User:Miniroovigilante/Stuffofimportance

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- somatostatin, CCK-A/B, gastrin, grehlin, calcineurin, calmodulin/Ca2+, PKA/PKC/ect., Nitric oxide synthase(s), Phosphatidylcholine(s),
 * research [the following]

Cell Mol Neurobiol. 1996 Apr;16(2):199-212. The modulation of brain dopamine and GABAA receptors by estradiol: a clue for CNS changes occurring at menopause. Bossé R, DiPaolo T. Source School of Pharmacy, Laval University, Québec, Canada. Abstract 1. Tardive dyskinesia is more important in postmenopausal women than men of comparable age and a peak of first episodes of schizophrenia is observed in postmenopausal women. The effect of ovariectomy (2 weeks or 3 months) in rats was investigated as a model of decreased gonadal function associated with menopause. 2. Frontal cortex D1 receptor density and affinity were similar in intact male compared to intact female rats and progressively decreased in density with time after ovariectomy, with no change of affinity. Striatal D1 and D2 receptors also decreased in density after ovariectomy for both receptor subtypes, with no change of affinity. Striatal D1 receptor density and affinity were similar in intact male and female rats, whereas the density of D2 receptors was higher in females. Treatment with estradiol for 2 weeks restored the D2 but not the D1 receptor changes. 3. In the substantia nigra pars reticulata, striatum, nucleus accumbens, and entopeduncular nucleus, a progressive increase in [3H]flunitrazepam specific binding associated with GABAA receptors was observed as a function of time following ovariectomy; this was corrected with estradiol treatment. In contrast, the opposite was observed for [3H] flunitrazepam binding in the globus pallidus, where ovariectomy decreased binding, which was corrected with estradiol replacement therapy. 4. Low prefrontal cortex dopamine activity with implications of D1 receptors in negative symptoms of schizophrenia is hypothesized. Furthermore, GABAergic overactivity in the internal globus pallidus-substantia nigra pars reticulata complex is hypothesized in tardive dyskinesia. 5. The present data suggest that gonadal hormone withdrawal by reducing brain dopamine receptors and producing an imbalance of GABAA receptors in the output pathways of the striatum may predispose to schizophrenia and dyskinesia.

[PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/pubmed/8743969

Experimental Neurology Volume 188, Issue 1, July 2004, Pages 128-138 doi:10.1016/j.expneurol.2004.03.022 | How to Cite or Link Using DOI Copyright © 2004 Elsevier Inc. All rights reserved. Cited By in Scopus (25) Permissions & Reprints

selective blockade of D3 dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate

M. A. Silverdalea, b, S. L. Nicholsona, P. Ravenscrofta, c, A. R. Crossmana, c, M. J. Milland and J. M. Brotchie, e, , a Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK b Department of Neurology, Hope Hospital, Salford M6 8HD, UK c Motac Neuroscience Ltd., Williams House, Manchester M15 6SE, UK d Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, F-78290 Croissy-sur-Seine, France e Toronto Western Research Institute, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8 Received 6 May 2003; Revised 19 December 2003;  accepted 29 March 2004. Available online 4 May 2004. Abstract To date, the lack of highly selective antagonists at the dopamine D3 receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D3 versus D2 receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D3-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D3 receptor stimulation. Indeed, stimulation of D3 receptors may be detrimental to the anti-parkinsonian properties of D2/D3 agonists. Selectivity for stimulation of D2, over D3, receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia

Acute and Chronic hypertension appears to be capable of disrupting the normal function of the Blood-brain barrier. Fenoldopam is a peripheral D1 agonist which is used to dialate blood vessels [and I guess, lower blood pressure also ? - ].

Unfortunately, it doesn't cross the BBB in amounts considered sufficient to induce effects there =[the brain, I don't know the correct word for it, ].

What I was wondering, was if the trials/experiments [attempting to determine the extent of Fenoldopam's BBB penetration,] were performed on Healthy and/or non-hypertensive subjects.........x

--I am not familiar with BL etiquette, due to my NEWT status,..... subsequently I apologize if this thread is posted in the wrong place and/or should be in the "giant pharmacology thread thing".


 * I'm tired of using 'NooB' as a descriptive for myself/various individuals,.. so I made up a new word, NEWT just sounded cool.

List of Various Cool Meds

Modafinil, Disulfiram, Parnate, Memantine, Amphetamine, Ritalin, Tegaserod, Tramadol, Codeine, Gabapentine, Moclobemide, Rasagiline, Buprenorphine, Tandospirone, Amisulpride, MDAI, Riluzole, Ceftriaxone,

Other cool (but not as cool, currently) meds

Pramipexole, ropinirole, Tianeptine,

ways to increase proper conversion of Tramadol/Codeine

Inhibit CYP3A4, Induce CYP2D6

Dopamine metabolism/synthesis mechanisms/info:

Dopamine metabolism= -MAO-A significant, most of brain, at least 50% ++++ -MAO-B weak, small portion of brain, less tan 50% contritbution ++ -COMT? significant, specifically prefrontal cortex? ++++ -Dopamine-beta hydroxylase? only in noradrengic neurons?

DA synthesis=

-Phenylalanine-Phenylalanine Hydroxylase-L-Tyrosine-Tyrosine Hydroxylase-L-DOPA-Dopa Decarboxylase-Dopamine -cofactors/requirements......

MAO-A/B Irreversible/RIMA, COMT inhibitors, other modulators= -Tranylcypromine, Quercetin, Kaempferol, EGCG, Carbidopa, Entacapone, Moclobemide, Allicin? Disulfiram(other D-beta-hydrox. inhibitors?=......),

precursors= L-dopa/carbidopa (Sinemet)

DA modulation/release enhancers/increase modulators: = Agonism/positive=5ht1a? (sorta), 5ht2a, CCK-A, Antagonism/negative= 5ht2c (others?), GABA-B, mAChR 1/4 (others?), NMDA? CCK-B to research further/determine/figure out= adrenergic, mAChR, nAChR, 5ht-various, NMDA, AMPA, ryanodine, ghrelin, gastrin......ect

calmodulin modulates basal mu-Opioid receptor activity, Cisplatin-induced anorexia is blocked/reduced by 5h2b/c/3 antagonists, M4 receptor strongly inhibits D1 activity and other Dopamine release/activity, M2/4 receptors are inhibitory autoreceptors for acetylcholine, all mAChRs modulate Dopamine activity/release....methylphenidate-induced worsening of psychosis in psychotic people is blocked by acetylcholinerase inhibitors/(raising acetylcholine)....psychosis = (maybe?) imbalance of DA and ACh activity/release/receptors...also Parkinsons, depression....mAChR blockade reduces (maybe) glutamate-induced neuronal death and stuff. "These results indicate that riluzole inhibits 5-HT3-induced ion currents directly by slowing channel activation in NCB-20 neuroblastoma cells." ?? ....5ht3 antagonists = help reduce fibromyalgia symptoms, in a U-shaped dose-response curve( for one specific 5ht3 antag.?) 5ht3/GABA/CCK are co-expressed significantly, as are mAChr/D-something receptor....Mu-opioid receptor = basal/constitutive activity, (like 5ht2a/c)....naltrexone/naloxone - inverse agonists? "Naloxone and naltrexone suppressed basal [(35)S]GTP gamma S binding (acting as "inverse agonists") only after morphine pretreatment, but not in drug-naive animals."........=reformation of Mu-opiate receptors (like GABA-A subunits) after chronic agonism? calmodulin-5ht2c-Ca2+-ERK/GRK/PK modulation....