1. Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions. (Published in Proc Natl Acad Sci U S A. 110:4093-4098, 2013) 2. Withdrawal from long-term methamphetamine self-administration 'normalizes'neurometabolites in rhesus monkeys: a 1 H MR spectroscopy study 1H magnetic resonance spectroscopy has demonstrated alterations in several neurometabolites in methamphetamine (METH)-dependent individuals in brain regions implicated in addiction. Yet, it is unclear whether these neurochemicals return to homeostatic levels after an individual abstains from drug use, a difficult question to address due to high recidivism and poor study retention in human subjects. We thus utilized a non-human primate model of addiction to explore the effects of long-term drug exposure and withdrawal on brain neurochemistry. Ten rhesus macaque monkeys on an active METH self-administration protocol (average use 4.6 0.8 years, average daily intake between 0.4 and 1.2 mg/kg) and 10 age- and sex-matched drug-naive controls (CONT) served as subjects. Concentrations of several neurochemicals were evaluated at several timepoints following withdrawal from drug availability (10 monkeys at 1 week and 1 and 3 months, and 6 monkeys at 6 and 12 months;CONT examined at one timepoint). At 1 week following METH withdrawal, we found increases in myo-inositol in anterior cingulate cortex in the METH group relative to CONT. These alterations showed a linear pattern of decreased levels ('normalization') by 1 year of abstinence. We also found decreases in glutamine and Glx (composed mainly of glutamate and glutamine) in the caudate-putamen of the same animals at early withdrawal that showed a similar linear pattern of increasing concentration by 1 year. These results demonstrate that despite protracted, long-term use, neurochemical changes seen following long-term drug administration do not persist following prolonged abstinence, suggesting therapeutic effects of long-term withdrawal from drug use. (Published in Addiction Biology, in press) 3. Methamphetamine neurotoxicity-induced attenuation of resting state functional connectivity between the dorsolateral caudate putamen and cortical regions Methamphetamine (METH) abuse leads to neuronal toxicity and cognitive and motor deficits that continue into abstinence. However, toxicity-induced alterations in neurocircuitry remain to be understood. In this rodent magnetic resonance imaging (MRI) study, we applied resting-state functional connectivity analysis (RSFC) to determine acute and longitudinal effects of METH-induced neurotoxicity on neurocircuitry. It was hypothesized that RSFC of the caudate putamen (CPu) with cortical areas would be impaired while other brain circuits may compensate for this dysfunction. Male Sprague-Dawley rats received neurotoxic doses of METH (n=50) or saline (n=25) in a single day. Core temperature was recorded at regular intervals. Rats were imaged -2 days (scan 1, pretreatment), 14 days (scan 2), and 3 months (scan 3) after METH under 0.5% isoflurane anesthesia + dexdomitor infused s.c. at 0.025 mg/kg/hr. Brains were harvested for analysis of neurotransmitters and metabolites (n=8/group after scan 2;n=17/group after scan 3). METH-induced striatal dopamine depletion in animals sacrificed after scan 2 negatively correlated with METH-induced hyperthermia. Therefore, temperature was used as a surrogate for toxicity in imaging regression analysis. Regression analysis of the difference score between scan 2 and 1 with average temperature during injections revealed a negative correlation between degree of toxicity and circuit strength between the dorsolateral CPu (dlCPu) and the retrosplenial cortex (RSCx), and between the dlCPu and the posterior parietal cortex (PPC). The difference score between scan 3 and scan 2 for the dlCPu seed revealed no significant correlation, suggesting there was no recovery of this circuit alteration. This circuit is thought to be involved in higher order sensory processing and integration of sensorimotor information for navigation control of habitual actions. Therefore, reduced circuit strength between the dlCPu and the RSCx and PPC may related to known deficits in goal-directed behavior and memory. Further, dopamine receptor density is correlated with information transfer between the prefrontal and PPC. These brain regions may provide a circuit based target for research and treatment interventions. (Presented in SfN 2012) 4. CART peptide induces neuroregeneration in stroke rats Utilizing a classic stroke model in rodents, middle cerebral artery occlusion (MCAo), we describe a novel neuroregenerative approach using the repeated intranasal administration of cocaine- and amphetamine-regulated transcript (CART) peptide starting from day 3 poststroke for enhancing the functional recovery of injured brain. Adult rats were separated into two groups with similar infarction sizes, measured by magnetic resonance imaging on day 2 after MCAo, and were treated with CART or vehicle. The CART treatment increased CART level in the brain, improved behavioral recovery, and reduced neurological scores. In the subventricular zone (SVZ), CART enhanced immunolabeling of bromodeoxyuridine, a neural progenitor cell marker Musashi-1, and the proliferating cell nuclear antigen, as well as upregulated brain-derived neurotrophic factor (BDNF) mRNA. AAV-GFP was locally applied to the SVZ to examine migration of SVZ cells. The CART enhanced migration of GFP(+) cells from SVZ toward the ischemic cortex. In SVZ culture, CART increased the size of neurospheres. The CART-mediated cell migration from SVZ explants was reduced by anti-BDNF blocking antibody. Using (1)H-MRS (proton magnetic resonance spectroscopy), increases in N-acetylaspartate levels were found in the lesioned cortex after CART treatment in stroke brain. Cocaine- and amphetamine-regulated transcript increased the expression of GAP43 and fluoro-ruby fluorescence in the lesioned cortex. In conclusion, our data suggest that intranasal CART treatment facilitates neuroregeneration in stroke brain. (Published in J Cereb Blood Flow Metab. 33:300-310, 2013)
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