Neural processing of a cocaine-associated odor cue revealed by functional MRI in awake rats.

Using an olfactory conditioning procedure, brain stimulation reward threshold measurements, and functional magnetic resonance imaging (fMRI), we investigated brain stimulation reward threshold change and fMRI neural activation in response to a cocaine-associated odor cue. In the first brain stimulation experiment, over 10 days of rate-frequency curve-shift testing, rats were administered intravenous cocaine (1.0mg/kg) paired with a contextual cue of peppermint odor previously placed in the operant chamber or they were given vehicle treatment (no cocaine) in the presence of no olfactory cue. Following a 14-day drug-free rest period, rats were again given the rate-frequency curve-shift threshold test with or without the odor cue. In a second experiment, rats were similarly conditioned with a peppermint odor but with intraperitoneally delivered cocaine (10mg/kg). After a 14 day rest period, rats were imaged on a 7-T MRI for their blood oxygen level dependent (BOLD) in response to the cocaine-paired peppermint odor versus an unpaired neutral lemon odor. In the brain stimulation experiment, expected significant reward threshold shifts were produced by cocaine and, importantly, about half that level of shift was produced by the paired contextual olfactory cue. In the fMRI experiment, the insular cortex showed a significantly greater BOLD activation in cocaine-treated versus saline-treated animals to the olfactory cue, but not with the unpaired lemon scent. These data are in agreement with previous studies suggesting a role of the insular cortex in attributing reward value (positive or negative) to conditioned odor stimuli.

A phenotypic model recapitulating the neuropathology of Parkinson's disease.

This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8-9 month old, ovariectomized Long-Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11-12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5-6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2'-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the identification of biomarkers to identify patients in early stage, PD.