The results of the present study demonstrate that cocaine-dependent subjects have lower levels of endogenous dopamine relative to healthy comparison subjects. Thus, the decrease in baseline D2/D3 receptor binding potential (nondisplaceable binding potential) seen in the cocaine-dependent subjects cannot be attributed to differences in the percentage of D2/D3 receptors occupied by dopamine, and the endogenous dopamine levels may have masked even greater differences between cocaine-dependent and healthy comparison subjects than those differences observed previously.
We assumed that the AMPT-induced increase in D2
receptor binding potential resulted from a reduction in the percentage of receptors bound to endogenous dopamine rather than upregulation of D2
receptors in the setting of dopamine depletion. This assumption was based on previous studies of rodents (3
), which showed that acute dopamine depletion with reserpine, 6-hydroxydopamine, or AMPT did not produce D2
receptor upregulation in the short-term. Notably, the investigators using AMPT (3
) designed their experiment in rodents to emulate their analysis of human subjects, and high-dose AMPT (400 mg/kg per day) was administered in the rodents for the same time period used for the human subjects. Compared with saline-treated animals, no difference was seen in D2
, indicating that receptor upregulation did not occur. However, based on the literature published to date, it is unknown if there are differences in receptor externalization between humans and rodents. In addition, although this dosing regimen is expected to result in a 70%–80% depletion of striatal dopamine (4
), the exact degree of depletion is not known in the absence of animal studies.
The lower levels of endogenous dopamine seen in the present study are consistent with some, although not all, preclinical studies of rodents. Previous studies (13
) have shown either no change or a decrease in the levels of endogenous dopamine in rodents following chronic exposure to cocaine. As outlined in , these studies are almost evenly split between those showing a decrease in baseline levels of dopamine in cocaine-treated rats relative to comparison rats and those showing no difference in this measure. The methods between these studies vary in terms of the amount of cocaine administered, method of cocaine administration (self-administered, investigator-administered, or yoked-administered), and duration of cocaine administration. In general, the studies showing a decrease in endogenous dopamine used a higher dose of cocaine for longer periods of time. In addition, more of these studies used cocaine self-administration, which may be a more accurate reflection of the pattern of cocaine use in humans.
Previously Reported Levels of Baseline Dopamine in Cocaine-Treated Rodents
In the present study, cocaine dependence was associated with a lower AMPT-induced change in [11
C]raclopride binding in the striatum, measured as a whole, and in each of the striatal subdivisions, with the exception of the posterior caudate. There was no significant difference in the baseline measures of D2
receptor binding potential in this brain region between cocaine-dependent and comparison subjects. This finding is consistent with our previous study (2
), which also showed no difference in baseline measures of D2
receptor binding potential in the posterior caudate in a separate cohort of cocaine-dependent and comparison subjects. Together, these data suggest that the posterior caudate is spared in cocaine dependence, both in terms of baseline D2
receptor binding potential and levels of endogenous dopamine, although the rationale for this is not clear. The caudate posterior to the anterior commissure has been rarely investigated in animal studies, and thus it is unknown if there is some inherent difference in this brain region that would cause it to be spared. Moreover, to our knowledge, no other imaging investigator group has compared D2
receptor binding potential between cocaine-dependent and comparison subjects in this brain region, and it will be important for this finding to be replicated.
Although, to the best of our knowledge, this is the first report to measure levels of endogenous dopamine in cocaine-dependent subjects, several previous studies have used PET or SPECT and AMPT to estimate endogenous dopamine levels in healthy comparison subjects. Laruelle et al. (3
) used [123
I]iodobenzamide and AMPT (8 g over a 48-hour period), which produced a 28% (SD=16%) increase in binding potential and a 70% (SD=12%) decrease in homovanillic acid levels in nine healthy subjects. Abi-Dargham et al. (4
) used this same method to assess the occupancy of D2
receptors by endogenous dopamine in schizophrenia patients relative to healthy comparison subjects. AMPT-induced dopamine depletion significantly increased D2
receptor availability by 19% (SD=11%) in patients with schizophrenia relative to 9% (SD=7%) in healthy comparison subjects. Verhoeff et al. (5
) conducted two studies using [11
C]raclopride to measure levels of endogenous dopamine in healthy comparison subjects. The first study reported that AMPT (4.5 g over a 25-hour period) increased [11
C]raclopride binding by 18.5% (SD= 3.0%) in the striatum and produced a 71% (SD=11%) decrease in plasma homovanillic acid levels in six healthy comparison subjects (5
). In their second study, six comparison subjects were imaged with [11
C]raclopride, and AMPT administration (5.35 g over a 29-hour period) resulted in a significant increase in binding potential (13.3% [SD=5.9%]) in the striatum and decreased homovanillic acid levels (62% [SD=17%]) (6
As a result of limited scanner resolution, these previous studies imaged the striatum as a whole and could not separate the signal among the caudate, putamen, and ventral striatum. More recently, studies using the PET radiotracer [18
F]fallypride, which also labels the D2
receptor, and AMPT have measured endogenous dopamine in the subdivisions of the striatum using a high-resolution PET scanner. Riccardi et al. (30
) reported that AMPT (71.4 mg/kg) increased binding potential by 8.8% in the caudate, 11.2% in the putamen, and 10.6% in the ventral striatum in healthy subjects. However, a subsequent study (31
) showed no effect of a lower dose of AMPT (3 g/70 kg per day for 44 hours) on [18
F]fallypride binding in healthy comparison subjects.
Thus, our results in healthy comparison subjects are comparable with those previously reported in the literature, which demonstrate that approximately 10%–20% of D2
receptors are occupied by endogenous dopamine. In addition, we observed no difference among the subdivisions with respect to the percent of D2
receptors occupied by endogenous dopamine in either cocaine-dependent subjects or healthy comparison subjects. This finding in the healthy comparison group is consistent with that of Riccardi et al. (30
), who did not report a difference in the percent of occupied D2
receptors among the caudate, putamen, and ventral striatum in healthy subjects. However, Kegeles et al. (32
) recently reported that, in schizophrenia, the percent of AMPT-induced increase in [11
C]raclopride differed among the striatal subregions and was higher in the anterior caudate compared with the other subdivisions. In the present study, we observed no difference in the AMPT-induced change in [11
C]raclopride binding among the striatal subregions in the cocaine-dependent subjects, suggesting that the levels of endogenous dopamine are fairly uniform throughout the striatum.
It is important to note that previous studies of cocaine dependence have also shown a reduction in presynaptic dopamine release in response to a psychostimulant, measured as a decrease in [11
C]raclopride binding (1
). The increase in synaptic dopamine following psychostimulant administration results in a decrease in [11
C]raclopride binding, presumably as a result of competition between dopamine and the radiotracer for the receptors, although the mechanism is likely more complex than competition alone (34
). In cocaine-dependent subjects, there is a blunting of psychostimulant-induced radiotracer displacement relative to comparison subjects, which is generally interpreted as a reduction in presynaptic dopamine release. However, it is possible that an increase in the percent of D2
receptors occupied by dopamine could produce a blunting of psychostimulant-induced radiotracer displacement. If more receptors are occupied by dopamine in the baseline condition, then fewer receptors would be available to bind to the surge of dopamine produced by the stimulant challenge. In this scenario, it is possible that cocaine dependence is associated with normal or even elevated presynaptic dopamine release (sensitization), but this phenomenon is masked by a high percentage of D2
receptors occupied by dopamine. However, the results of the present study suggest that the blunted stimulant-induced [11
C]raclopride displacement cannot be ascribed to the percent of D2
receptors occupied by endogenous dopamine. Although there may still be other issues that affect this measure of synaptic dopamine (36
), our study demonstrates that an excess of baseline dopamine in cocaine-dependent volunteers is not likely a factor.
Interestingly, only three cocaine-dependent subjects in the present study experienced extrapyramidal symptoms, measured with the Extrapyramidal Symptom Rating Scale, relative to seven healthy comparison subjects. This was unexpected, given that previous studies (37
) have suggested that cocaine abuse increases the risk of extrapyramidal side effects in patients treated with high-potency neuroleptics. However, the cocaine-dependent subjects exhibited less change in endogenous dopamine following AMPT administration, which suggests that the relative change in endogenous dopamine, rather than the absolute levels, may contribute to the development of extrapyramidal symptoms.
In summary, the results of the present study indicate that cocaine dependence is associated with a decrease in the levels of striatal dopamine. Taken in the context of previous studies, these results contribute to a series of findings that provide consistent evidence that cocaine dependence is associated with a decrease in dopamine transmission in the striatum. Imaging studies have shown that cocaine dependence is associated with a reduction in D2
receptors, stimulant-induced presynaptic dopamine release, reduced striatal dopamine synthesis, and—now—a reduction in endogenous dopamine (1