, Volume 294, Issue 2, pp 133-140

Comparison of short and long-lasting effects of pargyline on cerebral dopamine metabolism

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Summary

Behavioural and somatic responses to l-DOPA in rats are potentiated by short-term pretreatment with pargyline. It was therefore of interest to study the influence of the delay between pargyline pretreatment and l-DOPA-injection on the fate of the latter in rat brain.

In rats treated with pargyline (50 mg/kg s.c.), the half-lives of recovery of striatal MAO activity and normal endogenous contents of homovanillic and 3,4-dihydroxyphenylacetic acids in striatum ranged from 9 to 14 days.

The same treatment led to a marked increase (50-100-fold) in the accumulation of 3H-methoxytyramine in whole brain and, though less so, in 3H-dopamine formed from i.v. 3H-DOPA. Recovery from this effect of pargyline, however, was more rapid with a half-life of 15–19 h. Similar changes were observed when 3H-DOPA or 3H-dopamine was injected intracisternally, indicating that the phenomenon did not take place in the cerebral blood capillary walls, which are known to contain DOPA decarboxylase and MAO activities.

The only labelled deaminated metabolite of dopamine in the brain after 3H-DOPA i.v. was 3H-homovanillic acid, which was strongly reduced 2 h after pargyline, but normalized after 24 h of pretreatment with the MAO inhibitor.

When 3H-α-methyldopa instead of 3H-DOPA was injected, no increase in 3H-α-methyldopamine and its O-methylated derivative was produced by pargyline pretreatment. Moreover, in an experiment in which the animals were pretreated with pargyline at various times up to 21 days, a second injection of the MAO inhibitor 1.5 h before 3H-DOPA restored the increase in 3H-DA+3H-MT observed with a single treatment with pargyline 1.5 h before the labelled amino acid.

These results suggest that this short-lasting effect of the MAO inhibitor is related to the MAO inhibitory properties of the drug.

The threshold dose of pargyline for producing the short-term effect was about 10 times higher than that for an overall MAO (DA deaminating) inhibition. However, it seems unlikely that this was due to near maximal inhibition of overall MAO activity, i.e. that it occurred only when MAO was inhibited by more than, say, 90%.

The data reported suggest the existence of a small portion of an additional form of MAO with a rapid turnover and with a marked capacity to deaminate dopamine or methoxytyramine, and a greater resistance to inhibition by pargyline than cerebral MAO in general.