Effects of a secondary and a tertiary amine tricyclic antidepressant on cerebral biogenic amines as a function of mouse strain: a comparative neurotoxicological evaluation.
The effect of equal-dose regimens of amitriptyline and nortriptyline on the concentrations of serotonin, dopamine and major acidic metabolites was compared in 5 distinct brain regions as a function of inbred mouse strain. Amitriptyline increased to a greater extent the regional brain serotonin levels in the albino BALB/c mouse than did nortriptyline. Both drugs increased serotonin levels but decreased cerebral 5-hydroxyindoleacetic acid levels in some distinct brain regions of the black C57BL/6 mouse strain. The results suggest a strain-dependent differential increase in brain serotonin turnover in specific mouse strain brain regions which may account for the greater incidence of amitriptyline-induced sedation and seizures. The BALB/c mouse was also found to be more sensitive than the C57BL/6 strain to the action of both drugs on dopamine and major acidic metabolites with amitriptyline showing more regional brain potency than nortriptyline. The data suggest an increase in dopamine turnover particularly in brain areas associated with motor function and posture which may account for tricyclic-antidepressant-induced extrapyramidal disorders. The results also indicate that the C57BL/6 mouse strain may be of experimental value for studying the mechanism underlying tricyclic-induced adverse reactions relevant to sedation and movement disorders as a function of genetic predisposition.
Messiha
F S
FS
Department of Pharmacology, University of North Dakota School of Medicine, Grand Forks 58203.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000639:Amitriptyline / Q000633:toxicity*; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009498:Neurotoxins; D009661:Nortriptyline / Q000633:toxicity*; D009928:Organ Specificity; D012701:Serotonin / Q000378:metabolism; D013045:Species Specificity
D001679:Biogenic Amines; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D000639:Amitriptyline; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D009661:Nortriptyline; D004298:Dopamine