In vivo studies on the dopamine re-uptake mechanism in the striatum of the rat: effects of benztropine, sodium and ouabain

We used the push-pull perfusion technique to study the in vivo changes in dopamine (DA) levels in the rat striatum in response to treatments which could affect DA re-uptake into the nigrostriatal DA terminals. Benztropine (10-6 M), a potent DA uptake inhibitor induced a 1.7-fold increase in DA levels in the perfusates compared to basal levels. Perfusion with a Na+-free medium in which Na+ was replaced with either Tris-Cl or choline-Cl in equimolar proportions induced respectively 6.5- and 8.5-fold increases in DA levels in the perfusates. Perfusion of media containing NaCl:Tris-Cl (50:50) or NaCl:choline-Cl (50:50) did not significantly alter the levels of DA in the perfusates. Ouabain (10-6 M) did not significantly alter DA levels but at a concentration of 10-4 M, there was a 5.3-fold increase in DA levels in the perfusates compared to basal levels. These results thus demonstrate that the raised DA levels in the extracellular space in response to benztropine is due to the action of the drug in blocking the uptake of DA. The dependence of the uptake mechanism on the presence of Na+ in the external medium and hence on metabolic energy (Na pump) is clearly demonstrated. However, the massive elevation of DA levels under these conditions cannot be due solely to an inhibition of DA uptake but to the carrier-mediated DA exit from cytoplasmic stores resulting from a running down of the ionic gradient

Stimulation of dopamine release by activation of the voltage-sensitive sodium channel by scorpion venom neurotoxin

Scorpion venom neurotoxins open sodium channels and thus may enhance neurotransmitter release by increasing membrane permeability to sodium. This study carried out in vivo examined the effects of the scorpionAndroctonus australis neurotoxin (ScAaTx) on the levels of dopamine (DA) in push-pull perfusates of the striatum of chloral hydrate-anaesthetised rats. ScAaTx (2.5, 5.0 and 10.0 ng/µl) stimulated DA release in a dose-dependent manner. The release of DA induced by ScAaTx (10 ng/µl) was completely blocked when the brain site was perfused with Ca2+-free CSF containing 2 mM EGTA or in the presence of TTX (10-5 M). These results indicate that the potent stimulatory effects of ScAaTx on neostriatal DA release in vivo are mediated via voltage-sensitive sodium channels

Study of Cgrp-Receptors in Human Isolated Middle Meningeal Arteries Using Bibn4096Bs, Compound 1, and HαCgrp(8-37)

Calcitonin, CGRP, adrenomedullin, and amylin require both CRLR (calcitonin-gene receptor like receptor) and receptor activity modifying proteins (RAMP1, RAMP2, and RAMP3) in different combinations for expression of selective, functional receptors[1]. We investigated whether the antagonists BIBN4096BS[2], Compound 1 (WO98/11128, [3]), and CGRP(8-37) are functionally selective for CGRP receptors in human middle meningeal arteries (HMMA)

Temporal changes in the messenger RNA levels of cellular immediate early genes and neurotransmitter/receptor genes in the rat neostriatum and substantia nigra after acute treatment with eticlopride, a dopamine D2 receptor antagonist.

The cellular immediate early genes are involved in the transcriptional events associated with the dopaminergic regulation of neurotransmitter expression within neurons of the neostriatum. To characterize these events in detail, quantitative in situ hybridization histochemistry was used to assess the temporal effects of acute dopamine receptor blockade with eticlopride, a dopamine D2 receptor antagonist, on the messenger RNA expression of the immediate early genes and neurotransmitters/receptors in the caudate-putamen and ventral tegmental area/substantia nigra pars compacta of the rat. Groups of rats were injected with a single dose of either isotonic saline or eticlopride (0.5 mg/kg i.p.) and killed at various time intervals ranging from 5 min to 24 h and frozen brain sections processed by in situ hybridization histochemistry. Using computerized image analysis, the changes in messenger RNA expression for c-fos, c-jun, jun B, jun D, nerve growth factor I-A and nerve growth factor I-B and for neurotensin, glutamate decarboxylase, proenkephalin, the dopamine D1 receptor and the short and long isoforms of the D2 receptor were examined in the caudate-putamen. In the ventral tegmental area and substantia nigra pars compacta, the messenger RNA expression of the above early response genes and that for neurotensin, tyrosine hydroxylase, cholecystokinin and the D2 receptor isoforms were also examined. In the neostriatum, eticlopride caused a rapid increase in c-fos messenger RNA with significantly increased levels at 10 min (P < 0.01). The levels peaked at 30 min and thereafter declined to control levels. A similar profile was observed for jun B messenger RNA, although levels were still significantly (P < 0.01) elevated at 1 h and declined to basal levels thereafter. No significant changes were observed for c-jun, jun D, nerve growth factor I-A and nerve growth factor I-B messenger RNAs. In the dorsolateral neostriatum, there was an increase in proneurotensin messenger RNA 10 min after eticlopride, this increase becoming significant (P < 0.01) at 60 min. Levels were maximal at 2-6 h and decreased after 12 h to basal levels. There were small increases in proenkephalin messenger RNA, but these were not significant (P < 0.05) until 6 h after the injection. Eticlopride did not have any significant effects on the messenger RNA levels for glutamate decarboxylase, the D1 receptor and the short and long isoforms of the D2 receptor.(ABSTRACT TRUNCATED AT 400 WORDS