Isoprenaline increases brain concentrations of administered l-dopa and l-tryptophan in the rat

A small dose of isoprenaline or saline was administered intraperitoneally to rats 20 min before the administration of one of the amino acids l-dopa or l-tryptophan. Isoprenaline caused a marked increase in the brain concentration of the administered amino acid. Isoprenaline has previously been shown to cause a decrease in at least some of those plasma amino acids which compete with l-dopa and tryptophan for carrier-mediated transport into the brain. The effect of isoprenaline on the concentrations of dopa and tryptophan in the brain is suggested to be at least partly caused by a change in the relationship between endogeneous and administered amino acids. It is also possible that a direct effect of isoprenaline on the blood-brain barrier transport system contributes to the effect.The reported finding might be of clinical interest in view of the therapeutic importance of aromatic amino acids with a central site of action.     

Reduced brain serotonergic activity after repeated treatment with β-adrenoceptor antagonists

Rats were treated subchronically (14 days) or acutely (single dose) with the ₁-selective adrenoceptor antagonist metoprolol or the ₂-selective adrenoceptor antagonist ICI 118,551. Metoprolol (350 mg/kg/day for 14 days, orally) significantly reduced the 5-hydroxytryptophan (5-HTP) accumulation when measured 30 min after inhibition of L-amino acid decarboxylase by NSD 1015 (100 mg/kg IP) in the limbic forebrain, the corpus striatum, the cerebral cortex, the brain stem, and in the cerebellum. ICI 118,551 (0.5 mg/kg, twice daily for 14 days, SC) also significantly reduced the 5-HTP accumulation in the same brain regions except in the corpus striatum and the brain stem. Simultaneously assayed tryptophan levels were largely unaffected. Thus sustained -adrenoceptor blockade causes a decrease in the in vivo rate of tryptophan hydroxylation in various rat brain regions. The subchronic treatments with metoprolol or ICI 118,551 also significantly reduced the endogenous levels of 5-hydroxytryptamine (5-HT) in the various rat brain regions studied. Acute treatment with either metoprolol (2 mg/kg SC) or ICI 118,551 (0.5 mg/kg SC) did not affect the 5-HTP accumulation or the endogenous 5-HT levels in the brain regions studied. This inhibitory effect on brain 5-HT systems produced by sustained -adrenoceptor blockade may be of significance both for the long-term cardiovascular action and for occasional neuropsychiatric side effects during -blocking therapy.     

A quantitative study in the rat on the relationship between imipramine levels in brain and serum

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 mol kg^-1, 350 ng–5mg 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 -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 2×36 mol kg^-1 (10 mg kg^-1), last dose 89 mol 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.deceased     

Effect of age on levels of diazepam in plasma and brain of rats

Summary The pharmacokinetics and distribution in brain and cerebellum of diazepam after a single dose were studied in middle aged (6 months) and old (18 months) rats. Following the single intravenous bolus of 5 mg/kg diazepam was eliminated more slowly in old rats (T _1/2()=3.1h) than in middle aged rats (1.4 h). This was due to an increase in the apparent volume of distribution Vd from 11.0 l/kg (control rats) to 29.5l/kg. Concentrations of diazepam in brain and cerebellum were in the same range (0.5–1.1 ng/mg) in both groups after this dose. We conclude that the distribution of diazepam is age-dependent which might be due to an altered body composition.     

Lipophilicity and brain disposition of clonidine and structurally related imidazolidines

Summary The apparent partition coefficients (P) of clonidine and 27 of its structurally related imidazolidines were determined in the octanol/buffer (pH=7.4) system as a measure of lipophilic behaviour. Lipophilicity of the imidazolidines is limited to the free bases and the principle of additivity is valid for this series of structurally similar compounds.Brain concentrations of clonidine and a number of its derivatives, achieved at the moment of maximal decrease in blood pressure, were determined following intravenous administration to anaesthetized rats. These brain concentrations represent the maximally attainable values. The ratio of log brain concentration/ dose administered intravenously, log (C_brain/C_i.v.), was employed as a measure of the penetration ability of the imidazolidines into the brain. The octanol/buffer (pH=7.4) system proved a satisfactory reference model in order to describe the transport process of the present imidazolidines from the blood to the brain. The penetration ability of these compounds into the brain could be expressed mathematically by a highly significant, parabolic relationship in log P. Ideal lipophilic character for optimal brain concentrations is connected with a log P value of 2.16.     

Clonidine-induced locomotor hyperactivity in rats

Summary The -adrenergic agonist, clonidine, causes sedation in normal rats. The present study demonstrates that clonidine evokes strong locomotor stimulation in rats pretreated with 6-hydroxydopamine plus reserpine. Similar, but less intensive hyperactivity is observed in rats given clonidine after combined pretreatment with 6-hydroxydopamine plus p-chlorophenylalanine plus -methyl-p-tyrosine, or with reserpine plus low doses of yohimbine. The -adrenolytic drugs, phenoxybenzamine, phentolamine and aceperone, as well as high doses of yohimbine, antagonise the clonidine-induced locomotor stimulation; in contrast, the dopamine receptor blocking agents, pimozide and spiroperidol, exert no antagonistic effect. The results indicate that in the brain of normal animals, clonidine predominantly activates presynaptic -adrenoceptors on noradrenergic neurones and thereby induces sedation. After destruction of the noradrenergic fibres by 6-hydroxydopamine plus reserpine, activation of postsynaptic -adrenoceptors prevails so that hyperactivity results.This study was supported by Polish Academy of Sciences (10.4). Preliminary accounts were presented at the Pharmacology Meeting, Hannover, September 14–17, 1976 and at the 1 st Joint Symposium of Hungarian and Polish Pharmacological Societies, Zakopane, October, 13–15, 1976     

The functional pool of brain catecholamines: Its size and turnover rate

Behavioral data are reviewed that give evidence for an indiscriminate involvement of brain catecholamines (CA), especially dopamine (DA), in nervefunction, regardless of the time elapsed from their synthesis. Critical analysis of biochemical and pharmacological studies shows that a clear-cut distribution of brain catecholamines in two compartments [newly synthesized (NS) and main storage] is not at all established, and moreover that there is no adequate proof that the difference in turnover rates attributed to these two supposed pools is due to a preferential extraneuronal release of NS-CA during nerve function rather than to a preferential (nonfunctional) intraneuronal deamination of NS-CA, or at least of NS-DA.     

Spastic paraplegia associated with addison's disease: Adult variant of adreno-leukodystrophy

Summary Clinical and pathological features of an adult variant of adreno-leukodystrophy (ALD) are presented. A male with clinical and laboratory signs of Addison's disease (AD) developed at age 22 a slowly progressing paraplegia with slight sensory deficits in both legs and bladder and sphincter dysfunctions; he died at age 24 in an AD crisis. Autopsy revealed hyperplasia of lymphatic tissues, lymphocytic infiltrates in various organs including the CNS and adrenocortical atrophy with prominence of large ballooned, sometimes bizarre and occasionally striated cortical cells. CNS lesions consisted in incomplete demyelination of long tracts of brain stem and spinal cord with accentuation in the pyramical tracts; in these areas, perivascular cuffs of epitheloid histiocytic cells contained a strongly PAS-positive non-sudanophilic material. Electron microscopy demonstrated massive storage of leaflet structures in perivascular histiocytes identical to the lamellar profiles previously described as specific for ALD. Some leaflets were found in close contact with compact lamellar arrays and with an electron-dense fingerprint material within astrocytes.In our case, the spastic paraplegia-AD syndrome which has been described previously in several clinical observations could be neuropathologically classified as an adult variant of ALD. Several differences to classical ALD occurring in young boys are stressed: the predominance of the endocrine disorder probably accounting for some of the perivascular lymphocytic infiltrates within the CNS; the absence of both clinical and pathological signs of diffuse cerebral involvement and the peculiar topistic pattern of CNS lesions and the very slow evolution of neurological signs paralleled by the absence of active sudanophilic demyelinating lesions. The possible mechanism of demyelination and the nature of the suggested metabolic defect in ALD are discussed. The ultrastructurally prominent leaflet structures may originate from myelin remnants, thus relating ALD to pathological storage of a myelin degradation product.

---

Zusammenfassung Klinische und pathologische Befunde einer adulten Form der Adrenoleukodystrophie (ALD) werden dargestellt. Ein Patient mit klinischem Bild und Laboratoriumsbefunden der Addison-Krankheit (AD) entwickelte im Alter von 22 Jahren eine sehr langsam zunehmende Paraspastik mit geringer Hypaesthesie in beiden Beinen und Blasenund Mastdarmstörungen; er verstarb im Alter von 24 Jahren in einer AD-Krise. Bei der Autopsie fanden sich eine Hyperplasie des lymphatischen Apparats und lymphocytäre Infiltrate in verschiedenen Organen einschließlich des ZNS; beide Nebennieren waren atroph mit Hervortreten großer ballonierter, etwas bizarrer Rindenzellen mit gelegentlicher cytoplasmatischer Streifung. Im ZNS fanden sich pseudosystematische inkomplette Entmarkungen der langen Bahnen in Hirnstamm und Rückenmark mit Betonung der Pyramidenbahn, charakterisiert durch perivasale Manschetten epitheloider histiocytärer Zellen, die ein stark PAS-positives sudannegatives Material enthielten. Elektronenoptisch wurde eine massive Speicherung eines lamellären Materials in perivasalen Histiocyten nachgewiesen, welches mit den als spezifisch für die ALD angesehenen Einschlüssen übereinstimmte. Einige derartige Strukturen zeigten einen engen Zusammenhang mit kompakten Lamellenaggregaten und mit einem elektronendichten fingerprint-Material innerhalb von Astrocyten.In diesem Fall konnte das Paraplegie-AD-Syndrom, welches mehrfach bereits klinisch beschrieben worden war, aufgrund neuropathologischer Befunde als adulte Variante der ALD klassifiziert werden. Die Unterschiede dieser Form zur klassischen ALD, welche üblicherweise Knaben betrifft, werden hervorgehoben: das Überwiegen der endokrinen Symptomatik, was das Auftreten perivasaler Lymphocytensäume im ZNS zum Teil bedingen dürfte; das Fehlen klinischer und pathologischer Hinweise auf diffuse Beteiligung des Großhirns und die spezielle Topik der ZNS-Läsionen und die geringe Progredienz der neurologischen Symptomatik, welche im Einklang mit dem Fehlen florider sudanophiler Entmarkungsvorgänge steht. Der Mechanismus der Entmarkung und die Art der vermuteten metabolischen Störung bei der ALD werden diskutiert. Die elektronenoptisch charakteristischen lamellären Strukturen könnten aus dem Myelinabbau stammen, und damit könnte bei der ALD eine pathologische Speicherung eines Myelinabbauprodukts vorliegen.

     

Monoamine acid metabolites in ventricular CSF of patients with brain tumours

Summary Homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in ventricular CSF were determined in 19 patients (12 female 7 male) with brain tumours. No relationship was found between ventricular fluid pressure (VFP) and levels of HVA and 5-HIAA. A relationship was observed between ventricular CSF, HVA concentrations and tumour induced alterations in CSF dynamics. HVA concentrations were very high in patients whose tumours involved the third ventricle, the aqueduct, or the fourth ventricle, producing marked alterations in CSF flow. HVA concentrations significantly lower than in controls were observed in cases where tumours involved the lateral ventricles. Concentrations of acid metabolites in patients with little or no alteration in CSF dynamics corresponded with those in patients with other neurosurgical disorders.     

Effects of monosodium glutamate on somatic development, obesity and activity in the mouse.

Neonatal mice 1 and 5 days of age and older mice 25 days of age were injected with an increasing dose of monosodium glutamate (MSG) for a ten-day period and observed for at least 150 days. Both male and female animals in the 1- and 5-day age group treated with MSG showed large increases in weight over controls along with a shortened body length. The MSG group also showed decreases in locomotor and explatory behavior. The 25-day animals took much longer to show effects or failed to show any effects, indicating that the MSG-induced changes studied are age dependent. Possible methodological considerations accounting for conflicting reports in the MSG literature are discussed in light of the present findings.