Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration.

There is substantial comorbidity between stress disorders and substance use disorders (SUDs), and acute stress augments the locomotor stimulant effect of cocaine in animal models. Here we endeavor to understand the neural underpinnings of comorbid stress disorders and drug use by determining whether the glutamatergic neuroadaptations that characterize cocaine self-administration are induced by acute stress. Rats were exposed to acute (2 h) immobilization stress, and 3 weeks later the nucleus accumbens core was examined for changes in glutamate transport, glutamate-mediated synaptic currents and dendritic spine morphology. We also determined whether acute stress potentiated the acquisition of cocaine self-administration. Acute stress produced an enduring reduction in glutamate transport and potentiated excitatory synapses on medium spiny neurons. Acute stress also augmented the acquisition of cocaine self-administration. Importantly, by restoring glutamate transport in the accumbens core with ceftriaxone the capacity of acute stress to augment the acquisition of cocaine self-administration was abolished. Similarly, ceftriaxone treatment prevented stress-induced potentiation of cocaine-induced locomotor activity. However, ceftriaxone did not reverse stress-induced synaptic potentiation, indicating that this effect of stress exposure did not underpin the increased acquisition of cocaine self-administration. Reversing acute stress-induced vulnerability to self-administer cocaine by normalizing glutamate transport poses a novel treatment possibility for reducing comorbid SUDs in stress disorders.

Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens.

Repeated administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. Here we explore the mechanisms in the nucleus accumbens (NAc) whereby an acute restraint stress augments the acute locomotor response to cocaine. This was accomplished by a combination of behavioral pharmacology, microdialysis measures of extracellular dopamine and glutamate, and Western blotting for GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor (AMPAR). A single exposure to restraint stress 3 weeks before testing revealed that enduring locomotor sensitization to cocaine was paralleled by an increase in extracellular dopamine in the core, but not the shell subcompartment, of the NAc. Wistar rats pre-exposed to acute stress showed increased basal levels of glutamate in the core, but the increase in glutamate by acute cocaine was blunted. The alterations in extracellular glutamate seem to be relevant, as blocking AMPAR by 6-cyano-7-nitroquinoxaline-2,3-dione microinjection into the core prevented both the behavioral cross-sensitization and the augmented increase in cocaine-induced extracellular dopamine. Further implicating glutamate, the locomotor response to AMPAR stimulation in the core was potentiated, but not in the shell of pre-stressed animals, and this was accompanied by an increase in NAc GluR1 surface expression. This study provides evidence that the long-term expression of restraint stress-induced behavioral cross-sensitization to cocaine recapitulates some mechanisms thought to underpin the sensitization induced by daily cocaine administration, and shows that long-term neurobiological changes induced in the NAc by acute stress are consequential in the expression of cross-sensitization to cocaine.

Clinical correlative evaluation of an iterative method for reconstruction of brain SPECT images.

BACKGROUND: Brain SPECT and PET investigations have showed discrepancies in Alzheimer's disease (AD) when considering data deriving from deeply located structures, such as the mesial temporal lobe. These discrepancies could be due to a variety of factors, including substantial differences in gamma-cameras and underlying technology. Mesial temporal structures are deeply located within the brain and the commonly used Filtered Back-Projection (FBP) technique does not fully take into account either the physical parameters of gamma-cameras or geometry of collimators. In order to overcome these limitations, alternative reconstruction methods have been proposed, such as the iterative method of the Conjugate Gradients with modified matrix (CG). However, the clinical applications of these methods have so far been only anecdotal. The present study was planned to compare perfusional SPECT data as derived from the conventional FBP method and from the iterative CG method, which takes into account the geometrical and physical characteristics of the gamma-camera, by a correlative approach with neuropsychology. METHODS: Correlations were compared between perfusion of the hippocampal region, as achieved by both the FBP and the CG reconstruction methods, and a short-memory test (Selective Reminding Test, SRT), specifically addressing one of its function. A brain-dedicated camera (CERASPECT) was used for SPECT studies with 99mTc-hexamethylpropylene-amine-oxime in 23 consecutive patients (mean age: 74.2 +/- 6.5) with mild (Mini-Mental Status Examination score > or =15, mean 20.3 +/- 3), probable AD. Counts from a hippocampal region in each hemisphere were referred to the average thalamic counts. RESULTS: Hippocampal perfusion significantly correlated with the MMSE score with similar statistical significance (p < 0.01) between the two reconstruction methods. Correlation between hippocampal perfusion and the SRT score was better with the CG method (r = 0.50 for both hemispheres, p < 0.01) than with the FBP method (r = 0.37 and 0.43, respectively for the right and left hemisphere, p < 0.05 and p < 0.02). The bootstrap procedure showed that such correlation indexes were statistically different both in the right (p < 0.01) and in the left (p < 0.05) hemisphere. CONCLUSION: These results are interpreted as a better performance of the CG reconstruction method in correctly detecting counts from hippocampal ROI. By using the same gamma-camera or collimator, alternative methods for brain SPECT reconstruction may improve quality of data and then help SPECT diagnostic accuracy.