Further aspects of nomifensine pharmacology.

Abstract 1 The dopamine (DA) agonist properties of nomifensine and its metabolites were investigated in the rat using pharmacological tools (with (+)-amphetamine and apomorphine as control agents) and the intracerebral injection technique. 2 Nomifensine induced an intense stereotypic behaviour which was resistant to pretreatment with α-methyl-p-tyrosine (α-MPT) (similarly with apomorphine), but was abolished by a combined pretreatment with α-MPT and reserpine (similarly with (+)-amphetamine). Nomifensine and apomorphine were both relatively more resistant to neuroleptic blockade than (+)-amphetamine. Chronic lesions of the medial and dorsal raphe nuclei abolished or markedly reduced the effects of nomifensine and apomorphine but caused only a small reduction in the (+)-amphetamine response. 3 In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway nomifensine induced ipsilateral circling in a similar manner to that induced by (+)-amphetamine. In animals with unilateral electrolesions of the substantia nigra and asymmetric electrolesions of the medial raphe nucleus, nomifensine induced marked ipsilateral and contralateral circling, respectively (similarly with both apomorphine and (+)-amphetamine). 4 The M1 (4-hydroxyphenyl derivative) and M2 (3-methoxy-4-hydroxyphenyl derivative) metabolites of nomifensine virtually mimicked the stereotypic action of the parent drug. M3 (the 3-hydroxy-4-methoxyphenyl derivative) was inactive in this test. All three metabolites induced ipsilateral circling in the 6-OHDA circling model. The response to M3 was weakest. 5 The M1 metabolite induced DA-like effects after bilateral injection into the striatum (hyperactivity and stereotypy) after unilateral injection into the striatum (contralateral asymmetries), and after bilateral injection into the nucleus accumbens (hyperactivity). The M2 and M3 metabolites were inactive or only weakly active in these tests. 6 This data indicates an antiparkinsonian potential for nomifensine and its M1 metabolite. The psychomotor stimulation caused by nomifensine may be an additional benefit over existing treatments for affective disorders.