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Notes: Abstract— Drugs possessing (chlorpromazine, haloperidol, clozapine, thioridazine and sulpiride) or lacking (benzoctamine and perlapine) antipsychotic activity were compared with respect to their ability to enhance x-methyl-p-tyrosine-induced dopamine disappearance from the mesolimbic area and corpus striutum of rat brain. In addition, their effects on the endogenous concentrations of homovanillic (HVA) and 3.4-dihydroxyphenylacetic (DOPAC) acids in these two brain areas were determined.Some of the drugs enhanced dopamine disappearance in the mesolimbic area more than in the striatum. The most active in this respect were sulpiride. perlapine and chlorpromazine. By contrast, haloperidol was slightly more active in the striatum than in the mesolimbic area.None of the drugs was more efficient in elevating HVA levels in the mesolimbic area than in the striatum. However, there were large differences in the relative extent of the HVA increases in the two regions. Benzoctamine, perlapine and chlorpromazine increased HVA concentrations in the mesolimbic area nearly as much as in the striatum. Thioridazine and haloperidol, however, elevated striatal HVA much more effectively.Haloperidol and clozapine increased the DOPAC concentration in both areas to about the same extent. The other drugs were more active in the striatum. The largest difference between both regions was shown by chlorpromazine.Perlapine and benzoctamine, both lacking antipsychotic activity, produced much larger increases of HVA than of DOPAC. This is in contrast to the results obtained with true neuroleptics and may reflect an involvement of release phenomena in the action of these two drugs on dopamine metabolism.These results suggest that a preferential increase of dopamine turnover in the mesolimbic area is not necessarily linked to a better ratio of antipsychotic activity vs. extrapyramidal side effects. Moreover, an antiacetylcholine component of dopamine receptor blocking drugs does not seem to be a prerequisite for preferential activity on dopamine turnover in the mesolimbic system.

Notes: Abstract— A new method has been developed for the separation of histamine and its metabolites after intracisternal injection of [3H]histamine into the rat brain, involving solvent extraction and subsequent thin-layer chromatography.The effect of graded doses of the MAO inhibitors deprenil and pargyline, which at relatively low doses inhibit preferentially the B form (phenethylamine deaminating) of the enzyme, and clorgyline, which mainly inhibits the A form (serotonin, noradrenaline and dopamine deaminating) on the brain levels of intracisternally injected [3H]histamine and its labelled metabolites was studied and compared to MAO A and B activity as determined with the substrates serotonin and phenethylamine, respectively. In addition, the time-course of the effects of a single dose of pargyline (50mg/kg subcutaneously) was investigated. No [3H]imidazoleacetic acid could be detected in any of the control or treated animals. [3H]Histamine accounted for 9–12% of the total extracted radioactivity and this was not altered significantly by pretreatment with any of the MAO inhibitors up to high doses, at which both MAO A and B activities were completely inhibited.In the controls, 40–43% of the total extracted radioactivity was [3H]methylhistamine and 28–30% was [3H]methylimidazoleacetic acid. Deprenil and pargyline caused [3H]methylhistamine levels to increase in a dose-dependent manner up to about 150% of control levels and those of [3H]methylimida-zoleacetic acid to decrease concomitantly to about 10% of control levels. Clorgyline in doses up to 10 mg/kg subcutaneously (s.c.) had no effect on the levels of these two metabolites. The dose-response curves of the effects of deprenil and pargyline on [3H]methylimidazoleacetic acid levels were congruent with those of the MAOI effects on MAO B activity and not with those on MAO A activity.Pargyline (50 mg/kg s.c.) had a long lasting effect on the accumulation of [3H]methylhistamine and [3H]methylimidazoleacetic acid. Recovery occurred within 21 days, and the half-lives observed were 5.3 and 5.6 days, respectively. This compares well to the half-life for the recovery of MAO B activity reported earlier after the same dose of pargyline (5.5 days).These results suggest that methylhistamine is metabolized selectively by MAO B in rat brain. Moreover, the fact that clorgyline, at doses where phenethylamine deamination is already considerably inhibited, did not affect the deamination of methylhistamine, suggests that the latter is an even more selective substrate for MAO B than phenethylamine itself.Therefore, small doses of deprenil (0.3–3 mg/kg s.c.) or pargyline (1–3 mg/kg) can be used to influence histamine catabolism without interfering with catecholamine or serotonin deamination.

Notes: Summary A highly specific and sensitive method for the determination ofβ-phenylethylamine (PEA) in biological material is presented. It involves prepurification of the extracts on Sep-Pak C18 cartridges, derivatization with heptafluorobutyric acid anhydride, gas chromatography on 50 m capillary columns and quantification by chemical ionization mass spectrometry. Using this method, levels of PEA in the rat brain and the effects of various monoamine oxidase (MAO) inhibitors thereon have been determined. PEA control levels were found to vary considerably: the lowest and highest values found were 0.4 and 12.5 ng/g tissue (n=25). Within one and the same control group, the variation was somewhat smaller. The preferential or specific inhibitors of MAO A, amiflamine, cimoxatone, CGP11305 A, moclobemide and toloxatone did not alter rat brain PEA even at high doses. In contrast, the preferential inhibitors of MAO B, deprenil, pargyline and MD 780236, as well as the nonselective agent tranylcypromine, caused strong (up to about 60-fold) increases. The threshold doses corresponded to those which caused about an 80 % inhibition of MAO B as measuredex vivo. The method was also used to determine the concentration of PEA in human CSF (mean 17.3±3.3 ng/ml, range 3–45 ng/ml, n=15) and urine (males: mean 35±5μg/g creatinine, range 3.8–219μg/g, 78 control days of a total of 12 subjects; females: mean 35±6μg/g creat., range 2.7–266μg/g, 55 control days of a total of 8 subjects).

Notes: Summary Phenylethylamine (PEA) and the monoamine metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the cerebrospinal fluid (CSF) of nine paranoid schizophrenics before and after three weeks of neuroleptic treatment. Patients were classified according to the Research Diagnostic Criteria and rated by means of the Brief Psychiatric Rating Scale. A significant increase was seen in HVA CSF concentrations during neuroleptic treatment (p〈0.01). No influence was found on levels of PEA, 5-HIAA, and MHPG. Concentrations of both MHPG and 5-HIAA correlated positively with those of HVA. These results in combination with previous findings do not support the contention that PEA and NA metabolisms are grossly disturbed in paranoid schizophrenics whereas involvement of other neurotransmittersi.e. dopamine, seems more probable.

Notes: Summary Potentiation of the effect of haloperidol on dopamine metabolism by the 5-HT uptake inhibitor CGP 6085 A, and antagonism of this effect by the 5-HT antagonist mianserin were observed in the mesolimbic area and the frontal cortex of the rat brain. A similar effect was reported earlier in the corpus striatum. This suggests that serotoninergic modulation of dopamine neurons is a generally-occurring phenomenon in the brain.