Desipramine treatment decreases 3H-nisoxetine binding and norepinephrine transporter mRNA in SK-N-SHSY5Y cells. Effects of serine mutations in transmembrane domain 7 of the human norepinephrine transporter on substrate binding and transport. Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss. Rx drugs

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Brain Res Bull. 1999 Jul 1;49(4):291-5.
Desipramine treatment decreases 3H-nisoxetine binding and norepinephrine transporter mRNA in SK-N-SHSY5Y cells.

Zavosh A, Schaefer J, Ferrel A, Figlewicz DP.

Department of Psychology, University of Washington, Seattle, USA.

The antidepressant desipramine has been shown to decrease synaptic membrane concentrations of the norepinephrine re-uptake transporter (NET) in vivo and in vitro, on both an acute and a chronic basis. The possible contribution of decreased NET synthesis to the chronic downregulation of the NETs has not been definitively established. In this study, we treated SK-N-SHSY5Y cells with 100 nM desipramine for 24 or 72 h, and measured 3H-nisoxetine binding (as an estimate of NETs) and NET mRNA by quantitative reverse transcription polymerase chain reaction. Similar to what has been reported previously, membrane 3H-nisoxetine binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points). However, a significant decrease (64 +/- 8% of paired control) of NET mRNA was observed only at the 72-h time point. We conclude that decreased NET synthesis may contribute to the chronic, but not acute, effect of desipramine to downregulate the NET.

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J Neurochem. 1999 Aug;73(2):656-64.
Effects of serine mutations in transmembrane domain 7 of the human norepinephrine transporter on substrate binding and transport.

Danek Burgess KS, Justice JB Jr.

Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.

Two serine residues in the beta-adrenergic receptor (beta-AR) have been proposed to form hydrogen bonds with the catechol moiety of the ligand and contribute to the activation of the receptor. These conserved serine residues in the dopamine (DA) and norepinephrine transporters (DAT and NET, respectively) have also been shown to affect substrate transport in the rat DAT. In the present work, hydrogen bonding interactions between the corresponding serine residues in the human NET (hNET), 354 and 357, and the hydroxyl groups on the substrate were systematically evaluated by examining the transport and binding properties of DA and several single hydroxyl analogues of DA at wild-type and serine-to-alanine-substituted transporters. A comparison of [3H]nisoxetine binding at the serine 354 mutant, in which K(D) increased 70-fold from the wild-type value, with the binding of DA, m-tyramine (m-TYR), and p-tyramine (p-TYR) at mutant 354, where the increase in Ki was less dramatic, revealed that serine 354 is more influential in inhibitor than substrate binding. The binding of m-TYR and p-TYR at the serine 354 and serine 357 mutants did not show a direct interaction between one serine and one substrate catechol hydroxyl group. DA, m-TYR, and p-TYR binding affinity did not deviate from the wild-type value at the serine 357 and double mutant transporters. At these two transporters, however, the Km of DA uptake increased, suggesting that the roles of serine 357 and serine 354 in substrate transport are different from their roles in binding. The K'm for induced efflux of DA decreased at the serine 357 mutant compared with the wild-type, whereas the K'm at the serine 354 mutant was the same as that of the wild-type. Further investigation of the role of substrate hydroxyls in the transport process revealed no difference between the transport of m-TYR or p-TYR, as measured indirectly through their induced efflux of DA, at any of the mutants. Although these serines are influential in inhibitor and substrate binding to the transporter and substrate uptake and efflux, they do not appear to be involved in a direct hydrogen bond interaction with substrate, suggesting that the pattern of distinct hydrogen bonding interactions at the beta-AR does not exist at the hNET.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10428062&dopt=Abstract

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Neuropharmacology. 1999 Jul;38(7):955-63.
Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss.

Matsumoto K, Uzunova V, Pinna G, Taki K, Uzunov DP, Watanabe H, Mienville JM, Guidotti A, Costa E.

Department of Psychiatry, The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, 60612, USA.

Allopregnanolone [3alpha-hydroxy-5alpha-pregnan-20-one] (ALLO), a potent neurosteroid that positively modulates gamma-aminobutyric acid (GABA) action at various GABA(A) receptor subtypes is synthesized in nanomolar concentrations and stored non uniformly in various brain structures of mammals. We have measured brain ALLO content and its precursors by negative ion chemical ionization-mass-spectrometry after purification and separation of the different steroids with HPLC and gas chromatography. Our procedure measures steroids in the femtomolar range with structural information and unsurpassed selectivity. We were able to establish an association between the decrease in content of ALLO in mouse brain cortex elicited by either long-lasting social isolation or by the administration of 17beta-17 [bis (1-methylethyl) amino carbonyl] androstane-3,5-dilene-3-carboxylic acid (SKF 105111). an inhibitor of Types I and II 5alpha reductases, and the shortening of the righting reflex loss elicited by pentobarbital (PBT). SKF 105111 added to cortical brain slices in concentrations up to 10(-5) M failed per se to alter GABAergic currents or their potentiation by PTB recorded from pyramidal neurons. Fluoxetine (1.45 or 2.9 micromol/kg i.p.) doses that fail to change the PTB-induced loss of righting reflex and the level of brain ALLO in group-housed mice normalized both parameters in socially-isolated mice. In addition, we could detect both fluoxetine actions in socially isolated mice pretreated with doses of p-chlorophenylalanine (1.2 mmol/kg i.p. at 72, 48, and 24 h) that substantially inhibit brain serotonin 5HT synthesis as shown by an 80% drop of brain 5HT content. These studies for the first time have provided evidence suggesting that the endogenous cortical stores of ALLO physiologically upregulate GABAergic tone and by such a mechanism play a permissive or facilitatory role on the PTB-induced loss of the righting reflex. In the absence of such a permissive physiological influence by endogenous ALLO, the righting reflex inhibition by PTB is down regulated.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10428414&dopt=Abstract

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