3-Methoxytyramine accumulation: Effects of typical neuroleptics and various atypical compounds

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Abstract
The accumulation of 3-methoxytyramine (3-MT), the O-methylated metabolite of dopamine (DA), in rat striatum was used to assess the effects of drugs on dopaminergic activity. This was accomplished by pretreating rats with pargyline to completely inhibit 3-MT catabolism. Under the conditions used, 3-MT accumulation was linear over time for at least 90 minutes. Apomorphine and γ-butyrolactone, drugs which depress the activity of DA-containing neurons, decreased striatal 3-MT accumulation; whereas typical neuroleptics (haloperidol, fluphenazine, chlorpromazine), which increase the activity of DA-containing neurons, increased striatal 3-MT accumulation. In addition, a number of other drugs which block DA receptors and exert various atypical actions on dopaminergic functioning were examined. These “atypical” compounds (clozapine, buspirone, molindone) also increased striatal 3-MT accumulation, but were generally less potent than the typical neuroleptics examined. Moreover, the potencies of the typical neuroleptics and “atypical” compounds that were tested appear to be somewhat related to their affinities for D-2 DA receptors, as measured by their abilities to displace 3H-spiperone from rat striatal membrane preparations. Interestingly, this relationship was less evident when NaCl was omitted from the 3H-spiperone binding assay buffer. The potential antipsychotic drugs, BW 234U and SCH 23390, were also investigated for their effects on 3-MT accumulation and 3H-spiperone binding, and they were relatively inactive in both of these measures of dopaminergic activity. The observation that SCH 23390, a D-1 DA receptor antagonist, had negligible effects on 3-MT accumulation suggests that D-1 receptor blockade, unlike D-2 blockade, may have minimal effects on DA release. The relevance of the above findings to understanding the effects of drugs on dopaminergic transmission and the advantages of measuring 3-MT accumulation instead of basal 3-MT concentrations are discussed.