1. Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system We employed high-resolution functional MRI and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naive, anesthetized rats. A single i.v. nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased rCBV in many neocortical areas. In contrast, dose-dependent differences in rCBV responses were most pronounced in limbic regions, such that the increases in rCBV seen at 0.1 mg/kg nicotine in limbic regions, were not seen following 0.3 mg/kg in accumbens, hippocampus, amygdala and several other limbic areas. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, these subcortical limbic structures showed only a weak trend for tolerance. These systems provide pharmacodynamic insight into the regional heterogeneity of acute nicotine tolerance development within the brain, which may be relevant to behavioral and neurobiological mechanisms associated with initial frequent tobacco consumption. 2. Methamphetamine withdrawal in Rhesus monkeys Protracted abstinence from methamphetamine (MA) was studied over the course of 1 year in a group (n=10) with 1 to 8 years of MA self-administration experience and compared to an age and sex-matched control group (n=10). The isoflurane anesthetized MA group received a 0.35 mg/kg i.v. MA challenge at 1 day, and 1, 4, 12, 26 and 52 weeks after last MA use. The drug-naive controls received a single MA challenge. At week 26 of abstinence in MA animals both the peak (p <0.002) and 150-min average heart rate (p <0.016) increases as well as peak blood pressure increases (p <0.001) following MA were significantly elevated above abstinence day 1 levels suggesting enhanced cardiovascular (CV) sensitivity to MA. Concurrent metabolic studies showed no changes in plasma MA over 12 months. Echocardiography demonstrated signs of cardiotoxicity (decreased left ventricular ejection fraction and cardiac output) at 3 months of abstinence but not at 12 months. These data demonstrate the development of CV sensitization to MA peaking around 6 months of abstinence. Importantly both CV sensitization and cardiotoxicity appeared to be reversible as they returned to or approached control levels after 1 year of abstinence. Brain imaging data analysis is ongoing. 3. Neuroplastic changes in the medial prefrontal cortex predict cocaine but not sucrose self-administration history We employed a rodent self-administration (SA) and abstinence model to investigate neuroadaptations associated with prolonged forced withdrawal after long-term cocaine SA. Since natural rewards such as food activate the mesolimbic reward system in a partially overlapping fashion as cocaine, we also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed ratio one, long access schedule (6 hrs/day for 20 days). A third group of nave, sedentary rats served as a negative control. Following 30 days of abstinence, an acute cocaine challenge was administered to all 3 groups during functional magnetic resonance imaging (fMRI). A strong positive fMRI response was seen in the drug-nave group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. However, 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. 4. Neural response to drug-associated odor cues in rats exposed to long-access cocaine self-administration Using fMRI in combination with self-administration behavioral experiments in rodents we provide an evidence of differential responses to reward-associated olfactory cues in rats with history of chronic cocaine and sucrose self-administration and functional interactions of information processing in cortico-limbic-striatal system involved in reward goal-directed and instrumental behavior. Several components of this system may be co-activated during anticipation of reward and encoding the reward outcome values as a result of different cortico-striatal projection convergence. Our data indicate that cocaine associated behavior engaged the same brain circuits in striatum and mPFC activated by natural rewards, but neuronal encoding associated with stimuli representing drug vs natural rewards are distinct. These findings provide insight into the encoding processes associated with stimuli that represent drug versus natural reward determined within the same behavioral context and put a light on understanding the relevance of alteration in normal reward-related brain activity in the context of drugassociated environment. 5. Electrophysiological changes in rats exposed to cocaine self-administration 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). Over the 5-h SA session and the 1-h post SA period, both LFP (slow and fast frequency bands) and single neuron activity were increased. Within sessions the very first cue signaling the onset of a cocaine SA session selectively and significantly increased the 28-31 Hz LFP bandwidth power and single neuron firing rate for approximately 30 sec. Analysis of the last 15 responses of each SA session demonstrated a significant elevation in power of the 8-11 Hz bandwidth in the 2 sec preceding the bar press and a significant decrease in power for frequencies above 36 Hz occurring 24 to 30 sec after the bar press. The present LFP recordings are consistent with single neuron responses and show that OFC afferent input and local processing undergo a net increase during presentation of a cocaine-associated cue and the onset of cocaine seeking. These findings along with EEG and BOLD responses support the involvement of an increase in OFC neuronal activity in mediating responses to cues and cocaine. 6. Neuroplastic changes of perilesional tissue in stroke rats treated with amphetamine 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 (FA) 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. Our data further indicate that there is a correlation between the changes of behavioral recovery and changes of FA in the amphetamine-treated animals. 7. Neurobiological changes in a rat model of chronic neuropathic pain The aim of the study is to identify neuroadaptations in a rat model of chronic neuropathic pain by examining longitudinal alterations of brain structure and function using MRI. Multimodal MRI techniques, including high-resolution structural imaging, diffusion tensor imaging, resting-state fMRI, and task-driven fMRI are used to assess the brain alterations in 4 weeks following the spared nerve injury (SNI) surgery. Preliminary results showed altered brain activation, functional connectivity, and grey matter volume in the SNI-treated rats.
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