A low dose of xylamine produces sustained and selective decreases in rat brain norepinephrine without evidence of neuronal degeneration.
The effects of a chronic partial depletion of rat cortical NE by a single dose of xylamine (20 mg/kg i.p.) on pre- and postsynaptic noradrenergic functionality were studied 4 hr, 14, 21 and 35 days after treatment. This dose of xylamine resulted in a 40 to 50% selective decrease in cortical levels of NE and the major metabolites of NE, 3,4-dihydroxyphenylethyleneglycol and 3-methoxy-4-hydroxyphenylethyleneglycol and, when measured after 35 days, [3H]desipramine binding and dopamine-beta-hydroxylase activity were at control levels, which would indicate that the NE nerve terminals in the cortex were intact. The 21- or 35-day deficit of NE did not affect alpha-1, alpha-2, beta, dopamine2, 5-hydroxytryptamine, or gamma-aminobutyric acidB receptor densities, or the beta receptor mediated adenylate cyclase activity. In addition, desipramine (10 mg/kg i.p.) administration for 14 days (days 20 through 34) was able to down-regulate beta receptor number (16% decrease) and reduce NE-stimulated adenylate cyclase activity (22% decrease), indicating that postsynaptic plasticity was still maintained. Affective disorders do not appear to be associated with a substantial (or readily measurable) decrease in brain NE concentrations and there is no consistent evidence of an altered beta receptor responsiveness. Thus, partial depletion of NE with xylamine might represent a biochemical model reflecting the involvement of NE in depression which could be used to investigate more sensitive markers of altered noradrenergic function.
Dudley
M W
MW
Merrell Dow Research Institute, Cincinnati, Ohio.
Siegel
B W
BW
Ogden
A M
AM
McCarty
D R
DR
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003891:Desipramine / Q000494:pharmacology; D006892:Hydroxydopamines; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D008297:Male; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D009638:Norepinephrine / Q000032:analysis*; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000187:drug effects*; D012701:Serotonin / Q000032:analysis
D006892:Hydroxydopamines; D009588:Nitrogen Mustard Compounds; D011941:Receptors, Adrenergic; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C026131:xylamine; D016627:Oxidopamine; D003891:Desipramine; D009638:Norepinephrine