PubMed · 14337850
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C W WILSON. 1965-09-04. AMPHETAMINE.. https://doi.org/10.1016/s0140-6736(65)91459-5
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RATIONALE: Regulation of dopamine release and synthesis occurs via pre-synaptic dopamine (DA) D2/D3 autoreceptors (DARs). Mapping of DAR function in vivo is difficult and is usually best assessed using invasive measures of DA release, such as microdialysis at discrete sites. We wished to show that pharmacological magnetic resonance imaging (phMRI) may prove useful for this purpose. OBJECTIVE: To demonstrate that the relative cerebral blood volume (rCBV) changes induced by amphetamine can be modulated by DA D2 receptor antagonists and agonists in a manner consistent with modulation of DAR function and to compare these effects with microdialysis. METHODS: We used phMRI with iron oxide contrast agents to map changes in rCBV in response to an amphetamine challenge, pre-treatment and post-treatment with varying doses of the D2 antagonist eticlopride and the D2 agonist quinpirole. We also compared the effects of D2 antagonism using microdialysis measurements of DA release. RESULTS: Antagonism of D2 receptors with eticlopride potentiated rCBV changes induced by amphetamine in the nucleus accumbens and caudate putamen in a dose-dependent manner. The amphetamine-induced increase in rCBV in the accumbens in animals pre-treated with eticlopride was paralleled by a similar percentage increase in DA release measured by means of microdialysis. Conversely, agonism of D2 receptors using quinpirole reduced amphetamine-induced rCBV changes in the caudate putamen and nucleus accumbens. The effects of both quinpirole and eticlopride on amphetamine-induced rCBV changes were largest in the nucleus accumbens. CONCLUSIONS: These results suggest that phMRI may potentially prove useful to map DAR function non-invasively in multiple brain regions simultaneously.
Amphetamine (AMPH) is a well-known anorectic agent. The mechanism underlying the anorectic response of AMPH has been attributed to its inhibitory effect on hypothalamic neuropeptide Y (NPY), an orexigenic peptide in the brain. However, there is still lack of genomic or in situ immunohistochemical evidence to prove it. The present study was aimed to assess the molecular mechanism of AMPH anorexia by immunostaining of hypothalamic NPY protein in the area of paraventricular nucleus (PVN) and by detecting the change of hypothalamic NPY mRNA level using RT-PCR. Results revealed that an AMPH treatment might reduce the expression of NPY at both transcriptional and posttranslational levels. Comparatively, a treatment of clomipramine, a serotonin transporter inhibitor, was unable to reduce NPY mRNA level, revealing the noninvolvement of hypothalamic NPY gene in serotonin anorexia. Our results provided genomic and in situ immunohistochemical evidence to confirm the mediation of hypothalamic NPY neurons in the anorectic action of AMPH.
Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects on dopaminergic (DA) neurons. In this study, we investigated whether the effects of VEGF were dose-dependent or not. First, VEGF was shown to be neuroprotective on 6-hydroxydopamine (6-OHDA)-treated murine DA neurons in vitro, although the 1 ng/ml of VEGF displayed more neuroprotective effects than 100 ng/ml. Furthermore, using 2 sizes of capsules (small/large) with different secreting quantities, 6-OHDA-treated rats receiving the small capsule filled with VEGF-secreting cells (BHK-VEGF) into the striatum showed a significant decrease in amphetamine-induced rotational behavior in number and a significant preservation of TH-positive fibers compared to those receiving the large BHK-VEGF capsule as well as those receiving BHK-Control capsule. Rats receiving the large BHK-VEGF capsule showed much more glial proliferation, angiogenesis, and brain edema around the capsule than those with the small one. High-dose administration of VEGF might cause poor circulation related to brain edema, although low-dose administration of VEGF displays neuroprotective effects on DA neurons. Our results demonstrate the importance of administration dose of VEGF, suggesting that low-dose administration of VEGF might be desirable for Parkinson's disease.