This study investigated the potential utility of fMRI as a neuroimaging technique to examine drug dependence using a robust animal model of drug withdrawal. Two groups of rats chronically pretreated with incremental doses of morphine sulfate (2, 7, 15, 30, 40, 50, 50, and 50 mg/kg--subcutaneous injection) were subjected to opioid precipitated withdrawal (using the opioid antagonist, naloxone) and subsequently behaviorally assessed or gradient-echo imaged under urethane anesthesia. Whole brain, group statistical parametric maps revealed statistically significant changes in signal intensity following administration of 1 mg/kg naloxone (corrected for multiple comparisons: P < 0.05, T > 5.03). Control groups within the fully crossed designs did not exhibit any statistically significant changes in behavior or signal intensity changes. Regional patterns of modulated activity include the retrosplenial, piriform, insular, entorhinal, cingulate, visual and auditory cortices, posterior fields of the hippocampus, and in particular the dentate gyrus. Such areas are consistent with biochemical correlates of morphine withdrawal and time profiles derived from our behavioral observations (P < 0.02). A notable lack of signal intensity changes in a number of subcortical areas suggests a possible confound associated with fMRI under anesthesia. This paper reports the first whole brain fMRI examination of an animal model of drug withdrawal, we believe there is considerable scope for extrapolation of our methods to a multitude of pharmacological applications-most notably in conjunction with other techniques in the development of potential therapeutic agents for drug dependence.
A core structural and functional motif of the vertebrate central nervous system is discrete clusters of neurons or 'nuclei'. Yet the developmental mechanisms underlying this fundamental mode of organisation are largely unknown. We have previously shown that the assembly of motor neurons into nuclei depends on cadherin-mediated adhesion. Here, we demonstrate that the emergence of mature topography among motor nuclei involves a novel interplay between spontaneous activity, cadherin expression and gap junction communication. We report that nuclei display spontaneous calcium transients, and that changes in the activity patterns coincide with the course of nucleogenesis. We also find that these activity patterns are disrupted by manipulating cadherin or gap junction expression. Furthermore, inhibition of activity disrupts nucleogenesis, suggesting that activity feeds back to maintain integrity among motor neurons within a nucleus. Our study suggests that a network of interactions between cadherins, gap junctions and spontaneous activity governs neuron assembly, presaging circuit formation.
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