Development Of New Approaches To Neuroimaging with PET and SPECT

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Part of this project determined if differences in nAChR density between smokers and non-smokers could be shown in vivo with PET and to determine the neuroanatomical extent of the difference. We used dynamic PET imaging with 2F-18F-A-85380 (2FA) to measure total volume of distribution (VT) in non-smokers and heavy smokers. Values for VT obtained by several modeling methods using a metabolite-corrected arterial input function for 2FA yielded similar results. The thalamus (TH), midbrain (MB), pons (P), cerebellum (CB), frontal cortex (FC), putamen (PUT) and corpus callosum (CC) were sampled. VT was significantly higher in smokers than in nonsmokers in CB, FC, MB, P and PUT. PET imaging of nAChRs suggests that it can be used to study the role of nicotine-induced upregulation of nAChRs in smoking behaviors and in smoking cessation. Quantifying nAChRs in this study required arterial blood sampling and dynamic scanning as the 2FA was administered as a bolus injection. A second part of this project evaluated the less invasive bolus plus constant infusion (B/I) paradigm for quantifying nAChRs. Volunteers underwent a bolus injection study and a study in which the 2FA was administered by B/I to evaluate the feasibility of using shorter scan times and data from venous blood. VT values from the B/I studies were very similar to those calculated from bolus studies. Test/retest showed a high reproducibility of VT measurements. We conclude that B/I methodology will be useful for clinical and research studies of human brain nAChRs. Male squirrel monkeys underwent quantitative studies of nAChRs with 2FA. Non-displaceable volumes of distribution (VDnd) were determined following blockade of 2FA specific binding by nicotine infusion. Binding potential (BP*) values, estimated using CB and muscle as reference regions, were compared for reproducibility of measurements. Administration of 2 mg/kg/day nicotine via osmotic pump nearly completely saturated specific binding to nAChRs and led to a very small changes in VT in CB and muscle (-9.4% and 0.6%, respectively), suggesting limited specific binding of 2FA in these areas. VT measured in muscle in 15 monkeys was reasonably constant but VDnd in studied brain regions exceeded VT in muscles by a factor of 1.3. Applying this factor and using muscle as a reference region, BP* values were in a good agreement with those obtained using CB as a reference region, suggesting that nAChRs can be accurately quantified using muscle as a reference region. Potential predisposing factors (e.g., presmoking density of nAChRs) for becoming addicted to nicotine are difficult to evaluate in humans for ethical reasons. We used five squirrel monkeys to determine whether the density of nAChRs before exposure to nicotine would predict an animal's motivation to self administer nicotine. Binding potential for 2FA prior to nicotine exposure was measured and this value negatively correlated with the animal's number of responses made under the progressive ratio schedule, suggesting that low nAChR density in people may be a predisposing factor for becoming a smoker. As nicotine use increases the density of nAChRs, smoking may be a way to "normalize" receptor density. We used microPET to quantify nAChRs in the rat brain, measuring BP* in anesthetized rats that were imaged repeatedly over six months. Using a B/I paradigm, 2FA was administered intravenously over 8 to 9 h. Steady state conditions developed within 5 h. A 2-h nicotine infusion initiated 2 h before the end of scanning displaced specifically bound 2FA. BP* averages for TH, forebrain, and CB were consistent with nAChR distribution in rat brain measured in vitro. Studies of nAChR occupancy determined that 0.29 nmol/kg/h nicotine occupied 50% of the nAChRs. A novel radioligand F-18 NIDA131 for imaging extrathalamic nAChRs was characterized in vitro and in vivo. The Kd and T1/2 off dissociation of NIDA131 measured in vitro were 4.9 pM and 81 min, respectively. The in vivo patterns of radioactivity distribution for F-18NIDA131 and 2FA were similar and matched the distribution of nAChRs. F-18NIDA131 exhibited better in vivo binding properties than 2FA, and accumulated in monkey brain to a substantially greater extent. VT and VDnd were substantially greater than those of 2FA. The toxicity of NIDA131 in mice was comparable to 2FA and was consistent with a 2300 fold higher affinity for alpha4beta2* nAChRs than for alpha3beta4* nAChRs. These results suggest that F-18 NIDA131 is promising for studying extrathalamic nAChR in humans. Nicotine may function as a gateway drug to illicit drug use as it produces cross sensitization to opioids in rats in a conditioned place preference (CPP) paradigm. We utilized CPP to test the hypothesis that nicotine produces behavioral cross sensitization to stimulants and demonstrated that nicotine pretreatment enhances the rewarding effects of amphetamine for at least 3 to 5 days following the cessation of nicotine, with this effect dissipating within 19 days. The underlying mechanism involves alpha4beta2 nAChRs as a competitive alpha4beta2 antagonist effectively blocks development of nicotine-induced cross sensitization. An alpha7 nicotinic antagonist also blocked cross-sensitization at doses that do not block nicotine self-administration in rats. This study clearly demonstrated that nicotine produces cross-sensitization to the rewarding effects of both psychostimulants measured with CPP. Traumatic experiences in early childhood are associated with increased risk for developing stress-related disorders (e.g., depression, anxiety, posttraumatic stress and substance abuse). Rearing infant macaques with same-aged peers (PR) is an established model of early adversity and induces high levels of anxiety-like behavior in monkeys. Chronic early stress affects expression and function of 5-HT1A receptors (5HTR) and human data suggest sex differences in 5HTR expression. Based on the hypothesis that PR animals would exhibit differences in 5HTR expression from mother reared (MR) animals and that this effect may be related to sex, we measured 5HTR density with F-18 FPWAY and PET in male and female monkeys. The results showed a significant rearing by sex interaction. In females, greater 5HTR density was observed in the dorsomedial prefrontal cortex in PR than in MR animals. In contrast, 5HTR density was lower in PR males in the medial cingulated cortex compared to MR males. These results suggest that early life stress affects the available density of 5HRT differently in males and females. Early life stress is also linked to structural brain abnormalities in adults and children. However, it is unclear if these volumetric brain changes are present before disease onset or if they reflect the consequences of the disease progression. To identify structural abnormalities that may predict increased risk for subsequent stress-related neuropsychiatric disorders, we acquired anatomical brain images in MR and PR juvenile rhesus monkeys. Compared to MR controls, we found an enlarged cerebellar vermis, medial prefrontal and dorsal anterior cingulate cortex. We propose that these enlargements are a structural phenotype for a high risk to stress-related neuropsychiatric disorders. Moreover, we found decreased hippocampus volume in females exposed to stress. Interestingly, this effect was evident before the gender-specific hormonal influences that occur during puberty, suggesting that an increased womens vulnerability to mood and anxiety disorders may be present during childhood.