There is an emerging consensus that the ventral tegmental area is critical for the initiation of sensitization to psychostimulants, but that the nucleus accumbens is central to its expression once it is established. Although the mesolimbic dopaminergic system is an important component subserving this behavior, the mPFC has been shown to play a role in sensitization as well. The neuroanatomical and neurochemical basis of this behavior has been extensively reviewed (Robinson and Becker, 1986Go; Kalivas and Stewart, 1991Go; Wolf, 1998Go; Pierce and Kalivas, 1997Go).

Wolf and her colleagues, in an elegant series of studies on the initiation or development of sensitization, have shown that ibotenic acid lesions of the mPFC prevent the development of sensitization to the locomotor effects of both repeated amphetamine and cocaine administration, but did not alter the stereotypic responses to these drugs (Wolf et al., 1995Go; Li and Wolf, 1997Go; Wolf, 1998Go). Similar lesions can also block the initiation of sensitization to the intraventral tegmental area administration of amphetamine (Cador et al., 1997Go). In contrast to the effects on the development of sensitization, similar ibotenic acid lesions made after the initiation phase did not disrupt the expression of sensitization to the repeated administration of amphetamine (Li and Wolf, 1997Go; Wolf, 1998Go). When more discrete ibotenic acid lesions were made to distinguish between dorsal and ventral portions of mPFC, Kalivas and his co-workers (Pierce et al., 1998Go) demonstrated that dorsal prefrontal cortex lesions, but not ventral prefrontal cortex lesions, significantly attenuated the expression of cocaine-induced sensitization. Once again, a distinction between subregions of the prefrontal cortex appears to be critical in discerning its role in cocaine-related behaviors. Although dorsal prelimbic lesions such as those in previous studies (Weissenborn et al., 1997Go; Pierce et al., 1998Go) may alter the conditioned or associative properties of stimuli associated with drugs and influence cocaine-related behaviors in this way, the role of other portions of mPFC, e.g. ventral prelimbic and infralimbic cortices, has yet to be explored in as much detail.

The way in which the prefrontal cortex is subdivided may be of particular relevance for determining its functions. The parcellation of mPFC is frequently based on cytoarchitectonic characteristics or in terms of thalamic connectivity. However, patterns of connectivity with the striatum provide another framework for conceptualizing the subdivisions of the prefrontal cortex. The dorsal prelimbic cortex projects largely to the core of the nucleus accumbens, whereas the ventral prelimbic and infralimbic cortices project primarily to the shell (Berendse et al., 1992Go; Brog et al. 1993Go; Wright and Groenewegen, 1995Go). The potential differential functions of these subdivisions of the mPFC may reflect, and in part be responsible for, the differences in the functionality of the core and shell of the nucleus accumbens as substrates of the effects of drugs of abuse. Just as a great deal of attention has been focused on the differences between the subterritories of the nucleus accumbens of late, it may be equally important to distinguish between the subterritories of the mPFC in order to elucidate their respective functional roles.


    Mapping of Prefrontal Cortex in the Rat Following Cocaine Self-administration
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Although a clear picture of the role of the mPFC in cocaine reinforcement or sensitization has not yet emerged, one consistent finding is the presence of changes in the orbitofrontal cortex after long-term exposure to cocaine in humans. Abstinent cocaine abusers, for example, display altered metabolic activity in the orbitofrontal cortex as long as 3 months following their last exposure to cocaine (Volkow et al., 1993Go). It is not possible to discern from studies in human drug-users whether such alterations are due to long-term drug intake or to the pre-existence of functional changes prior to any drug use. Prospective studies cannot be easily carried out in humans, but questions about the specific role of long-term exposure to an individual agent can be directly addressed in animal models, where an unbiased population can be investigated. Therefore, long-term consequences of exposure to cocaine have been the focus of a series of experiments from this laboratory using metabolic mapping methods in animal models of substance abuse.

A recent series of metabolic mapping studies have investigated changes in functional activity that accompany cocaine self-administration in rats (Graham and Porrino, 1995Go). In these studies, the 2-[14C]deoxyglucose (2-DG) method was applied to rats during self-administration sessions, and rates of energy metabolism were compared to those of rats receiving saline infusions in a pattern comparable to the cocaine infusions of selfadministering animals. Intravenous cocaine self-administration produced activation in the rostral portion of the nucleus accumbens, the postgenual anterior cingulate cortex, the lateral septum, basolateral amygdala, as well as structures directly related to movement. These data emphasize that it is the simultaneous activation of an interrelated network of brain regions that respond to cocaine self-administration, rather than a single structure or simple pathway.

One important finding in these studies was that the pattern of changes in glucose utilization associated with cocaine self-administration differed depending on the duration of exposure to cocaine. In those rats that had longer cocaine self-administration experience (>2 weeks), activation was also found in the infralimbic and ventral prelimbic portions of the medial prefrontal cortex, the dorsal and ventral CA1 and CA3 subfields of the hippocampus, and the central nucleus of the amygdala, in addition to the brain regions listed above. Since these effects of cocaine are not present following the initial stages of self-administration, but appear to develop over time, they are unlikely to be necessary for cocaine reinforcement. Rather, they are more likely to be involved in processes associated with later stages of drug use, e.g. craving, escalating drug use, or the development of negative consequences such as increased levels of anxiety and panic.

In addition, the findings that specific alterations in cerebral metabolic activity associated with prolonged cocaine selfadministration were localized within ventral portions of medial prefrontal cortex, i.e. infralimbic and the adjacent ventral portion of the prelimbic cortex, and were not found in more dorsal regions of medial prefrontal cortex, i.e. dorsal prelimbic cortex and anterior cingulate, again emphasize the presence of functional heterogeneity within the prefrontal cortex.


    Mapping Non-human Primate Prefrontal Cortex Following Cocaine Self-administration
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
These studies in rodents indicate that functional changes are found in rodent mPFC following prolonged cocaine selfadministration. Due to our relatively poor understanding of the homology of prefrontal cortex between rodent and primate, however, these results present substantial problems for extrapolation across species. As a result, substance-abuse researchers have adopted strategies similar to those of other investigators studying cognitive functions of prefrontal cortex by turning to non-human primate models.

The primate studies conducted in our laboratory which are discussed here were directed at the identification of the brain regions and circuits in which functional activity is altered by the administration of cocaine in two distinct contexts. In our first study (Lyons et al., 1996Go), cocaine-naive monkeys were administered an intravenous bolus of cocaine (1.0 mg/kg) or saline, and the 2-DG procedure was started immediately afterward. Cocaine administration decreased cerebral glucose utilization in a discrete set of structures that included both cortical and subcortical portions of the limbic system. Within the striatum, for example, glucose metabolism in the core and shell regions of the nucleus accumbens was markedly decreased, and smaller decrements were seen throughout the caudate and the anterior putamen.

Within the prefrontal cortex, a highly confined pattern of altered activity was found concentrated on the ventral and medial surfaces. In order to establish the exact topography of the response to cocaine in the orbitofrontal and medial cortices, a more detailed analysis of this region was performed following the cytoarchitectonic boundaries described by Carmichael and Price (Carmichael and Price, 1994Go, 1996Go). Figure 2Go shows the topography of these sites on a flattened map of the prefrontal cortex in the monkey. Functional changes were greatest in the regions comprising most of areas 11, 12 and 13. Functional change also occurred in diminishing magnitude within the surrounding areas: rostrally in area 10, caudally in the anterior insula in areas Iam, Iai, Iapm, Iapl and area G, and medially in area 14 and areas 25, 32, 24a, 24b and 24c of the anterior cingulate. These effects were in marked contrast to what was observed in other neocortical areas in which no functional changes in sensory, motor or other association areas were evident. The effects of the acute cocaine administration were, therefore, clearly localized to anterior limbic cortical areas. On the basis of the neuroanatomical connectivity patterns, Carmichael and Price (Carmichael and Price, 1996Go) have proposed that the orbital and medial prefrontal cortex can be subdivided into two distinct networks: an orbital prefrontal network comprised of areas in the posterior, lateral and central parts of the orbital cortex; and a medial prefrontal network comprised of areas along the medial wall and the gyrus rectus. Thus, in the study by Lyons et al. (Lyons et al., 1996Go) an acute dose of cocaine produced functional consequences in substantial portions of both of these networks (Fig. 2Go).



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Figure 2.  Distribution of changes in rates of local cerebral glucose utilization in the prefrontal cortex, as assessed by the 2-[14C]deoxyglucose method, accompanying the acute intravenous administration of cocaine (1 mg/kg) in drug-naive cynomolgus monkeys. Shown on the left are three coronal sections adapted from the atlas of Szabo and Cowan (Szabo and Cowan, 1984Go). On the right is a representative unfolded two-dimensional map of the prefrontal cortex adapted from Carmichael and Price (Carmichael and Price, 1994Go). The color coding indicates the differing degrees of decreases in glucose utilization. Cytoarchitectonic areas are defined according to Carmichael and Price (Carmichael and Price, 1996Go). The most intense changes were concentrated in areas 13 and 14. The magnitude of the effect diminished gradually more medially in areas 25, 32 and in the anterior cingulate (24a). Moderate changes were also found rostrally in areas 10 and 11 and caudally in the anterior insular cortex.

 
A second study focused on the consequences of long-term exposure to cocaine self-administration and how that experience alters the functional response to a dose of cocaine. In these studies, rates of glucose utilization in monkeys with long histories of cocaine self-administration (Nader and Reboussin, 1994Go; Nader and Bowen, 1995Go) were compared to rates of cocaine-naive control monkeys. Briefly, self-administering monkeys responded under a fixed-interval 5 min schedule of cocaine (0.3 mg/kg/injection) presentation during daily 4 h sessions. Average session intake of cocaine for the three monkeys was ~1.35 mg/kg, and lifetime cocaine intakes ranged between 431 and 588 mg/kg, delivered over a period of 18–22 months. On the day of the final procedure, self-administering animals made a single lever press to receive a single cocaine infusion (1.0 mg/kg; comparable to the dose used in studies with cocaine-naive monkeys) and the 2-DG method initiated immediately thereafter.

Rates of glucose utilization in self-administering monkeys in this study were compared to rates in cocaine-naive controls used in other experiments. Within the mesolimbic system, cocaine altered cerebral metabolism throughout the ventral striatum, but the most intense changes were found within the shell of the accumbens. Functional activity was also significantly affected in the basolateral, lateral and medial nuclei of the amygdala, as well as in the bed nucleus of the stria terminalis.

The pattern of cortical cerebral metabolism in self-administering monkeys (Fig. 3Go) was strikingly different from that observed in cocaine-treated naive monkeys (Fig. 2Go). Changes in functional activity occupied a far more restricted expanse of the orbital and medial prefrontal cortex following chronic exposure to cocaine than in naive monkeys. Changes were confined largely to the caudal portion of the orbitofrontal cortex in portions of the anterior insular cortex (areas Iam, Iai and Iapm), within the caudomedial portion of area 13 (area 13a), and along the length of the gyrus rectus (areas 14c and 14r). Functional activity in portions of the anterior cingulate cortex along the medial wall, specifically area 24c, was also altered by cocaine infusions in these animals. The administration of cocaine following chronic self-administration exposure resulted in functional changes that were more concentrated within the caudal aspects of the medial network of Carmichael and Price (Carmichael and Price, 1996Go). This is in contrast to the effects of cocaine in drug-naive subjects in which territories comprising both the medial and orbital networks were affected (see Fig. 4Go; cf. Figs 2 and 3GoGo).



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Figure 3.  Distribution of changes in rates of local cerebral glucose utilization in the prefrontal cortex, as assessed by the 2-[14C]deoxyglucose method, accompanying the intravenous self-administration of cocaine (1 mg/kg) in rhesus monkeys with 18–22 months of cocaine self-administration experience. Shown on the left are three coronal sections adapted from the atlas of Szabo and Cowan (Szabo and Cowan, 1984Go). On the right is a representative unfolded two-dimensional map of the prefrontal cortex adapted from Carmichael and Price (Carmichael and Price, 1996Go). The color coding indicates the differing degrees of decreases in glucose utilization. Cytoarchitectonic areas are defined according to Carmichael and Price (Carmichael and Price, 1994Go). The most intense changes were concentrated in the caudomedial part of area 13, the anterior insular cortex (within the caudal regions of the orbitofrontal cortex) and area 14. The effects of a cocaine infusion to chronically exposed monkeys is significantly different from the pattern of changes in drug naive animals (see Fig. 2Go).

 


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Figure 4.  Summary diagram depicting the distribution of changes in functional activity within the monkey orbital and medial prefrontal cortex that accompany cocaine administration. Shading denotes a glucose utilization change of >10%. Note the restricted pattern of changes in cocaine-experienced monkeys as compared to drug-naive monkeys. Those areas projecting predominantly to the core are represented by darker shading and those projecting predominantly to the shell by lighter shading. In cocaine-experienced animals, changes in functional activity occur almost exclusively in those regions that project to the shell of the nucleus accumbens. In contrast, in drug-naive animals, functional changes are present in areas that project to both shell and core. These differences in the patterns of functional changes associated with cocaine administration parallel the changes observed in striatum. Metabolism is altered in both shell and core portions of the ventral striatum of cocaine-naive monkeys, but in experienced animals, metabolism changes are focused within only the shell.

 
The subdivisions of medial and orbital prefrontal cortex affected by cocaine administration in these studies are those in which olfactory, gustatory and visceral information processing occurs (Morecraft et al., 1992Go; Barbas, 1993Go; Rolls and Baylis, 1994Go; Carmichael and Price, 1995Go). These portions of the caudal orbitofrontal cortex are believed to be responsible for learned associations between taste and smell and reinforcement, specifically linking olfactory or gustatory cues to reward (Rolls, 1996Go). Selected neurons in the caudal orbitofrontal cortex are activated when a taste stimulus is rewarding, or if the taste stimulus predicts a reward. Moreover, the responsiveness of specific neurons to stimuli depends on the motivational level of the monkey (Critchley and Rolls, 1996aGo,bGo). Neurons discharge more intensely when the animal is hungry, but when satiated the stimulus no longer alters firing. This suggests that one function of these portions of cortex is to ascribe reward value to specific stimuli in a dynamic fashion (Rolls et al., 1996Go; Tremblay and Schultz, 1999Go). Although the cerebral metabolic data presented here provide no direct evidence per se of a relationship between prefrontal activity and cognitive function, it is tempting to speculate that cocaine may influence the higher-order processing of converging sensory and visceral information that takes place in these brain areas, as well as the formation of associations between various stimuli with the presence of reward.

The restricted changes in cortex following chronic exposure directly parallel the topography of the changes in functional activity within the striatum. In the striatum, chronic cocaine administration also produced a restricted pattern of changes in glucose utilization with the most intense changes occurring in the shell of the nucleus accumbens. It is important to note, as shown in Figure 4Go, that the portions of the orbital and medial prefrontal cortex affected by cocaine in these chronically exposed monkeys predominantly innervate the shell of the nucleus accumbens (Haber, et al., 1995Go; Kunishio and Haber, 1994Go; Chikama et al., 1997Go) (also S.N. Haber, personal communication). In contrast, the cerebral metabolic changes induced by cocaine in drug-naive monkeys were found in both the core and the shell of the nucleus accumbens, as well as in prefrontal cortical regions which innervate both the core and shell. The restriction of functional changes to the projection fields of the shell in cocaine-experienced monkeys parallels the changes within the infralimbic and ventral prelimbic cortices of rats following longer periods of cocaine self-administration experience (Graham and Porrino, 1995Go). These portions of rodent mPFC send selective projections to the shell of the nucleus accumbens (Berendse et al., 1992Go; Brog et al. 1993Go; Wright et al., 1995). In both the rodent and the primate, then, functionality appears to follow patterns of cortico-striatal connectivity.


    Final Considerations
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
Studies of animal models of substance abuse can make important contributions to our understanding of the role of orbital and medial prefrontal cortex in addiction. Studies in animals are necessary for an appreciation of the functional relevance of specific subdivisions of the orbital prefrontal cortex and how these subdivisions may relate to one another. Because lesions in humans rarely obey cytoarchitectonic boundaries, the interpretation of studies in human patients can be confounded by the involvement of multiple cortical areas. Experimental lesions can be placed with far greater precision, and it is also possible to manipulate transmitter systems individually in order to identify the role of each. Another important consideration is the inability to distinguish pre-existing conditions from deficits that accrue from chronic drug exposure. Animals can be tested prior to exposure to drugs, and preand post-drug measures can be compared. Furthermore, drug use in animal models can be controlled and restricted to single substances. Polydrug abuse in humans makes it exceedingly difficult to identify the consequences of any individual substance.

There are, however, many issues that can only be confronted in studies of human addicts. There are aspects of human drug use and abuse that are difficult to model in animals. The contribution of various co-morbid psychiatric disorders to the deficits observed in drug addicts cannot be studied in animals, for example. It is not possible to identify the role that the cortical dysfunction accompanying psychiatric disorders plays in predisposing individuals to become drug addicts. It will be important, therefore, to seek answers from multiple complementary levels of analysis encompassing both animal models and studies in human addicts.

The present discussion first highlighted the importance of recognizing the heterogeneous nature of prefrontal cortex in rodents and primates, and the current need to conduct experiments that define the role played by subregions of frontal cortex in animal models of substance abuse. This paper then described experiments which indicate that the cerebral metabolic response to cocaine changes after prolonged self-administration in both rodents and primates, particularly within limbic prefrontal cortices. These data suggest that information processing within prefrontal cortex changes as exposure increases, which in turn may be important for different phases of the addictive process. The topography of functional changes in orbital and medial prefrontal cortex in the initial phases of substance abuse is likely to be quite different from the topography of the functional changes in later phases of abuse or during withdrawal. In order to fully understand the neurobiological underpinnings of long-term cocaine use and addiction, therefore, it will be important to establish the role played by differing anatomical territories within orbital and medial prefrontal cortex during the time-course of chronic cocaine intake.

Finally, the dichotomy of the nucleus accumbens into shell and core has provided an important framework for the identification of the neurobiological basis of the behaviors that accompany substance abuse. It may be useful at this point to hypothesize with regard to cocaine adminstration that the anatomical conception of the accumbens shell be broadened to include the portions of the cortex innervating the shell. Activity in this entire continuum extending from the orbital and medial prefrontal cortex through the shell to the extended amygdala may be important for the processing of the effects of drugs and drug-related stimuli in the context of long-term selfadministration.


    Notes
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
We thank Hilary Smith, Cory Freedland, and James Daunais for helpful comments on this manuscript and Mack Miller for his work on the figures. This work was supported by National Institutes of Health Grants DA09085 (L.J.P.), DA06634 and DA 11251 (D.L.).

Address correspondence to: Linda J. Porrino, Ph.D., Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA. Email: lporrino{at}wfubmc.edu.


    References
 Top
 Abstract
 Introduction
 Brain Reward Circuitry
 Problems in Defining...
 Cocaine Self-administration and...
 Cocaine Sensitization and the...
 Mapping of Prefrontal Cortex...
 Mapping Non-human Primate...
 Final Considerations
 Notes
 References
 
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