1. Neuronal processing of nicotine in acute abstinent rats This study used pharmacological fMRI to investigate the effects of acute and chronic nicotine, and acute abstinence on the brains response to acute nicotine administration. Tolerance and withdrawal are important characteristics of nicotine, as they are powerful motivational drives to increase drug intake (due to tolerance) or to prevent abstinence (to avoid unpleasant withdrawal effects). Secondly, after nicotine is taken for a long time, the brain undergoes long lasting changes, or plasticity, resulting in the development of tolerance, such that abruptly stopping nicotine produces withdrawal. Functional magnetic resonance imaging (fMRI) was used to study the effects and sites of action of nicotine in the brains of rats that were nave, tolerant or abstinent, providing information of how tolerance develops in different areas throughout the brain and to what extent these areas are involved with nicotine withdrawal. (Manuscript in preparation) 2. Imaging neuroadaptations associated with long-term cocaine self-administration in a rat model Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self‐administration. Results suggest that the magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. This region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals. (Published in NeuroImage, 2012) 3. Heroin self-administration and incubation in rats Studies in human drug addicts suggest that relapse to heroin and other drugs of abuse can occur after exposure to environmental cues associated with drug use (e.g., syringes, places where drugs were taken). The purpose of this submission is to further explore the brain mechanisms underlying the time-dependent changes in drug seeking after withdrawal from heroin. We investigated brain function before and after heroin self-administration, and following 16 days forced abstinence, or incubation period, using several magnetic resonance imaging approaches (resting state functional connectivity, cerebral blood perfusion, and cue- (odor) induced changes in BOLD). We hypothesized that incubation of heroin craving (or time-dependent increases in cue-induced heroin seeking after withdrawal) involves changes in brain regions implicated in learning, emotion and addiction. We used a within- and between-subjects design wherein each rat undergoes all test procedures from pre-drug to post-drug withdrawal period. Rats in the control group underwent all the same surgical and behavioral procedures as the rats in the heroin self-administration group, except that they only had saline available. Data acquisition is complete, and analysis is in progress. 4. Methamphetamine toxicity in rats Methamphetamine-induced neurotoxicity is characterized by dopamine and serotonin depletion together with their respective metabolites (DOPAC, 5-HIAA) and transporters (DAT, SERT), altered glutamate and GABA signaling, gliosis, apoptosis, and oxidative stress, leading to cognitive and motor deficits. Human imaging studies have revealed structural differences between methamphetamine users and controls. However, it is not known whether these structural differences are pre-existing or caused by METH.
Our first aim, therefore, is to examine acute and long-term microstructural changes in an animal model of METH toxicity in order to determine whether structural differences result from METH-toxicity. We will apply diffusion imaging using the diffusion kurtosis model shown to be sensitive to microstructural changes in an animal model of traumatic brain injury. Changes in cerebral glucose metabolism, indicative of neuronal activity levels, together with cognitive improvements have been observed with METH abstinence, but without measurable corresponding changes in white and grey matter structures. Further, in animal models of METH toxicity, locomotor performance improves without corresponding improvement in biochemical markers, suggesting that observed improvements may result via compensatory mechanisms.
Our second aim i s to determine the acute impact of METH toxicity on brain function and structure, and to examine how brain function and structure is further modified long-term using a within and between subject experimental design. We will use resting state functional connectivity (rs-FC), Amplitude of Low Frequency Fluctuation (ALFF), and DKI MRI and magnetic resonance spectroscopy (MRS) methods optimized for non-invasively investigating changes in brain structure and function over time. 5. Cocaine-induced neural and behavioral adaptations in an awake marmoset imaging model The goal of this study is to explore the short- and long-term consequences (on behavior and brain structure/function) of cocaine exposure in monkeys. We have procured the requisite hardware (helmets, cradle, etc.) and imported the behavioral training techniques in order to collect functional brain data from conscious monkeys. We have completed the training and have been scanning 4 monkeys weekly. These data will serve as the baseline to observe the evolution of structural and functional (resting state coherence) changes that occur in the brain during and following long-term exposure to cocaine (doses for which were determined in separate cohorts of monkeys). We have also employed a test of cognitive function (CANTAB) using positive reinforcement techniques to train monkeys to respond to stimuli presented on a touch-sensitive screen. We currently have trained and tested 4 animals on the reversal paradigm (a test of cognitive flexibility), and an additional 5 animals have been added to the training protocol and are currently undergoing training procedures. 6. Withdraw effects of Rhesus monkeys with chronic methamphetamine self-administration Cardiovascular (CV) sensitivity during protracted abstinence from methamphetamine (MA) was studied over 1 year in a group (n=8) averaging 6 years of MA self-administration experience and compared to age-matched controls (n=10). While anesthetized with isoflurane, the MA group received a 0.35 mg/kg IV MA challenge at 1 day, and 1, 4, 12, 26 and 52 weeks after the last MA use. Controls received a single MA challenge, which produced increases in mean arterial pressure and heart rate. Significant (Pc <0.05) but short-lived tolerance to the pressor effects of MA was present on Day 1 and Week 1 in the MA group. However, sensitization developed to the increases in both diastolic pressure (Week 12;Pc <0.05) and heart rate (Week 26;Pc <0.05). Concurrent pharmacokinetic studies of plasma MA concentration demonstrated that sensitization was not due to metabolic changes. Echocardiography demonstrated signs of cardiotoxicity (decreased left ventricular ejection fraction (Pc <0.01) and decreased cardiac output (Pc <0.05)) at 3 months of abstinence, which either normalized or approached normal levels at 12 months. In summary, the delayed development of CV sensitization to MA emerged between 3 and 6 months of abstinence and coincided with signs of cardiotoxicity. Importantly both CV sensitization and cardiotoxicity appeared to be reversible as they approached control levels after 1 year of abstinence. (Manuscript in preparation)
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