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The location of probenecid-sensitive elimination mechanisms of monoamine metabolites from the cerebrospinal fluid of the cat was determined with ventriculo-cisternal or ventriculo-lumbar perfusion techniques. These techniques were described in detail. Levels of endogenous homovanillic acid and 5-hydroxyindoleacetic acid were assayed in the perfusate. Probenecid administration induced the most marked increase of the levels of the monoamine metabolites in the ventriculo-lumbar perfusates. It was concluded that probenecid blocked the transport of both metabolites from the spinal subarachnoid space. [ABSTRACT FROM AUTHOR]

Probenecid inhibits the efflux of acid monoamine (MA) metabolites from the CNS. The probenecid-induced accumulation of these metabolites in the CSF in man supplies data on the central turnover of the corresponding amines. In this study an attempt was made to establish whether probenecid also exerts an influence on the metabolism of the MA precursors: tryptophan and tyrosine. The principal conclusions were the following. [ABSTRACT FROM AUTHOR]

In depressions, varying therapeutic effects have been obtained with 5-HT precursors. This is possibly due to the fact that the group of the depressions is pathogenetically heterogeneous; that, specifically, some types do and other types do not entail disturbances in the central 5-HT metabolism; and that only the former types are 'precursor-sensitive'. This hypothesis was tested in a preliminary pilot study, and confirmed. The central 5-HT consumption was assessed on the basis of the probenecid test. In this experiment, 5-HTP was for the first time given in large doses over a considerable period of time. [ABSTRACT FROM AUTHOR]

The influence of i.v. administered probenecid on the 5-HIAA concentration in the CSF was studied in a group of patients with vital ('endogenous') depression and a non-depressive control group. The average increase of the 5-HIAA concentration in the CSF after probenecid administration was smaller in the depressive group than in the control group. Moreover, the depressive group included patients with a normal as well as patients with a subnormal probenecid effect. This could mean, that the group of v tal depressions encompasses two biochemically different categories: patients with and patients without demonstrable disturbances in the metabolism of 5-HT in the brain. [ABSTRACT FROM AUTHOR]

It was demonstrated that the influence of i.v. administered probenecid on HVA concentration in CSF was less pronounced in a group of retarded depression than in a group of non-retarded depression and a non-depressive control group. The figures corresponded to that found in Parkinson patients. These findings suggest a decreased consumption of dopamine in the brain in retarded depression. This might be understood as an indication that, disorders of cerebral dopamine metabolism are related not so much to a specific nosological entity as to a given motor status, possibly that of hypokinesia. [ABSTRACT FROM AUTHOR]

In test animals, 4-chloro-N-methylamphetamine (CMA) and 4-chloro-amphetamine (4-CA) cause a decrease in the cerebral 5-HT and 5-HIAA concentrations; they exert no appreciable influence on catecholamine concentrations. In man, these compounds have a therapeutic effect on depression. In terms of antidepressant effect, they resemble not so much the nonchlorinated amphetamine derivatives as the true antidepressants. This paper considers the question whether the influence of CMA and 4-CA on the 5-HT metabolism is based on inhibition of 5-HT synthesis. No arguments to support this hypothesis were found; findings obtained did support the postulate that these compounds are 5-HT depletors. In conclusion, a possible explanation of the antidepressant effect of chlorinated amphetamine derivatives is offered. [ABSTRACT FROM AUTHOR]

CMA (p-chloro-N-methylamphetamine) lowers the cerebral 5-HT concentration in test animals but has virtually no effect on the catecholamine concentrations. Moreover, this compound was found to behave in depressive patients like an antidepressive drug, not like a central stimulant of the amphetmine type. The study described was conducted in order to establish whether CMA influences the overall metabolism of indoleamines in man. Such an influence was clearly demonstrable. Our findings are consistent with the hypothesis that CMA releases 5-HT from its depots. It has not been explained why a considerable proportion of the released 5-HT is excreted unchanged and why the increase in 5-HIAA excretion is so small: the overall activity of MAO was found not to be inhibited. No indications of abnormal 5-HT degradation were found at this time. Patients with vital depressions who improved on CMA medication showed a lower 5-HIAA excretion before treatment than did patients who were refractory to CMA treatment. This is consistent with earlier observations. The possible cause of this phenomenon is discussed. Among the various possibilities considered, an abnormal 5-HT metabolism is regarded as the most plausible. Pertinent investigations are being continued. [ABSTRACT FROM AUTHOR]

Rats were injected with haloperidol (0.5-1.0 mg X kg-1). When the catalepsy score was almost maximal (60 s, measured by the bar-test), the rats were handled, exposed to cold (3 degrees C) or immobilized. After each of these stress procedures the catalepsy was significantly reduced. Handling of adrenalectomized rats gave no such reduction. Infusion of adrenaline (10 nmol X kg-1, given in 15 s), in contrast to that of isoprenaline and phenylephrine (both the same concentration as adrenaline) also reduced the haloperidol induced catalepsy. These findings indicate that neuroleptic catalepsy in rats is not only mediated through central but also through peripheral mechanisms, e.g. by the adrenal medulla.

The purpose of this study was to determine if non-pharmacological stimuli influence behavioural tolerance to haloperidol via striatal postsynaptic dopamine receptors. Rats received daily haloperidol and saline in two different environments for a period of 28 days. After this conditioning period half of the rats received haloperidol in the haloperidol-associated environment, whereas the other half received haloperidol in the saline-associated environment. All rats were tested for catalepsy and at the end of the last catalepsy test, striatal DOPAC, HVA and ACh were determined. Only the rats tested in the haloperidol-associated environment were behaviourally tolerant to haloperidol. In contrast, both groups were biochemically tolerant to haloperidol. These results indicate that environmental cue factors govern the development of behavioural tolerance to haloperidol, rather than biochemical factors (striatal DA super-sensitivity). In addition, these factors do not exert their influence on behavioural tolerance via striatal DA receptors.

Probenecid blocks the efflux of 5-hydroxyindole acetic acid (5-HIAA) from the central nervous system, and has therefore been used for turnover measurements of central 5-hydroxytryptamine (5-HT). This substance also elevates tryptophan (TP) levels in rat brain. In this investigation, the time courses of probenecid and TP levels in rat serum and brain after administration of probenecid were studied. Maximal levels of probenecid were reached within 15 min, followed by 50% decrease of serum TP and a 40% increase of brain TP. Brain levels of probenecid were about ten times lower than those in serum. Because TP level in brain is an important factor in the control of cerebral 5-HT synthesis, the effects of probenecid on 5-HT formation in rat brain were investigated. By means of the aromatic L-amino acid decarboxylase inhibitors Ro 4-4602 and NSD 1015, an enhancement of TP hydroxylation of about 35% was demonstrated. It was concluded that penetration of probenecid into the brain is very limited and that probenecid, in addition to blocking egress of 5-HIAA from the CNS, stimulates 5-HT synthesis.

The effects of several drugs and other treatments on the regional levels of Ca2+ in the brain of mice and rats were determined with an automated assay, based on the formation of a fluorescent calcein complex in a continuous flow system. The method is linear (between 1.5 and 5 micrograms Ca2+ ml-1), specific (no other cations present in the brain showed fluorescence) and sensitive (10-100 mg brain tissue can be analyzed). No major effects with the following drugs, given once or repeatedly to mice at high doses were found: morphine, naloxone, haloperidol, sulpiride, chlordiazepoxide, reserpine, ethanol, mercaptopropionic acid, or pentobarbital. Cold stress produced a transient increase in the regional levels of Ca2+ in the mouse brain. Lithium sulphate produced a small increase of brain Ca2+ 24 h after a high and toxic dose. Sleep deprivation for 24 h was ineffective in these experiments. Local application of kainic acid and tetrodotoxine to the rat striatum had no acute effects, but kainic acid produced a five to tenfold increase in the levels of striatal Ca2+ 2 weeks after injection. The present study does not support earlier published findings, which suggested that several behaviourally active drugs produce significant decreases of brain Ca2+. Moreover, it provides no evidence that the several therapeutic treatments that resulted in changes in body fluid Ca2+ also alter cerebral levels of Ca2+. On the other hand, the present data do suggest that damage to nervous tissue substantially influences Ca2+ metabolism.

Serum and brain levels of the tricyclic antidepressant drug imipramine (IMI) were studied in the rat under a variety of conditions. IV doses (range 1 nmol kg-1 to 15 mumol kg-1, 350 ng--5 mg kg-1) and administered 5 min before death, were linearly correlated with IMI levels in serum, frontal cortex, and cerebellum. In this experiment, the highest levels of IMI were achieved in the frontal and occipital cortex and the lowest levels were found in the brain stem. The regional distribution was more even in rats pretreated with thiopental or gamma-hydroxybutyric acid, drugs that alter cerebral blood flow. After 20 min or more, tracer amounts of IMI injected IV to IMI-pretreated rats [1 or 17 days, daily dose 2 x 36 mumol kg-1 (10 mg kg-1), last dose 89 mumol kg-1 (25 mg kg-1), 2--3 h before death] exhibited a distribution pattern in serum and various brain regions similar to that of the unlabeled drug. In the latter experiments, content (per volume) of the tracer or unlabeled IMI was more than 25-fold higher in various brain areas than in serum. It is concluded that despite large differences in drug levels in serum or brain, a close relationship is maintained under the conditions studied.