We found that rats with the lowest body weight at the time of the scan showed the highest binding availability in the ventral striatum and vice versa (). Body weight was also assessed at 1 and 2 months post scan and at all three times the correlation remained significant, and interestingly did not change (). Additionally, at 2 months post scan, we observed a similar significant and negative correlation between body weight and binding in the dorsal striatum. We also observed a significant positive correlation between weight gain and binding availability in the ventral striatum at 1 month post scan but not at 2 months (). No effects were found between binding availability in the dorsal striatum at 1 and 2 months post scan. Based on the prior findings of low D2R/D2R binding availability in obese individuals (Wang et al., 2004
) and rats (Thanos et al., 2008
), as well as the negative relationship between current and future body weight and D2R/D3R binding in non-obese rats shown in this paper, one would expect a negative relationship between weight gain and D2R/D3R binding availability (greater individual weight gain (hence greater individual body weight) would correlate with low D2R/D3R binding and vice-versa). However, the present results do not support this association: rats with high D2R/D3R binding availability in the ventral striatum gained more weight than rats with low D2R/D3R binding availability; but they weighed less. One interpretation may be that rats with lower weight (high D2R/D3R binding) are simply more likely to gain more weight than rats with greater body weight (low D2R/D3R binding) as a function of normal development. Indeed, growth charts from laboratory animal vendors show that at around the age the rats were scanned in our experiment (12-14 weeks), weight gain for Sprague Dawley rats slows down and begins to stabilize. It is possible that rats with low D2R/D3R binding may be characterized by accelerated weight gain earlier in life (before 12 weeks of age) than rats with high D2R/D3R binding. Therefore these rats would be characterized by greater body weight. Perhaps this is why we only see a significant effect at 1 and not 2 months post scan. Since we did not find significant correlations between D2R/D3R binding and food intake (at scan and 1 and 2 months post scan) these results suggest that abnormal D2R/D3R signaling observed in obese humans and rats in striatum may be due to metabolic issues more so than behavior (it was initially postulated that low D2R/D3R binding was a result of repeated dopamine increases in response to repeated feeding). Future studies are aimed at further investigating a role for striatal dopamine in metabolism.
After the 2 month body weight measurements, we evaluated CPP to cocaine in these same rats and found a significant and strong negative correlation between D2R/D3R binding availability in the ventral striatum measured 2 months prior to the CPP experiment and cocaine preference ().
These findings suggest that while both the dorsal and ventral striatum may be involved in body weight regulation, it is the ventral striatum that plays a primary role in mediating susceptibility to cocaine abuse. These results further suggest the potential for using D2R/D3R binding availability to predict future body weight and susceptibility to cocaine abuse in rodents. Indeed, it was recently reported that D2R/D3R binding availability with μPET predicted cocaine self-administration behavior in rats with genetic predisposition to a form of impulsivity (Dalley et al., 2007
). Furthermore, impulsivity and compulsivity have been shown to predict the development of addictive behavior (Belin et al., 2008
). Here, using μPET, we extend these findings to a general laboratory rodent model, the outbred Sprague-Dawley rat, and show that individual differences in D2R/D3R binding have a predictive value for both body weight gain and psychostimulant abuse liability. Using such a measurement, one can classify rodents into those that express susceptibility to increased body weight and drug abuse and those that do not. One can then identify specific genes and genetic polymorphisms that may be differentially expressed in these animals before and after the body weight changes and drug exposure. One can also use D2R/D3R binding availability as a screening method to minimize variability in behavioral experiments by taking into account the variability in levels of D2R/D3R binding availability, as has been recently suggested for functional magnetic resonance imaging experiments (Mohr and Nagel, 2010
). Findings from such studies can lead to the faster development of new treatments for obesity as well as drug addiction. Finally, since PET imaging using [11
C]raclopride is a non-invasive research paradigm that is routinely employed in clinical research, this approach may have the potential to be translated to humans in order to determine both individual susceptibility to weight gain as well as potential for cocaine abuse. Indeed, this has recently been demonstrated using another imaging modality, functional magnetic resonance imaging, where striatal response predicted subsequent weight gain in humans (Stice et al., 2010
Recent studies have suggested dissociable roles for the ventral and dorsal striatum in reinforcement learning as “critic” and “actor” respectively (O’Doherty et al., 2004
). These studies argue that the ventral striatum is involved in learning to predict rewards while the dorsal striatum maintains the behavior necessary to guide future decisions (Kahnt et al., 2009
). While preliminary, our findings support a functional dissociation between the dorsal and ventral striatum and extend the functional significance of these dissociable roles to encompass metabolic homeostatic mechanisms, like body weight regulation independent of feeding (we did not find significant correlations between binding availability and food intake). This notion arises from our findings that D2R/D3R binding availability in the ventral striatum correlated with body weight levels throughout the 2 month period following the scan (interestingly the correlation and significance values remained unchanged at each time point), while binding availability in the dorsal striatum showed no significant correlation at the time of scan, but a trend towards significance at 1 month, followed by a significant correlation at 2 months. These observations may suggest that D2R-mediated mechanisms in the ventral striatum are involved in predicting a set level of body weight, while complementary mechanisms in the dorsal striatum guide the necessary actions for ensuring that body weight is set to the levels predicted by the ventral striatum, perhaps via increases and decreases in energy expenditure (i.e. changes in metabolism, motor activity, etc.). A similar function of D2R/D3R may be involved in cocaine seeking behaviors since binding availability was found to predict future cocaine preference. However, unlike body weight measures, we did not assess cocaine preference longitudinally and therefore we do not know whether dorsal striatal binding availability may have correlated with cocaine preference at latter time-points, like it did for body weight. Nevertheless, this is an interesting idea and requires further substantiation.
In this study, we present evidence that D2R/D3R binding availability can be used to predict future body weight levels and cocaine preference in rats. We also show that individual differences in binding availability reflect individual differences in body weight and cocaine preference and vice-versa. Finally, our results suggest dissociable roles for the ventral and dorsal striatum in respectively “setting” and “maintaining” processes related to the regulation of body weight and cocaine preference.