Early life stress induces morphological and neurochemical changes in primate brain. Traumatic experiences in early childhood are associated with increased risk of developing stress-related disorders, which are linked to structural brain abnormalities. It is unclear whether these brain changes are present before disease onset or reflect the consequences of disease progression. Deformation-based morphometry, was applied to identify abnormalities in the whole brain development related to traumatic experience in early childhood. Rhesus monkeys were divided into a group raised with their mothers (mother reared) and a group raised with 3 age-matched monkeys (peer reared) for the first 6 months of life. Group difference maps showed enlarged dmPFC and ACC and decreased gp and vPFC in the peer reared group. Further, compared with controls, serotonin1A receptor availability was elevated in peer-reared females in the dmPFC, and decreased in peer-reared males in the ACC. These changes were mainly driven by decreased serotonin levels rather than changes in receptor density. These data suggest that early life stress induces morphological abnormalities and may be a structural phenotype for increased risk of stress-related neuropsychiatric disorders in human beings. Neuropharmacological consequences of chronic cocaine self-administration. A systems-level investigation of neuroadaptations in rats previously exposed to chronic cocaine self-administration revealed a decreased regional CBV, an index of neuronal activity, in ACC and OFC as compared to sucrose and control groups. Such hypoactivity is consistent with human imaging pointing to a role of the ACC and OFC in cocaine dependence. These data set the stage to provide comparative data for evaluation of this animal model of drug addiction. Functional MRI with Repeated Administration of Nicotine in Drug Nave Rats. Rapid tolerance develops to many of the behavioral and autonomic effects of nicotine. However, the central sites of nicotine tolerance are less well studied. Dose-related effects of nicotine on rCBV were observed throughout the brains of nave animals, but there was regional specificity as certain areas manifested inverted U-shaped dose-response curves while others exhibited monotonic curves. Acute tolerance developed in many neocortical and limbic-related cortical areas in both groups, but little tolerance developed in subcortical limbic structures. Nicotine methiodide, which does not enter the brain, yet increases blood pressure like nicotine, did not elicit changes in rCBV, thus demonstrating that the actions of nicotine occurred directly in the brain and not as a result of blood pressure changes. Functional MRI with Repeated Administration of Nicotine in Nicotine-Abstinent Rats. Rats received nicotine chronically for 12 days using osmotic pumps. Sensitized responses to the first nicotine dose developed, relative to nave rats, along with tolerance to the second dose. These data reveal another facet of the evolving plasticity in response to nicotine-induced changes within specific brain regions during tachyphylaxis in abstinent rats. Local field potential changes associated with the self-administration of cocaine in the rat orbitofrontal cortex. Local Field Potentials (LFP) from 16 electrode micro-arrays were recorded from the OFC of rats before, during, and after a cocaine SA session. Significantly more LFP spectral power was observed post compared to pre baseline in frequency bands greater than 20 Hz. A significant increase in LFP spectral power in 8-12 Hz band was observed in the 2 second epoch before the lever press. While increased spiking is thought to indicate output from the OFC, increased LFP activity reflects increased dendritic activity or input to the OFC. Thus, OFC appears to integrate afferent neural activity in preparation for the operant response for cocaine self-administration. Methamphetamine neurotoxicity. We found that single high doses of METH in rats dose-dependently increase cocaine SA. The increased SA appeared to be a compensatory response to reduced cocaine reward after METH. Further, METH produced large DA release followed by a significant reduction in striatal DA and DOPAC content, but without significant changes in striatal DA transporter levels. These findings suggest that METH caused striatal DA depletion or hypofunction without severe damage in DA terminals, which may contribute to the increased cocaine-taking behavior observed. Nicotine receptors and nicotine self-administration in squirrel monkeys. Factors underlying inter-individual differences in vulnerability to nicotine dependence are not well understood. Baseline levels of alpha4beta2* nAChRs were measured using PET in squirrel monkeys. Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs, suggesting that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Nicotine receptors in human smokers. We used PET measure total volumes of distribution in nonsmokers and heavy smokers. V(T)/f(P) was significantly higher in smokers than in nonsmokers in frontal cortex, midbrain, putamen, pons, cerebellum, and corpus callosum (but not thalamus). Nicotine receptor quantification in human brain. We conclude that B/I methodology will be useful for clinical and research studies of brain nAChRs. Nicotinic receptor PET ligand. A novel radioligand, 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine (NIDA522131), for imaging extrathalamic nicotinic acetylcholine receptors (nAChRs) was characterized in vitro and in vivo using PET.
