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Compulsive patterns of drug use are thought to be the consequence of drug-induced adaptations in the neural mechanisms that enable behavior to be flexible. Neuroimaging studies have found evidence of robust alterations in glutamate and dopamine receptors within brain regions that are known to be critical for decision-making processes in cocaine-dependent individuals, and these changes have been argued to be the consequence of persistent drug use. The causal relationships among drug-induced alterations, cocaine taking, and maladaptive decision-making processes, however, are difficult to establish in humans. We assessed decision making in adult male rats using a probabilistic reversal learning task and used positron emission tomography with the 11C]-(+)-PHNO and 18F]FPEB radioligands to quantify regional dopamine D 2/3 and metabotropic glutamate 5 (mGlu5) receptor availability, respectively, before and after 21 days of cocaine or saline self-administration. Tests of motivation and relapse-like behaviors were also conducted. We found that self-administration of cocaine, but not of saline, disrupted behavior in the probabilistic reversal learning task measured by selective impairments in negative-outcome updating and also increased cortical mGlu5 receptor availability following 2 weeks of forced abstinence. D 2/3 and, importantly, midbrain D 3 receptor availability was not altered following 2 weeks of abstinence from cocaine. Notably, the degree of the cocaine-induced increase in cortical mGlu5 receptor availability was related to the degree of disruption in negative-outcome updating. These findings suggest that cocaine-induced changes in mGlu5 signaling may be a mechanism by which disruptions in negative-outcome updating emerge in cocaine-dependent individuals. [ABSTRACT FROM AUTHOR]

Results from neuroimaging studies suggest that disruptions in flexible decision-making functions in substance-dependent individuals are a consequence of drug-induced neural adaptations. In addicted populations, however, the causal relationship between biobehavioral phenotypes of susceptibility and addiction consequence is difficult to dissociate. Indeed, evidence from animals suggests that poor decision making due to preexisting biological factors can independently enhance the risk for developing addiction-like behaviors. Neuroimaging studies in animals provide a unique translational approach for the identification of the neurobiological mechanisms that mediate susceptibility to addiction. We used positron emission tomography in rats to quantify regional dopamine D 2/3 receptors and metabotropic glutamate receptor 5 (mGluR5) and assessed decision making using a probabilistic reversal learning task. Susceptibility to self-administer cocaine was then quantified for 21 days followed by tests of motivation and relapse-like behaviors. We found that deficits specifically in reward-guided choice behavior on the probabilistic reversal learning task predicted greater escalation of cocaine self-administration behavior and greater motivation for cocaine and, critically, were associated with higher midbrain D 3 receptor availability. Additionally, individual differences in midbrain D 3 receptor availability independently predicted the rate of escalation in cocaine-taking behaviors. No differences in mGluR5 availability, responses during tests of extinction, or cue-induced reinstatement were observed between the groups. These findings indicate that our identified D 3 -mediated decision-making phenotype can be used as a behavioral biomarker for assessment of cocaine use susceptibility in human populations. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: A new radiotracer for imaging the serotonin 4 receptors (5-HT4) in brain, [18F]MNI-698, was recently developed by our group. Evaluation in nonhuman primates indicates the novel radiotracer holds promise as an imaging agent of 5-HT4 in brain. This paper aims to describe the whole-body biodistribution and dosimetry estimates of [18F]MNI-698. Methods: Whole-body positron emission tomography (PET) images were acquired over 240minutes after intravenous bolus injection of [18F]MNI-698 in adult rhesus monkeys. Different models were investigated for quantification of radiation absorbed and effective doses using OLINDA/EXM 1.0 software. Results: The radiotracer main elimination route was found to be urinary and the critical organ was the urinary bladder. Modeling of the urinary bladder voiding interval had a considerable effect on the estimated effective dose. Normalization of rhesus monkeys’ organs and whole-body masses to human equivalent reduced the calculated dosimetry values. The effective dose ranged between 0.017 and 0.027mSv/MBq. Conclusion: The dosimetry estimates, obtained when normalizing organ and whole-body weights and applying the urinary bladder model, indicate that the radiation doses from [18F]MNI-698 comply with limits and guidelines recommended by key regulatory authorities that govern the translation of radiotracers to human clinical trials. The timing of urinary bladder emptying should be considered when designing future clinical protocols with [18F]MNI-698, in order to minimize the subject absorbed doses. [Copyright &y& Elsevier]