Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time-course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaine < RTI-336 < RTI-150 < RTI-113 < RTI-177. Cocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were selfadministered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative-stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants.

The positron emission tomography (PET) tracer 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)-nortropane (18F-FECNT) is a highly specific ligand for dopamine transporter (DAT) that yields higher peak striatum-to-cerebellum ratios and offers more favorable kinetics than most 18F-radiolabeled DAT ligands currently available. The goal of this study is to validate the use of 18F-FECNT as a PET radiotracer to assess the degree of striatal dopamine terminals denervation and midbrain dopaminergic cell loss in MPTP-treated parkinsonian monkeys. Three rhesus monkeys received weekly injections of MPTP (0.2-0.5 mg/kg) for 21 weeks, which resulted in the progressive development of a moderate level of parkinsonism. We carried out 18F-FECNT PET at baseline (twice; ten weeks apart) and at week 21 post-MPTP injections. Postmortem stereological cell counts of dopaminergic neurons in the ventral midbrain, and intensity measurements of DAT and tyrosine hydroxylase (TH) immunoreactivity in the striatum were performed and correlated with striatal and ventral midbrain PET data. Three additional monkeys were used as controls for midbrain dopaminergic cell counts, and striatal DAT or TH immunoreactivity measurements. The correlation and coefficient of variance between 18F-FECNT test-retest specific uptake ratios were 0.99 (R2) and 2.65%, respectively. The 18F-FECNT binding potential of the ventral midbrain and striatal regions was tightly correlated with postmortem stereological cell counts of nigral dopaminergic neurons (R2 = 0.91), and striatal DAT (R2 = 0.83) or TH (R2 = 0.88) immunoreactivity intensity measurements. These findings demonstrate that 18F-FECNT is a highly sensitive PET imaging ligand to quantify both striatal dopamine denervation and midbrain dopaminergic cell loss associated with parkinsonism.

No abstract

The goal of the present study was to examine how social subordination stress and 5HTT polymorphisms affect the development of brain serotonin (5HT) systems during the pubertal transition in female rhesus monkeys. We also examined associations with developmental changes in emotional reactivity in response to a standardized behavioral test, the Human Intruder (HI). Our findings provide the first longitudinal evidence of developmental increases in 5HT1A receptor and 5HTT binding in the brain of female primates from pre- to peripuberty. The increase in 5HT1A BPND in these socially housed female rhesus monkeys is a robust finding, occurring across all groups, regardless of social status or 5HTT genotype, and occurring in left and right hemispheres of all prefrontal regions studied, as well as amygdala, hippocampus, hypothalamus, and raphe nuclei. 5HTT BPND also showed an increase with age in raphe, anterior cingulate cortex, and dorsolateral prefrontal cortex. These changes in brain 5HT systems take place as females establish more adult-like patterns of social behavior, as well as during the HI paradigm. Indeed, the main developmental changes in behavior during the HI (increase in freezing and decrease in submission/appeasement) were related to neurodevelopmental increases in 5HT1A receptors and 5HTT, because the associations between these behaviors and 5HT endpoints emerge at peripuberty. We detected an effect of social status on 5HT1A BPND in the hypothalamus and on 5HTT BPND in the orbitofrontal cortex, with subordinates showing higher BPND than dominants in both cases during the pubertal transition. No main effects of 5HTT genotype were observed for 5HT1A or 5HTT BPND. Our findings indicate that adolescence in female rhesus monkeys is a period of central 5HT reorganization, partly influenced by exposure to the social stress of subordination, that likely functions to integrate adrenal and gonadal systems and shape the behavioral response to emotionally challenging social situations.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [ 3 H]CBD-2115 had a K D value of 6.9 nM and a nominal B max of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [ 3 H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [ 3 H]flortaucipir (45 nM) or [ 3 H]MK-6240 (>50 nM). [ 18 F]CBD-2115 was reliably synthesized (3−11% radiochemical yield with molar activity of 27−111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5−0.65 standardized uptake value with fast clearance from normal tissues. [ 3 H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

Reboxetine analogs with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1-4 were synthesized. In vitro competition binding demonstrated that 1-4 have a high affinity for the norepinephrine transporter (NET) with K i 's = 1.02, 3.14, 3.68, and 0.30 nM (vs [ 3 H]nisoxetine), respectively. MicroPET imaging in rhesus monkeys showed that the relative regional distribution of

These results suggest that decreased availability of the brainstem and basal ganglia SERT represents a biomarker of depression and thus confirm and extend the role of dysregulation of brain serotonergic neurotransmission in the pathophysiology of depression and suicide.

Acute SSRI (selective serotonin reuptake inhibitor) treatment has been shown to attenuate the abuse-related effects of cocaine; however, SSRIs have had limited success in clinical trials for cocaine abuse, possibly due to neurobiological changes that occur during chronic administration. In order to better understand the role of serotonin (5HT) in cocaine abuse and treatment, we examined the effects of chronic treatment with the SSRI fluoxetine at clinically relevant serum concentrations on cocaine-related neurobiology and behavior. Rhesus macaques self-administering cocaine underwent a 6-week dosing regimen with fluoxetine designed to approximate serum concentrations observed in humans. Self-administration and reinstatement were monitored throughout the treatment and washout period. In vivo microdiaylsis was used to assess changes in dopaminergic and serotonergic neurochemistry. Positron emission tomography was used to assess changes in the 5HT transporter and 2A receptor binding potential (BP). Functional output of the 5HT system was assessed using prolactin levels. Cocaine-primed reinstatement and cocaine-elicited dopamine overflow were significantly suppressed following chronic fluoxetine treatment. 5HT2A receptor BP was increased in the frontal cortex following treatment while prolactin release was blunted, suggesting desensitization of the 5HT2A receptor. These effects persisted after a 6-week washout period. Measures of pre-synaptic serotonergic function and cocaine self-administration were unaffected. These data demonstrate that acute and chronic fluoxetine treatments exert different effects on cocaine-related behavior. Furthermore, chronic fluoxetine treatment causes alterations in 5HT2A receptors in the frontal cortex that may selectively disrupt cocaine-primed reinstatement. Fluoxetine may not be useful for treatment of ongoing cocaine abuse but may be useful in relapse prevention.