Effect of nomifensine on motor activity, dopamine turnover rate and cyclic 3',5;-adenosine monophosphate concentrations of rat striatum.

Abstract

Nomifensine (8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline hydrogenmaleate) is a new antidepressant with a pharmacological profile somewhat different from the classical tricyclic antidepressants. In doses higher than 1 mg/kg it increases motor activity in rats, an effect wich resembles that of amphetamines. Unlike amphetamine, its effect on motor activity cannot be blocked by pretreatment with α-methyltyrosine methylester (α-MT), only the combined pretreatment with α-MT and reserpine abolishes the stimulatory effect of nomifensine. Dopamine (DA) and Norepinephrine (NE) turnover are not increased by threshold doses of nomifensine which elicit hypermotility, only a tenfold higher dose is able to increase DA and NE turnover in striatum and teldiencephalon significantly. In contrast, (+)amphetamine increases DA turnover in striatum in threshold doses, which also increase motor activity and apomorphine decreases DA turnover in striatum in behaviorally active doses. Nomifensine, (+)amphetamine and apomorphine increase 3′, 5′-adenosinemonophosphate (cAMP) concentrations in rat striatum in a dose dependent manner. However the cAMP increment elicited by (+)amphetamine is dose dependent only within a limited range and reaches maximal values after 2.5 mg/kg, whereas nomifensine and apomorphine exhibit a linear dose response relationship between 5 and 15 mg/kg. These results are consistent with evidence from studies on NE and DA uptake and release in synaptosomes, which indicate, that nomifensine blocks NE uptake in noradrenergic and DA uptake in dopaminergic neurons very strongly. Inhibition of DA uptake in striatum, which is very poor in tricyclic antidepressants, may be responsible for the stimulatory effect of nomifensine on motor activity. Since nomifensine fails to increase DA turnover in strtiatum in doses, which elicit hypermotility, a DA release from dopaminergic neurons—as described for amphetamine-is unlikely to cause this behavior activation.