Rotational behaviour and neurochemical changes in unilateral N-methyl-norsalsolinol and 6-hydroxydopamine lesioned rats

In earlier studies the tetrahydroisoquinoline derivative N-methyl-norsalsolinol (2-MDTIQ) was discovered in lumbar cerebrospinal fluid and brain of patients with Parkinson's disease. To establish whether 2-MDTIQ is toxic to the dopaminergic system, 2-MDTIQ or 6-hydroxydopamine (6-OHDA) were stereotactically injected into the left medial forebrain bundle, and rotational behaviour and neurochemical changes were measured in female Wistar rats. Three weeks after lesioning rotational behaviour was assessed after administration of S(+)-amphetamine (5 mg/kg) and apomorphine (0.1 mg/kg). As expected, after 6-OHDA lesions S(+)-amphetamine as well as apomorphine markedly induced rotations ipsiversive or contraversive, respectively, to the lesion, and dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels of the ipsilateral caudate-putamen and accumbens nucleus decreased. Although a decline in the dopamine/DOPAC ratio indicated an enhanced dopamine turnover, striatal monoamine oxidase (MAO) activity remained unchanged when tested in vitro. After a 2-MDTIQ lesion S(+)-amphetamine also caused animals to rotate strongly, ipsiversive to the lesion, but there was no response to apomorphine administration. This 2-MDTIQ effect was not due to a reduction in dopamine metabolism of the ipsilateral caudate-putamen or mesencephalic structures, or, for example, a partial neurodegeneration of dopaminergic neurons, since dopamine metabolites levels and MAO activity were nearly unchanged. Thus, we suggest that 2-MDTIQ interacts with the effect of S(+)-amphetamine and probably leads to an insensitivity of the dopamine uptake/transporter system to S(+)-amphetamine in dopaminergic nigrostriatal neurons. An effect of 2-MDTIQ on presynaptic membranes of dopaminergic synaptosomes has never been reported, but will be an objective of our further studies.