1. Nicotine tolerance and withdrawal effects in rats fMRI studies using rCBV as a biomarker in anesthetized nondependent rats evaluated pairs of identical nicotine injections. Nicotine produced widespread activation throughout the brain, which was characterized by a biphasic dose-response curve and in general activation was greater in cortical areas compared to subcortical regions. Substantial tolerance developed in the same cortical regions whereas tolerance development was weak or minimal in subcortical regions. Dose and region-specific spatiotemporal patterns in brain response to nicotine were clearly apparent. In contrast, nicotine-dependent rats treated with a low dose of the nicotine antagonist mecamylamine produced deactivation in a more limited number of brain regions relative to the acute effects of nicotine. Further, this deactivation was correlated with behavioral signs of withdrawal in a parallel study conducted freely moving conscious rats. 2. Methamphetamine withdraw effects in Rhesus monkeys A colony of Rhesus monkeys with a long history of methamphetamine self-administration (METH) was used to assess the effects of long-term METH exposure and subsequent sustained abstinence on brain metabolite levels assessed by 1H MR spectroscopy (1H-MRS). In striatum, the METH group showed increasing levels of total choline-containing compounds (tCho) during the first month of abstinence that became significantly elevated during months 3 - 6 of drug withdrawal, as compared to control group (CONT). Similarly, the tCho/creatine (Cr) ratio was significantly higher both at early time points of abstinence (up to one month) and at 3-6 months of drug withdrawal, compared with CONT. In contrast, there were no differences in either tCho or tCho/Cr between CONT and METH groups 1 year after drug withdrawal. In the ACC, the METH group exhibited significantly lower glutamate (Glu), N-Acetylaspartate plus N-Acetylaspartylglutamate (NAA/NAAG) levels only during the first month of abstinence compared to CONT Relative to CONT, the level of myo-Inositol (mI)/Cr was higher in METH group during the first month of abstinence with no difference at later time points of abstinence. Our findings suggest that following long-term METH exposure, neuroadaptive changes occur that might contribute to some structural and functional plasticity in ACC and striatum, suggesting the potential efficacy of extended behavioral/cognitive therapy during METH abstinence. 3. Neuroadaptations in rats with Chronic exposure to cocaine and subsequent abstinence Chronic exposure to cocaine and subsequent abstinence results in molecular, cellular and chemical changes that may underlie cocaine craving and relapse. We hypothesize that these changes will lead to neuroadaptations at a system level, altering baseline perfusion, resting state functional connectivity, brain activity induced by injection of drug or in the presence of cues associated with drug self-administration. Preliminary data showed that baseline cerebral blood volume (CBV), functional connectivity, brain activation following acute injection of cocaine, and brain activity following the delivery of odors associated cocaine self-administration changed in brain regions primarily in the cortico-striatal-limbic system associated with reward. In addition, local field potentials (LFPs) and single neuron firing rates were recorded from OFC of rats before, during and after a cocaine self-administration session (SA). The cue signaling the onset of a cocaine SA was thought to evoke an increase in LFP activity OFC. As expected the first cue presentation of the SA session evoked LFP activity and high frequency LFP activity increased over the SA session. The firing rate of OFC neurons also increased during this period. 4. Neuroplasticity of perilesional tissue in stroke rats In this study we used diffusion-tensor imaging to assess plasticity of perilesional tissue following amphetamine treatment in a rat stroke model. The amphetamine-treated animals (n=16) showed higher fractional anisotropy values in areas surrounding the infarction, compared with the control groups (n=16) and the synaptophysin expression was significantly higher in the amphetamine-treated group, consistent with the imaging findings. We also found a significantly reduced lesion volume for animals with amphetamine treatments based on the T2-weghted imaging. 5. Neurobiological changes in a rat model of chronic neuropathic pain The study is to identify alterations in brain function that lead to the development of chronic pain, by examining longitudinal alterations of brain structure and function using magnetic resonance imaging (MRI) and spectroscopy (MRS) in a spared nerve injury (SNI) model of neuropathic pain in rats. Multimodal MRI techniques, including high-resolution structural imaging, perfusion imaging, diffusion tensor imaging, resting-state fMRI, fMRI with tasks, and MR spectroscopy are used to assess the brain alterations in 4 weeks following the SNI surgery. The imaging results are compared to the behavioral assessment of nociceptive thresholds 6. Awake imaging model of marmosets This study aimed at characterizing several core features of addiction, has begun pilot work to develop marmosets as a new model of addiction. Several steps towards the research and developmental phase of this project have been successfully accomplished. Namely: (1) The development and testing of the MRI hardware to be used with these animals; (2) Behavioral shaping and training of the marmosets to be tested for cognitive function with CANTAB, an executive function battery of tests for use with marmosets; (3) Behavioral testing using food-induced conditioned odor preference, a widely-used tool for assessing preferences in rodents (heretofore untested in marmosets). Marmosets were reliably trained to prefer an odor that, prior to food pairing sessions, bore no significance for the animals. This pilot study paves the way for future studies with cocaine-conditioned odor preferences. 7. Awake imaging model of rats This project is in the development stage. The restraint training and head restraint methods design are ongoing.
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