3‐Methoxytyramine Formation Following Monoamine Oxidase Inhibition Is a Poor Index of Dendritic Dopamine Release in the Substantia Nigra

Abstract

This study was undertaken, using microdialysis, to compare the extracellular concentration of 3-methoxytyramine and dopamine in dialysate from the striatum and substantia nigra, after pargyline (75 mg/kg), after pargyline plus amphetamine (3 mg/kg), and after pargyline plus reserpine (5 mg/kg) administration. Treatment with pargyline alone increased the extracellular dopamine concentration by 70% in the striatum and by 140% in the substantia nigra and induced in both regions a time-dependent accumulation of 3-methoxytyramine. The addition of d-amphetamine to pargyline increased the extracetlular dopamine concentration, compared with pargyline-treated controls, to the same extent in both the substantia nigra (maximally by 360%) and the striatum (maximally by 400%), but the concomitant increase of 3-methoxytyramine accumulation in the dialysate was relatively smaller in the substantia nigra compared with the striatum. Reserpine treatment decreased the extraceltular dopamine concentration in both regions below the detection level (<10% of basal value). When pargyline was added to reserpine, the striatal extracellular dopamine concentration increased to 50% of pargyline-treated controls and the striatal 3-methoxytyramine accumulation was less than in pargyline-treated controls. However, in the substantia nigra, the addition of pargyline to reserpine resulted in dopamine concentrations as high as after pargyline only and the 3-methoxytyramine accumulation was not changed compared with pargyline-treated controls. In summary, our results indicate that dopamine in the substantia nigra is released from reserpine-sensitive storage sites and that pargyline-induced 3-methoxytyramine accumulation is a poor indicator of the local dopamine release. The latter observation may be explained by the fact that the dopamine-metabolizing enzyme, catechol-O-methyltransferase, is located inter alia in the dopamine-containing cell bodies/dendrites in the substantia nigra, in contrast to the situation in the terminals in the striatum where catechol-O-methyltransferase is located only in nondopaminergic cells. Key Words: DopamineMicrodialysis-Substantia nigra-Striatum -3-Methoxytyramine-Catechol-O-methyltransferase.

High‐frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats

“…Pargyline inhibits MAO-catalysed DA metabolism (Planz et al 1972;Roth et al 1976;Waldmeier and Maitre 1976), thereby accumulating intraneuronal DA and increasing resting DA release (Butcher et al 1990;Di Chiara et al 1993;Elverfors et al 1997). This is further corroborated by the present data, showing a threefold increase in striatal extracellular DA levels in pargyline-treated animals.…”

The Dopamine Metabolite 3-Methoxytyramine Is a Neuromodulator

“…In fact, numerous studies have been performed on the analysis of DA release in various experimental paradigms by assessing accumulation of 3-MT tissue levels in brain tissue, often after blockade of MAO by pargyline [7], [38]. However, while later in vivo microdialysis studies have generally confirmed the association between extracellular levels of DA and 3-MT [37], the static tissue measures of 3-MT accumulation have proven to be quite inaccurate measures of dynamics of DA release [39], [40].…”

Extrastriatal dopaminergic circuits of the basal ganglia

“…Pleiomorphic vesicles have been detected in the symmetrical dendrodendritic synapses of SNc neurons (Groves and Linder, 1983) and have been shown more recently to express the vesicular monoamine transporter (Nirenberg et al, 1996). Vesicular storage of dopamine at the level of the SN is also supported by evidence that the nigral release of dopamine is sensitive to reserpine, a compound that depletes vesicular dopamine pools (Elverfors et al, 1997), as well as compounds that interfere with vesicular fusion and release (i.e., the 25 kDa synaptosome-associated protein SNAP-25; Bergquist et al, 2003). In addition, dendritic dopamine signaling can be terminated via the DAT as DAT blockade can enhance nigral dopamine levels (Robertson et al, 1991; Santiago and Westerink, 1992; Cragg et al, 1997; Cragg et al, 2001).…”