Development Of New Approaches To Neuroimaging with PET and SPECT

National Institute On Drug Abuse

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Abstract

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. Low serotonin1A receptor (5-HT1AR) binding, measured by both in vivo positron emission tomography (PET) and in vitro binding assays of post mortem brain tissue, is found in individuals with several stress-related neuropsychiatric disorders, including depression, social anxiety and panic disorders. Low serotonin1A receptor density during development is proposed as a trait characteristic leading to increased vulnerability of stress-related neuropsychiatric disorders. To assess the relationship between early-life stress and alterations in serotonin system during development, we used positron emission tomography. We measured serotonin1A receptor availability, density and apparent dissociation constant in different brain regions of juvenile rhesus monkeys exposed to early-life stress in the form of peer-rearing. Compared with controls, serotonin1A receptor availability was elevated in peer-reared females in the dorsomedial prefrontal cortex, and decreased in peer-reared males in the anterior and medial cingulate cortex. We speculate that these changes were mainly driven by decreased serotonin levels (measured as changes in apparent dissociation constant), rather than changes in receptor density. In addition, lower serotonin levels were found in females compared to males independent of early-life stress exposure. Early-life stress differentially affects the serotonin system in juvenile male and female monkeys. The decrease in serotonin levels found in juvenile females and animals exposed to stress provides a biological basis for the increased vulnerability to stress-related neuropsychiatric disorders in women exposed to early-life trauma what can lead to drug abuse. Marked interindividual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain alpha4beta2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of interindividual differences in midbrain nAChR levels on motivation to self-administer nicotine. Baseline levels of alpha4beta2* nAChRs were measured using 2-(18)Ffluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio (PR) schedule of reinforcement. Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs. The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D(2) receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and nonhuman primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems.