The results of this study show that response to a behavioral treatment for cocaine dependence is related to dopamine signaling in the limbic striatum, measured with PET as dopamine D2/3 receptor binding (BPND) and pre-synaptic dopamine release (ΔBPND). The cocaine dependent subjects who responded to a behavioral treatment that uses positive reinforcement and psychotherapy had higher D2/3 receptor binding and dopamine release (ΔBPND) compared to subjects who experienced relapse in this treatment setting.
Animal studies have previously shown that deficits in dopamine signaling in the nucleus accumbens impair operant conditioning, response inhibition, and behavioral flexibility with respect to reinforced behavior (26
). Lesioning the nucleus accumbens in rodents results in a profound deficit in the animals’ ability to choose appropriately between two reinforcers: they impulsively and consistently chose a lesser reward over a delayed reinforcer of greater value (27
). These findings suggest that dopamine signaling in the limbic striatum is critical for making the shift between competing reinforcers, such that in the setting of low dopamine transmission a habitual behavior is emitted, even in the presence of an alternative reward of greater value. We have demonstrated a similar finding in human cocaine abusers. In two cohorts of cocaine dependent volunteers, non-treatment seeking (10
) and treatment seeking (reported here), low dopamine release in the limbic striatum was associated with the choice to consume cocaine over alternative reinforcers. In each case, subjects with the low dopamine transmission made the non-adaptive choice between competing rewards. Our previous study in the laboratory gave subjects the choice between a low dose of cocaine (6mg) and $5, and the choices were weighted toward the money, since the street value of this dose of cocaine was less than $5. In the present study, subjects presented to the clinic in search of treatment, and could earn money for pursuing their goal. Therefore, in both the non-treatment and the treatment studies, the more adaptive response is to choose money and abstinence over cocaine, yet in both studies there were a number of subjects who reliably chose cocaine. The failure of the cocaine dependent subjects with low dopamine release to alter their behavior can be viewed as a perseverative error in the setting of competing rewards, or as a blunted brain reward system that is unable to respond to alternative sources of reward.
Ultimately the question is whether PET radioligand imaging in human cocaine abusers can be used to guide the development of better treatment. Imaging studies have consistently shown that dopamine transmission is blunted in cocaine dependent subjects compared to controls, measured as four different parameters: 1) reduced baseline D2/3
receptor binding (BPND
) of the post-synaptic neurons (9
); 2) decreased pre-synaptic dopamine release (ΔBPND
); 3) reduction in pre-synaptic neuronal stores of dopamine (28
); and 4) reduced baseline levels of endogenous dopamine (29
). The present study investigated the association between dopamine transmission and response to treatment, and these results show that a positive response is associated with higher D2/3
receptors and greater methylphenidate-induced dopamine release compared to those who failed treatment. These findings suggest that increasing striatal dopamine transmission would be the most appropriate strategy for converting treatment non-responders to responders, either by increasing D2/3
receptors or increasing pre-synaptic dopamine. Previous studies in rodents have shown that using a viral vector to increase striatal D2
receptors reduces the animals’ preference for drugs of abuse (14
). Combined with the data from the present study, it can be surmised that increasing D2/3
would improve treatment response, but this technology is unlikely to translate into human use in the near future.
Another approach is to increase pre-synaptic dopamine release. A number of previous clinical trials have investigated medications that increase striatal dopamine transmission, and while some report success, others do not (31
). One reason for this inconsistency may be that medications that are known to increase dopamine transmission in the non-addicted brain may have a minimal effect in the addicted brain, as shown by this study. Notably, a recent study by Schmitz et al (32
) reported that treatment of cocaine abusers with contingency management and levodopa/carbidopa, which would be expected to improve dopamine transmission by increasing pre-synaptic stores in the striatum, resulted in a greater response to treatment compared to placebo. Another approach may be to increase dopamine transmission by targeting other receptor systems, such as the kappa or acetylcholine receptors (for review see (33
) or others. Together, these findings strongly suggest that the combination of pharmacology to address the deficit in dopamine transmission combined with a behavioral treatment that presents tangible alternatives to cocaine use, may provide the best approach for the treatment of cocaine addiction.
This study also examined the effect of treatment on dopamine receptor binding and pre-synaptic dopamine release. No effect of treatment was seen in the nine treatment responders who were scanned before and after treatment, contrary to our hypothesis. However, it is interesting that the treatment responders did not differ from the control subjects prior to treatment, suggesting that pre-synaptic dopamine was largely intact in the responders to begin with. Among the non-responders, only six returned for scans after 3 months, and there was also no change in dopamine receptor binding or dopamine release, which is expected since these subjects had continued their cocaine use.
Previous studies using fMRI have investigated the correlation between brain activation and treatment response (35
). Kosten et al (35
) showed that low treatment effectiveness correlated with greater cue-induced activation of sensory, motor, and limbic cortical areas while Moeller et al (36
) used a working memory task to show that cocaine dependent subjects with low thalamic activation had a poor treatment response. A limitation of PET imaging with [11
C]raclopride is that our investigations are limited to the striatum and other brain regions are also likely to play a critical role in the human condition (for review see (37
)). However, imaging with [11
C]raclopride allows a more direct investigation of the aberration in chemistry that occurs with drug addiction, which may provide more guidance in the selection of candidate medications.
Based on previous studies in both animals and humans showing that the limbic striatum is most directly involved in reward related behaviors, we limited our initial analysis to the limbic striatum. With this constraint, both BPND
were significantly lower in the non-responders. However, had we used correction for multiple observations (which would have been necessary had out hypothesis included all regions) only the finding with ΔBPND
would have reached significance. Interestingly, in our previous study (10
) we saw no correlation between the choice to self-administer cocaine and BPND
, which suggests that the BPND
effect is less than that of ΔBPND
. Another limitation of this study is that the left and right regions were averaged and not analyzed individually, such that there could have been an effect of laterality that we did not see. In addition, while the stimulant-induced decrease in [11
C]raclopride binding correlates with pre-synaptic dopamine release (6
), recent studies have shown that receptor internalization or dimerization play a key role (7
In conclusion, the findings from this study are as follows: 1) compared to controls, striatal dopamine signaling is blunted in cocaine dependent subjects, 2) within the cocaine dependent subjects, a positive response to treatment was associated with greater dopamine signaling; 3) treatment itself did not change dopamine transmission. These findings, combined with data from previous studies, strongly suggest that improving dopamine transmission may be the most appropriate treatment strategy for cocaine dependent subjects who seek treatment, but relapse nonetheless.