The present study is the first to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates. Initial experiments characterized the acute effects of cocaine administered noncontingently in drug-naïve rhesus monkeys. Repeated baseline determinations of cerebral blood flow prior to drug administration were reliable, and brain activation maps normalized to global flow showed prominent cocaine-induced activation of prefrontal cortex localized primarily to the dorsolateral regions. Subsequent experiments characterized the effects of cocaine during active drug self-administration protocols in the same subjects. They were trained initially to respond for intravenous injections of cocaine under a fixed ratio 20 schedule in the presence of a red light, and the stimulus lights changed to white during drug infusion. Appropriate stimulus control of self-administration behavior was established, as evidenced by a lack of responding in the absence of the red light. Compared to noncontingent cocaine administration, the pattern of brain activation induced by self-administered cocaine during the simple fixed ratio schedule differed qualitatively. The area of major activation included anterior cingulate cortex, a region associated with the extended limbic system. A final series of experiments using a complex second-order schedule determined the pattern of brain activation induced by drug-associated stimuli in the absence of cocaine. When the effects of drug-associated stimuli were determined during extinction, there were marked increases in regional cerebral blood flow in the dorsomedial prefrontal cortex, indicating robust cortical activation. Collectively, the results document qualitative differences in the pattern of brain activation induced by cocaine during contingent versus noncontingent drug administration. Moreover, drug-associated stimuli can induce robust activation of prefrontal cortex in subjects with a complex history of drug use. The brain activation induced by cocaine and drug-associated stimuli provides a conceptual framework for characterizing the effects of potential medications on brain activity in awake, behaving monkeys.
The differences observed in the pattern of brain activation following noncontingent versus self-administered cocaine is consistent with a growing literature reporting both quantitative and qualitative differences in the response to cocaine depending on whether the drug is administered passively or self-administered. For example, the presence or absence of response dependency can significantly alter the lethal effects of cocaine in rats (Dworkin et al. 1995
). Similarly, self-administered cocaine leads to greater increases in extracellular dopamine in the nucleus accumbens of rats compared to response-independent drug administration (Hemby et al. 1997
). Of particular relevance to the present study, the brain metabolic effects of self-administered cocaine in rhesus monkeys (Porrino et al. 2002
) differed qualitatively from results obtained in previous experiments utilizing noncontingent drug administration in drug-naïve monkeys (Lyons et al. 1996
). Specifically, cocaine self-administration induced a more restricted distribution of changes in functional activity in the medial and orbital prefrontal cortex. Another notable difference was the elevation in cerebral metabolic rates within the dorsolateral and dorsomedial prefrontal cortex of the self-administering animals. In the present study, the history of drug intake also may have contributed to the differences observed following noncontingent versus contingent drug administration. The effects of noncontingent cocaine administration were determined in drug-naïve subjects, whereas self-administration training by necessity required a more extended drug history. Significant differences have been reported in the brain metabolic effects of self-administered cocaine in the striatum of rhesus monkeys based on duration of drug exposure (Porrino et al. 2004
). Specifically, in the initial phases of cocaine exposure, self-administration significantly decreased activity in the ventral striatum. In contrast, extended exposure lead to more intense and widespread metabolic effects that included most aspects of the caudate and putamen.
Second-order schedules of drug self-administration allow the investigation of more complex behavioral sequences than do simple schedules and accordingly may better reflect the human condition (Katz and Goldberg 1991
; Schindler et al. 2002
). Importantly, brief stimulus presentations are critical to the acquisition and maintenance of responding, providing a reliable method to evaluate the effects of conditioned stimuli on drug self-administration behavior. The present study utilized a second-order schedule of cocaine self-administration to characterize the effects of conditioned stimuli on cerebral blood flow under extinction conditions and demonstrated robust activation of prefrontal cortex in the absence of pharmacological effects. It should be noted, however, that the lack of direct pharmacological effects may have been due to the spacing of drug injections over a 30-min period, thereby leading to modest blood levels at the time of scan acquisition. The results obtained under extinction conditions are consistent with studies reporting conditioned responses to drug-associated environmental stimuli in humans. It is well documented that cocaine cues can effectively elicit physiological responses and self-reports of cocaine craving and withdrawal (Ehrman et al. 1992
). One potential mechanism is cue-induced dopamine release in the dorsal striatum (Volkow et al. 2006a
). Others have reported conditioned dopamine release in the ventral striatum in response to amphetamine cues (Boileau et al. 2007
). Interestingly, oral methylphenidate administration in cocaine abusers significantly increased dopamine in the striatum as measured by displacement of C11 raclopride but failed to induce craving unless subjects were concomitantly exposed to cocaine cues (Volkow et al. 2008
). Similarly, drug-associated cues have been shown to modulate the brain metabolic effects of stimulants in cocaine abusers. In one study, the brain metabolic effects of methylphenidate were enhanced in cocaine abusers when methylphenidate was administered in the presence of methylphenidate-associated cues (Volkow et al. 2003
). Drug-induced increases in self reports of “high” were also greater when subjects received methylphenidate in the presence of methylphenidate-associated cues, and self-report measures were significantly correlated with brain metabolic effects. Similar results have been reported for subjects who had minimal experience with stimulant drugs (Volkow et al. 2006b
). It is apparent that conditioning and environmental stimuli can modulate the neurochemical, physiological, and behavioral effects of stimulants, having a profound influence on their addictive properties.
Functional brain imaging has begun to define the neural circuitry underlying the acute pharmacological effects of cocaine, conditioned responses to cocaine-cues, and the experience of drug craving in humans. Activation of the anterior cingulate has been observed in response to acute administration of cocaine and related stimulants (Breiter et al. 1997
; Volkow et al. 1999
) and cocaine-related environmental cues (Maas et al. 1998
; Childress et al. 1999
; Kilts et al. 2001
; Wexler et al. 2001
). Moreover, activation of the dorsolateral prefrontal cortex has also been observed in response to cocaine (Kufahl et al. 2005
) and cocaine cues (Maas et al. 1998
; Grant et al. 1996
). These reliable regional effects highlight the important role of an integrated circuitry in the context of cocaine addiction. The anterior cingulate, part of the extended limbic system, is anatomically linked to the prefrontal cortex and nucleus accumbens and serves diverse functions including the integration of mood and cognition (Vogt et al. 1992
; Devinsky et al. 1995
). The dorsolateral and dorsomedial prefrontal cortices are activated during the performance of a variety of cognitive tasks that require working memory or goaldirected behavior (Fuster 1997
). Hence, it is apparent that the effects of cocaine and associated cues extend beyond the limbic system to engage brain areas underlying complex cognitive processes. In the present study, the same neuroanatomical regions as reported in humans subjects were activated during cocaine self-administration and extinction in rhesus monkeys, establishing strong validity for the nonhuman primate model employed. Elevations in rates of glucose utilization in the same brain areas following cocaine self-administration in rhesus monkeys have also been reported (Porrino et al. 2002
). Obviously, self-reports of drug craving cannot be obtained in animal studies. However, the distinct pattern of brain activation observed in the present study may provide a novel functional measure to assess interventions designed to attenuate cue-induced changes in brain activity.
In summary, this is the first study to use functional brain imaging to document acute cocaine-induced changes in brain activity during active drug use in nonhuman primates. There are significant challenges associated with the conduct of imaging in behaving nonhuman primates that impose limitations in the experimental design and interpretation of results. Subjects must undergo extensive periods of training and habituation to immobilization. The establishment of reliable stimulus control of behavior in a technically demanding environment is difficult. Moreover, the costs associated with PET imaging can be prohibitive. Accordingly, the current study was restricted to a single dose of cocaine in each experimental condition. The qualitative differences observed may have been related, in part, to differences in the effective concentration of cocaine. The interpretation of results clearly would benefit from parametric manipulation of drug dose. In addition, the use of PET imaging and O15 water imposes limitations on the temporal resolution of brain activation and the identification of underlying neural circuitry. While fMRI allows for continuous measurement of cerebral blood flow with outstanding temporal resolution, the technology and environment create additional challenges for awake animal imaging. Despite the inherent challenges and limitations, the results obtained in the present study are consistent with studies reporting the acute effects of cocaine or cocaine cues on brain activity in humans. The identification of neural circuits underlying the direct pharmacological and conditioned stimulus effects of cocaine may be highly relevant toward efforts to develop pharmacological treatments for cocaine addiction. There is recent evidence to suggest that the pattern and time course of brain activation in response to cocaine cues may predict treatment outcomes in human addicts (Kosten et al. 2006
). Moreover, pretreatments with a selective serotonin transporter inhibitor were effective in blocking cocaine-induced brain activation in rhesus monkeys (Howell et al. 2002
). It remains to be determined whether similar pharmacological treatments will be equally effective in attenuating cue-induced brain activation.