Drugs of abuse such as nicotine, cocaine, and heroin are major problems plaguing the industrialized world. While each of the aforementioned drugs targets a different neurotransmitter system (cholinergic, dopaminergic, and opioid, respectively), there is a general consensus that much of the rewarding effects of the drugs act through the mesocortical limbic dopaminergic system including the sublenticular extended amygdala, hypothalamus, nucleus accumbens, striatum, and frontal cortex. This reward pathway is common to many other drugs of abuse, such as alcohol, as well as behaviors such as sex , video games , and even music . Thus, there is a number of ways for investigating drugs of abuse using fMRI or phMRI. For instance, the effects of the drugs of abuse on cognitive or visual tasks targeting brain regions of interest can be studied. These effects can either be chronic or can be studied during administration of the drug of abuse [147-149]. In the latter case it is of paramount concern to understand the vascular effects of the drug in the absence of any cognitive challenge. Another potentially revealing approach is to study the effects of tasks targeting the reward circuitry in control and addicted populations [150,151]. Such studies maybe of great use in understanding the imbalances in such circuitry that may precipitate or predispose individuals towards abuse. Attention must be paid to the potentially adaptive changes that may take place in, for instance, the dopaminergic system consequent to abuse of the drugs. It is the latter state that may be probed using the acute challenge methodology discussed in Section 10.4.1. In our conception, the acute challenge methodology is most sensitive to the basal state of the target receptors in the brain, and thus in some ways can be likened to a PET study of the receptor populations.
In what follows we will summarize some of the acute challenge phMRI literature that has been published concerning both animal and human studies. We will focus on what may be learned from such studies rather than to catalog the findings.
This category is, by far, the most studied using phMRI methods. Drugs such as cocaine, cocaine analogs, and amphetamine have been studied in both humans and animals. The animal data are reasonably consistent, in that increased CBV or BOLD signal is generally noted in the basal ganglia [5,7,10,152]. More or less cortical activation is seen with the different drugs in dopaminergically related brain areas, such as frontal and insular cortex, similar to prior studies using PET or autoradiography. Data on humans are more difficult to interpret. The reason for this is multifarious. In humans, we are restricted to using the BOLD effect (or the even less sensitive imaging of CBF by MRI). Signal changes due to primary sensory stimuli, such as photic stimulation, are often larger than those detected following cognitive stimuli, thus the cocaine-induced effects (given the relatively small doses used in human studies — usually around 0.5 mg/kg compared with the 1 mg/ kg used in the rodent studies) are often rather small. In addition, work from Hans Breiter's laboratory has shown that expectancy is a severe confound of BOLD signal in, for instance, the nucleus accumbens, as it may determine the amplitude of the baseline BOLD signal . A number of other confounds remain in the human data where acute administration of cocaine can lead to either vasoconstriction, and subsequent decreases in CBV or BOLD in many different brain regions [112,153], but also increased BOLD in limbic areas such as the nucleus accumbens .
The study by Kaufman et al.  is interesting in that there were significant differences in the rCBV induced after 0.4 mg/kg cocaine administration between both men and women, and between women as a function of the menstrual cycle. Some of these decreases in BOLD or rCBV may be related to hyperventilation. Following an infusion of cocaine under double-blind conditions, cocaine-dependent subjects demonstrated significant increases in heart rate and mean arterial blood pressure and decreases in ETCO2 . This latter study demonstrated that correlation maps of the signal changes induced by infusion of cocaine with behavioral measures of either euphoria or craving showed dramatic differences. Craving tended to be associated with activation in the nucleus accumbens and amygdala, while the rush or euphoria tended to correlate with activity in the anterior cingulate, basal forebrain and ventral tegmental area. Administration of cocaine in a double-blind fashion (where neither the subject nor investigator know whether the subject is receiving cocaine or placebo) is required to eliminate the possibility that cues as to the injection will change expectancy, and thereby modulate the signal.
A more recent study of cocaine identified brain regions associated with craving, rush, high, and anxiety during cocaine self-administration in the magnet . The mesocortical limbic system is heavily involved in the high and craving. Numerous elements of the dopaminergic circuitry showed negative correlations of BOLD signal with the high and positive correlations in the same regions with craving. Interestingly, unlike in animal studies, many of these effects appear to be lateralized.
Other studies of brain regions involved in cocaine craving have examined the fMRI response to visual cues of cocaine use to stimulate craving [156,157]. Areas such as the anterior cingulate, dorsolateral prefrontal cortex, and caudate were significantly activated in cocaine-abusing subjects in response to visual cues. These studies do, however, point out that the response to a relatively small injection of cocaine will be a complicated effect of the multifarious cognitive and emotional responses to the drug, in addition to the direct pharmacologic and vasoactive effects.
Most of these studies have been successful in demonstrating the utility of phMRI for evaluating the effects of acute drug challenges to the dopaminergic reward circuitry. However, an assessment of changes in the dopamine system as a function of the addictive process, as well as withdrawal and therapy, has yet to be performed. Such a study could evaluate, for instance, the effects of addiction and withdrawal upon the D2 system, as decreases in D2 binding have been associated with increased cocaine craving and self-administration [158,159]. Such a study, might additionally evaluate changes associated in cocaine-induced activation by pretreatment with D2 agonists or antagonists. Another possibility is to examine changes that might occur in the dopamine transporter protein — the primary target of cocaine and amphetamine. Further correlation of the temporal changes in the acute challenge model (where one would plan to inject cocaine longitudinally in subjects) with the temporal changes in molecules such as CREB and A-FosB  would be invaluable in determining if those time courses were correlated. Such a study would have the capacity to associate potential changes in brain circuitry with molecular events known to correlate with behavioral profiles. For instance, increased CREB activity during the 25 days after cessation of cocaine has been shown to correlate with an acute withdrawal anhedonic effect. Buildup of A-FosB over later times correlated with potentiation of the abuse potential . Such a study (of course in animals) would be of great value when examined concomitantly with behavioral and phMRI studies. Luckily, in humans, repeated injections of cocaine in the laboratory setting do not seem to influence future abuse of the drug .
We discussed above the correlations between extracellular dopamine and the phMRI signal changes. Interestingly, in rhesus monkeys there were no correlations of extracellular dopamine with drug-seeking activity in response to visual cues. There were, however, huge increases in extracellular dopamine induced by cocaine . This is an important factor to keep in mind when trying to assess the origins of increased BOLD or CBF in the brain reward circuitry. Another very important confound is discussed below with respect to nicotine administration.
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