Effects of dopamine partial-agonist aminoergolines on dopamine metabolism in limbic and extrapyramidal regions of rat brain.

The aminoergolines SDZ-208-911, -208-912, and -212-327, weak partial D2 agonists with agonist/antagonist properties, are proposed as potential atypical antipsychotic agents with limited risk of extrapyramidal effects or hyperprolactinemia. The in vivo effects on dopamine (DA) metabolism in limbic (accumbens) and extrapyramidal (striatum) regions of rat brain were evaluated by measuring the accumulation of L-dihydroxyphenylalanine (DOPA) after inhibiting decarboxylation alone ("open-loop" model) or with added gamma-butyrolactone (GBL, autoreceptor model). All three aminoergolines markedly increased DOPA in both regions, dose-dependently, with only minor decreases when GBL was included, and so evidently lack appreciable agonist activity at D2-like autoreceptors and resemble typical neuroleptics in stimulating DA synthesis, without regional selectivity.

Interactions of fluoxetine with metabolism of dopamine and serotonin in rat brain regions.

Given evidence of inhibitory effects of serotonin on dopaminergic neurotransmission, a series of experiments sought neurochemical evidence of interactions between the selective serotonin transport inhibitor fluoxetine and the metabolism of dopamine (DA) or serotonin (5-HT) in regions of rat brain that might account for extrapyramidal side-effects associated with clinical use of fluoxetine. There were significant inhibitory effects of acute or repeated fluoxetine treatment on the turnover of 5-HT (accumulation of 5-hydroxytryptophan, or ratio of [5-hydroxyindoleacetic acid]/[5-HT]) in striatum, nucleus accumbens and frontal cerebral cortex, but only minor effects on metabolism of DA (accumulation of dihydroxyphenylalanine, or [homovanillic acid]/[DA] ratio), even at high doses or with repeated treatment, and no significant inhibition of the DA metabolism-increasing actions of haloperidol.

Dopamine D1 autoreceptor function: possible expression in developing rat prefrontal cortex and striatum.

Synthesis-modulating dopamine (DA) autoreceptor function was studied in vivo using gamma-butyrolactone (GBL) to block propagation along DA axons. DA synthesis was measured by the accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) after inhibition of aromatic L-amino acid decarboxylase. GBL treatment markedly increased DOPA accumulation in both the striatum and prefrontal cortex of developing rats. The selective DA partial D1 agonist SKF-38393 inhibited this GBL-induced rise in DA synthesis in both the striatum and prefrontal cortex of 15- and 22-day-old rats, but not in adults. The effects of SKF-38393 in developing rats were mimicked by the non-catechol D1 partial agonist CY-208-243, and were blocked by the D1 antagonist SCH-23390, suggesting receptor mediation. The mixed D2/D3 agonist quinpirole attenuated DA synthesis in striatum of both two-week-old and adult rats, but failed to inhibit the GBL-induced increase in DA synthesis in the developing prefrontal cortex. These findings suggest that synthesis-modulating D1-like receptor function may emerge transiently in the developing mammalian forebrain. In the adult striatum these functions appear to be subsumed by D2-like receptors, whereas all synthesis-modulating DA receptor function in prefrontal cortex appears to be essentially lost with maturation.

Flow cytometric analysis of DNA ploidy and S-phase fraction in breast cancer using cells obtained by ex vivo fine-needle aspiration: an optimal method for sample collection.

A total of 203 primary invasive breast cancers were sampled by ex vivo fine-needle aspiration (FNA), directly yielding adequate single cell suspensions for flow cytometric DNA analysis in 194 (96%). Labor-intensive and time-consuming steps of mechanical and enzymatic cellular disaggregation required by the use of fresh, frozen, or paraffin-embedded tissue were avoided, thereby minimizing preparation time. Conservation of tumor tissue allowed for the sampling of very small breast cancers. DNA ploidy and S-phase fraction data were comparable to flow cytometric data reported in other breast cancer studies using various sampling methods. Ex vivo FNA is the easiest and fastest method for sampling breast cancers for flow cytometric DNA analysis.

Dopamine D1 receptor development depends on endogenous dopamine.

Profound depletion of forebrain dopamine by 6-hydroxydopamine in neonatal rats (day 3) was associated with up to 82% loss of D1 receptor sites labeled with [3H]SCH-23390 at day 21. Administration of the selective D1 agonist SKF-38393 (days 6-18) abolished the correlation between D1 receptor density and DA concentrations, even with greater than 99% depletion of DA. In intact control animals, there was an inverse correlation between spontaneous variation in levels of DA and D1 receptor site density in forebrain tissue (r = -0.79) which also was abolished by treatment with the D1 agonist. Thus, D1 receptor density may be regulated by reciprocal regulatory processes during normal development, but may fail to develop in the absence of an adequate level of stimulation.

Effects of isomers of hydroxyaporphines on dopamine metabolism in rat brain regions.

The effects of isomers of di- and monohydroxyaporphines on cerebral dopamine (DA) metabolism were evaluated in representative extrapyramidal (corpus striatum) and limbic (nucleus accumbens septi) tissues of rat brain by three methods: (1) changes in the ratio of homovanillic acid (HVA) to DA, (2) accumulation of L-dihydroxyphenylalanine (DOPA) after inhibiting its decarboxylation to DA under "open-loop" conditions, as well as (3) after gamma-butyrolactone (GBL) pretreatment to provide selective effects at presynaptic DA autoreceptors. The DA-agonist R(-) isomers of the aporphines apomorphine (APO), N-n-propylnorapomorphine (NPA), and 11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) showed consistent dose-dependent inhibition of DA synthesis in both brain regions with all models; the neuroleptic haloperidol had the opposite effect in the first two models only, as expected. The S(+) isomers of NPA and 11-OH-NPa have shown behavioral evidence of antidopaminergic activity, especially in the limbic system. Unlike the neuroleptic, S(+)NPA did not show DA-synthesis enhancing actions in accumbens or striatal tissue but, instead, inhibited DA synthesis like its R(-) antipode in all three test paradigms. S(+)11-OH-NPa given alone produced minor changes in the HVA/DA ratio and did not antagonize R(-)11-OH-NPa, weakly increased accumulation of DOPA in the second model, and had no effect in the third--all without regional selectivity. In the test of autoreceptor functioning, the dihydroxyaporphine S(+)NPA, but not S(+)11-OH-NPa, inhibited DA synthesis and this effect, in turn, was largely reversed by haloperidol, as were the inhibitory effects of the three R(-)aporphines tested. In this model, however, neither S(+)NPA nor S(+)11-OH-NPa antagonized the DA-synthesis inhibiting effect of R(-)APO as haloperidol did. Overall, these results are consistent with evidence that R(-)NPA and 11-OH-NPa have high affinity at D-2 receptor sites in rat brain and show behavioral effects of typical DA agonists. The non-stereoselective inhibitory effects of NPA on DA synthesis may reflect its activity as a weak DA agonist with very low intrinsic activity, but may also include a direct "catechol-effect" on tyrosine hydroxylase. In contrast, R(-)11-OH-NPa appears to be a stereoselective D-2 agonist, active at autoreceptors as well as postsynaptic receptors, that lacks the nonstereospecific effects on DA metabolism of its catechol-aporphine congener. It may be a useful probe for the further characterization of dopamine receptors and autoreceptors.