Activation of α2-adrenoreceptors enhances haloperidol-induced suppression of operant behavior

Summary Inhibition of catecholamine synthesis by-methyl paratyrosine (-MT) was previously shown to potentiate the behavioral suppression caused by dopamine-receptor antagonists. This effect of-MT is in all probability due to inhibition of the compensatory increase in dopamine turnover induced by the dopamine receptor antagonists. In the present study we investigated the effect of the ₂-adrenoreceptor agonist clonidine on the haloperidol-induced suppression of food-reinforced lever-pressing behavior (fixed ratio 401) in rats. Small behaviorally inactive doses of clonidine were found, in analogy with-MT, to enhance the haloperidol-induced suppression of the lever-pressing behavior. The haloperidol-induced increase in dopamine synthesis (measured as the accumulation of DOPA after inhibition of aromatic amino acid decarboxylare) was antagonized by clonidine in the striatum as well as in the dopamine rich limbic regions. Prazosin, a selective ₁-adrenoreceptor antagonist had no effect on the clonidine induced behavioral changes. Idazoxane, a selective ₂-adrenoreceptor antagonist, counteracted both the behavioral and biochemical effects of clonidine, indicating that these effects of clonidine are mediated via its action on ₂-adrenoreceptors. The present findings provide support for the notion that ₂-adrenoreceptors may participate in the regulation of nigro-striatal as well as meso-limbic dopaminergic activity. It is suggested that ₂-adrenoreceptor agents, especially in combination with classical antipsychotics, might be of therapeutic value in the treatment of disorders associated with abnormal dopaminergic activity.     

Ethanol behaves as an NMDA antagonist with respect to locomotor stimulation in monoamine-depleted mice

Summary Previous studies have shown that administration of NMDA antagonists in combination with the ₂-adrenoceptor agonist clonidine results in a marked locomotor stimulation in monoamine-depleted mice, albeit the pattern of movement produced is highly stereotyped and primitive. Ethanol has recently been suggested to display NMDA antagonistic properties; hence, in the present study the ability of ethanol to produce locomotor activation in monoamine-depleted mice with a movement pattern similar to that produced by NMDA antagonists was investigated. It was found that neither ethanol nor clonidine given alone reversed the akinesia induced by pretreatment with reserpine (10 mg/ kg; 18 h) and -methyl-para-tyrosine (500 mg/kg; 2 h). However, when the drugs were combined a marked stimulatory effect was observed and, indeed, the animals displayed the same primitive locomotor pattern previously observed following treatment with NMDA antagonists in conjunction with clonidine. The locomotor response was effectively blocked by pretreatment with the selective ₂-adrenoceptor antagonists yohimbine (10 mg/kg) or idazoxan (10 mg/ kg) but not with the selective ₁-adrenoceptor antagonist prazosin (1 mg/kg). The present results suggest that ethanol in conjunction with ₂-adrenoceptor stimulation induces locomotion in monoamine-depleted mice via a mechanism that may involve interference with glutamate receptor-mediated neurotransmission.     

Involvement of postsynaptic α1- and α2-adrenoceptors in the flexor reflex activity in the spinal Rats

Summary Clonidine (0.2 mg/kg i.v.) and St 587 (1 mg/kg i.v.), selective agonsists of ₂- and ₁-adrenoceptors, respectively, increased the flexor reflex amplitude in the spinal rat. Yohimbine and rauwolscine, ₂-adrenoceptor antagonists, inhibited dose-dependently the effect of clonidine but not of St 587. However, prazosin and clozapine, ₁-adrenoceptor antagonists, diminished the action of both agonists in a dose-dependent manner. After central chemosympathectomy caused by 6-OH-DA or DSP-4 the response to clonidine did not differ from that in the sham-operated animals. In 6-OH-DA treated rats yohimbine (1 mg/kg i.v.) antagonized the effect of clonidine to the same extent as it did in unlesioned animals. It is concluded that the results are functional evidence that ₁- and ₂-adrenoceptors are present in the rat spinal cord, and stimulation of each receptor increases flexor reflex activity.     

Marked locomotor stimulation in monoamine-depleted mice following treatment with atropine in combination with clonidine

Summary The present study demonstrates that the muscarinic antagonist atropine and the -adrenergic agonist clonidine, though ineffective when administered separately, produced a pronounced locomotor stimulation in monoamine-depleted mice when combined. The atropine + clonidine-induced locomotor stimulation was counteracted by both the ₂-adrenoceptor antagonist idazoxan and the acetylcholinesterase inhibitor physostigmine. Thus, it is clear that simultaneous manipulations with cholinergic and adrenergic systems are as effective in restoring locomotion in monoamine-depleted mice as increasing central dopaminergic tone. This finding may have implications for the treatment of a movement disorder like Parkinson's disease.     

Adaptive and differential changes on β- and α2-adrenoreceptors mediated hyperthermia after chronic treatment with antidepressant drugs in the rat kept at high ambient temperature

Summary We found previously that the-agonist clenbuterol and the-agonist clonidine produced hyperthermia in rats kept at high ambient temperature, which effects were mediated by- and ₂-adrenoceptors, respectively. In the present paper this observation was used for testing the responsiveness of-or ₂-adrenoceptors, changed by a pharmacological manipulation,i.e., by chronic treatment with antidepressants. The animals were pretreated with desipramine, imipramine or amitriptyline twice a day for 1 or 2 weeks. All antidepressants significantly attenuated the clenbuterol-induced hyperthermia after 2 weeks of treatment. The effect of desipramine was stronger than that of the other antidepressants and appeared as little as 1 week after the treatment. The hyperthermic effect of clonidine was significantly reduced by repeated treatment with desipramine, increased after 2 weeks administration of imipramine, whereas amitriptyline produced no significant changes. In conclusion, these data suggest that, after repeated treatment, the antidepressants tested produce an adaptive decrease in function of-adrenoceptors while the same drugs exert differential effects on ₂-receptors. Moreover, clenbuterol induced hyperthermia may be a useful test for examining possible functional changes in-adrenoceptor sensitivity.     

Comparison of integrin adhesion molecules expressed by primary brain lymphomas and nodal lymphomas

The expression of 17 adhesion molecules was immunohistochemically examined in 5 primary cerebral lymphomas (PCL) and in 5 histologically similar nodal lymphomas (NL) to evaluate their possible involvement in selective targeting of lymphoma cells to the brain. PCL and NL tumor cells showed very similar expression patterns: they were consistently positive for ₃, ₄ and ₁ integrin chains; negative for ₂, ₆, ₃ and ₄ integrin chains; and heterogeneous for ₅, _L, _M, _X, ₂ and ₇ integrin chains, as well as for intercellular adhesion molecule-1 (ICAM-1) and the selectin LECAM-1. Loosely infiltrating PCL showed lower levels of the _L2 integrin than compact cell clusters. Vessels stained for ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). We conclude that the adhesion molecules implicated in the extravasation of non-neoplastic leukocytes (₄₁/VCAM-1 and _L2/ICAM-1) are also expressed by both PCL and NL. The adhesion molecules examined are apparently not selective mediators of lymphoma cell homing to the brain, but at least _L2 integrin might be related to the infiltration pattern of PCL within the brain parenchyma.Supported by the Sander Foundation     

Reciprocal interactions between α2-adrenoceptor agonist and neuropeptide Y binding sites in the nucleus tractus solitarius of the rat

Summary Interactions between a ₂-adrenoreceptor agonist and neuropeptide Y (NPY) binding sites have been studied in the rat medulla oblongata (MO) using biochemical binding techniques as well as quantitative autoradiography. Tritiated para-amino clonidine (³H-PAC; ₂-adrenoceptor agonist), idazoxan (³H-IDA; ₂-adrenoceptor antagonist) and iodinated neuropeptide Y (¹²⁵I-NPY) were used as radioligands. (1) Neuropeptide Y (NPY; 10^–8M) but not bovine pancreatic polypeptide (BPP) nor peptide YY (PYY 10nM) increased the K_D value of³H-PAC binding sites. However, intraventricular administration of a high dose of NPY (1.25nmol) did not change the³H-PAC binding characteristics in MO membrane preparations of these animals. (2) GTP 10^–4 lowered the affinity of³H-PAC binding. NPY (10 nM) had no additional effect, nor did NPYinfluence the GTP induced shift in potency of clonidine to displace³H-IDA from its binding sites. (3) In the autoradiographical experiments NPY (10nM) significantly reduced³H-PAC binding (2nM) in the nucleus tractus solitarius (NTS) area by 35%. (4) When clonidine, either given centrally in vivo (3.75nmol) or in vitro (10 nM) the binding of¹²⁵I-NPY was reduced (34 and 24%, respectively) in the NTS. When the monoamine receptors were irreversibly blocked in vivo by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 10 g i.e. 24h)¹²⁵I-NPY (0.5 nM) binding was increased by 137% in the NTS. This effect of EEDQ was prevented by pretreatment with the ₂-adrenoreceptor antagonist idazoxan.These results provide support for a direct intramembrane interaction between the ₂-receptor and the NPY receptor within the NTS and may be of importance in central cardiovascular regulation.     

Clonidine and a β-agonists induce hyperthermia in rats at high ambient temperature

Summary The effects of the-agonist clonidine and the-agonist clenbuterol on body temperature of rats kept at high ambient temperature (28°C) were studied. Both drugs induced a dose-dependent significant increase in temperature. The clonidine-induced hyperthermia was blocked by various a2-antagonists, yohimbine, rauwolscine and RX 781094 and the ₁-antagonists, prazosin and corynanthine but not by l-propranolol, spiperone, metergoline. The hyperthermic effect of clonidine was potentiated in rats after a lesion of the central noradrenergic terminals by DSP-4. The clenbuterol-induced hyperthermia was counteracted by 1-propranolol, yohimbine and rauwolscine but not by atenolol, prazosin, spiperone, metergoline. These observations indicate that clonidine and clenbuterol-induced hyperthermia is mediated by ₂-(postsynaptic) and-adrenoceptors, respectively. Moreover, in the latter effect ₂-adrenoceptors are involved. The simple temperature measurement can thus be used as a preliminary indicator of central ₂ or-agonistic properties of the screened drug.     

Ganglioside mapping of a human medulloblastoma xenograft

Summary The ganglioside patterns of medulloblastomas have never been established; in this study we report the ganglioside profile of the human medulloblastoma cell line TE-671 grown as a xenograft in nude mice. Gangliosides were isolated and structurally analyzed by fast atom bombardment mass spectometry following permethylation. Identification of individual gangliosides was also performed by immunostaining of high-performance thin-layer chromatography-separated bands. Total ganglioside levels of 0.20 mol/g of tissue were obtained, consistent with those reported for human glioma cell lines grown as xenografts; predominant monosialogangliosides of TE-671 xenografts were II³--NeuAc-LacCer (GM3) and II³--NeuAc-GgOse₃ Cer (GM2) but there were also relatively large proportions of IV³--NeuAc-LcOse₄Cer (3-isoLM1), IV³--NeuAc-nLcOse₄Cer (3-LM1) and a further ganglioside of the neolactoseries with an extra lactosamine moiety. The only oligosialoganglioside detected was IV³, II³--NeuAc₂-GgOse₄Cer (GD1a).Abbreviations: The gangliosides have been designated according to Svenerholm [18] GM3 II³--NeuAc-LacCer - GM2 II³--NeuAc-GgOse₃Cer - GM1 II³--NeuAc-GgOse₄Cer - 3-LM1 IV³--NeuAc-nLcOse₄Cer - 3-isoLMI IV³--NeuAc-LcOse₄Cer - Fuc-3-isoLMI IV³--NeuAc, III⁴-Fuc-LcOse₄Cer - GD1a IV³, II³--NeuAc₂-GgOse₄Cer - FAB-MS Fast atom bombardment-mass spectometry - GC-MS gas chromatography-mass spectometry Supported by NC1 RO1 CA11898 to Dr. Bigner and B8803X-00627-24B from the Swedish Medical Research Council to Dr. L. Svennerholm     

Impairment of Gsα function in human brain cortex of Alzheimer’s disease: comparison with normal aging

Summary. We examined the quantity and quality of G proteins in membrane preparations of post-mortem human brain, i.e. in parietal, temporal and occipital cortical regions, from normal subjects over age (17–89 years old) and with Alzheimers disease (AD) in comparison with aged-matched controls. In normal aging, the immunoreactivities determined of G_i, G_q and G were inversely correlated with age. The function of G proteins was examined by photoaffinity GTP analogue [azidoanilido GTP (AAGTP)] labelling. AAGTP labelling to G_s and G_i/o, and the ratio of G_s to G_i/o AAGTP labelling showed no age-dependent changes. In AD compared to age-matched controls, there were no significant differences in the levels of G_sH, G_sL, G_i, G_o, G_q and G subunits. Functional effects of G proteins, however, as measured by AAGTP labelling to G_s, but not to G_i/o, was significantly decreased in AD compared to controls in the parietal and temporal cortex, but not in the occipital cortex. These results suggest that the disturbances of post-receptor trans-membrane signalling in AD can be attributed to functional changes of G_s, and these are independent of alterations in the level for those proteins in normal aging.     

Attenuation of contractile responses to sympathetic co-transmitters in veins from subjects with essential hypertension

Neuropeptide Y (NPY), noradrenaline (NA) and ATP are cotransmitters of the sympathetic nervous system and exert vasocontractile effects. The aim of this study was to determine the role of these sympathetic co-transmitters in human hypertension. Subcutaneous vessels from 12 patients with essential hypertention and 12 matched controls were studiedin vitro. Vascular contractile responses to NPY, NA, ,-methylene ATP (,-mATP) and potassium were studied in isolated arteries and veins (diameter 0.1–1.1 mm) with intact endothelium. The dilatory effect of acetylcholine was used to test the endothelial function. There was no difference in potency (pD₂) or contractile response to NPY, NA or ,-mATP between hypertensive and control arteries. In veins, however, the contractile response to NPY was signficantly reduced in hypertensives and the responses to NA were unchanged. Furthermore, the sensitivity (pD₂) to ,-mATP was significantly reduced in veins from hypertensives. There was no difference in the dilatory response to acetylcholine between the hypertensives and the controls, neither in the arteries nor in the veins, indicating that the observed changes in vascular reactivity to NPY, NA and ,-mATP were not endothelium-dependent. In conclusion, the postjunctional contractile effect of NPY and sensitivity (pD₂) to ,-mATP, co-transmitters of the peripheral sympathetic nervous system, are attenuated in veins in essential hypertension.     

Increasedα 2;-adrenoceptor density in the frontal cortex of depressed suicide victims

Summary The density of brain ₂-adrenoceptors, quantitated by means of the binding of the agonist [³H]clonidine, was studied in post-mortem cortical membranes of matched control subjects and depressed suicide victims. In the depressed suicide group, the specific high affinity binding of [³H]clonidine was found to be significantly increased (B_max, 72% greater; p<0.01) without significant changes in the K_D value for the radioligand. These preliminary results indicate that ₂-adrenoceptor density in the high affinity state _2H) is increased in the brain of depressed patients and add strong support to the hypothesis that endogenous depression is related to supersensitive ₂-adrenoceptors.     

Expression of αB-crystallin in Alzheimer's disease

B-crystallin is a member of the small heatshock protein family. Under pathological conditions, the expression of B-crystallin increases in proliferating astrocytes, which suggests that this protein, in addition to glial fibrillary acidic protein (GFAP), can be a marker for gliosis in neurodegenerative diseases. Immunoblotting and immunohistochemical methods were used for the detection of B-crystallin in the brains of Alzheimer's disease (AD) patients and nondemented controls. An increase in B-cyrstallin expression was found in the brains of AD patients. Immunoreaction was present in reactive astrocytes, microglia, and oligodendrocytes, indicating that all types of glia respond to the stress associated with AD pathology. Colocalization of GFAP and B-crystallin was found in fibrous astrocytes. However, the intensity and range of B-crystallin expression appeared to be limited as compared with the large increase in the number of GFAP-positive astrocytes. This indicates that expression of B-crystallin is not a marker for gliosis in AD. Immunoreactivity to B-crystallin in both astrocytes and microglia was found mainly restricted to areas with senile plaques and neurofibrillary tangles, suggesting the association of B-crystallin with amyloid deposition in AD.Supported by a grant (No. EY08202) from the National Institutes of Health, Bethesda, USASupported by a fellowship of the Royal Netherlands Academy of Arts and Sciences     

GABA binding sites: their density,their affinity to muscimol and their behaviour against neuroactive steroids in human gliomas of different degrees of malignancy

Summary The aim of the present investigation was to answer the question if there exists a relation between the equipment of human gliomas with GABA binding sites and the degree of malignancy of these tumours diagnostically characterized according to WHO classification. The following parameters were assessed: the density, the affinity and the sensitivity to the modulating steroids 3 -hydroxy-5 -pregnane-20-one (3 OH-DHP) and 3 ,21dihydroxy-5 -pregnane-20-one (THDOC). Scatchard analysis and non linear computerization revealed that the occurrence of GABA sites was directly related to the degree of tumour malignancy: GABA sites were only detectable in lower malignant gliomas of WHO grade II but not in the very malignant glioblastomas. However, irrespective of the individual density to be detected all glioma GABA sites were sensitive to 3 -hydroxy-5 -pregnane-20-one (3 OH-DHP) and 3 ,21dihydroxy-5 -pregnane-20-one (THDOC) without exception. The effects of THDOC were due to increases in the number of binding sites whereas in the presence of 3 OH-DHP a decrease in affinity was noted, additionally. These findings support the view of a normal functional integrity of GABA receptors in gliomas.     

Colocalization of growth hormone (GH) and glycoprotein subunit α in GH-producing pituitary adenomas in acromegalic patients

Thirty-one consecutive cases of pituitary adenoma in acromegalic patients were studied by immunohistochemistry. All adenomas contained cells immunoreactive with the anti--subunit of gonadotropic hormones (; 0.6–53% of tumor cells) as well as with anti-growth hormone (GH; 4–74% of tumor cells). In serial section study, most cells immunoreactive with anti- were identical to cells immunoreactive with anti-GH. There was a positive correlation between the percentages of cells immunoreactive for in GH cells [(%)/GH(%)] and those for prolactin (PRL) in immunoreactive tumor cells {PRL(%)/[PRL(%)+GH(%)]} in mixed GH cell-PRL cell adenomas, suggesting that the -subunit may play a role in emergence of PRL cells.     

Effects of chronic antidepressant treatment on α1- and α2-adrenoceptors in the rat anococcygeus muscle

Summary The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the ₂-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the ₁-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied.Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic ₁-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic ₂-adrenoceptors to xylazine. These results show that the adaptative changes of -adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize ₁-adrenoceptors.     

Selective blockade of brainα 2-autoreceptors by yohimbine: Effects on motor activity and on turnover of noradrenaline and dopamine

Summary The motor activity of groups of three mice was increased by yohimbine at doses up to 3 mg/kg intraperitoneally. The turnover of dopamine and noradrenaline in the mouse brain, as assessed by the disappearance of catecholamines following treatment with the tyrosine hydroxylase inhibitor-methyltyrosine, was accelerated by yohimbine with a peak effect after 10 mg/kg intraperitoneally. Prazosin (3 mg/kg i.p.) completely antagonized the stimulatory effect of yohimbine on motor activity and on dopamine turnover but it somewhat potentiated the stimulatory effect on the turnover of noradrenaline. Amphetamine reversed the prazosin-induced hypomotility, indicating that prazosin can selectively block postsynaptic ₁-receptors.Yohimbine did not stimulate motor activity following 10 mg/kg and it retarded the turnover of dopamine following 30 mg/kg. These actions might be due to blockade of postsynaptic-receptors by yohimbine.The data indicate that yohimbine at low doses stimulates motor activity and dopamine turnover by selectively blocking ₂-autoreceptors leading to increased release of noradrenaline and subsequent activation of postsynaptic ₁-receptors.     

Progressive accumulation of ubiquitin and disappearance of α-synuclein epitope in multiple system atrophy-associated glial cytoplasmic inclusions: triple fluorescence study combined with Gallyas-Braak method

-Synuclein (S) and ubiquitin (Ub) are shared constituents of glial cytoplasmic inclusions (GCIs) and Lewy bodies (LBs), both composed of fibrillary structures. Staining profiles of GCIs were investigated with triple immunofluorescence involving immunostaining for S and Ub, both amplified with catalyzed reporter deposition, and a fluorochrome, thiazin red (TR) that has an affinity to fibrillary structures. After observation for the triple-fluorescent images, the sections were subsequently stained with the Gallyas-Braak method. Sections of putamen, cerebellar white matter and motor cortex from patients suffering from multiple system atrophy (MSA) with varying duration of the disease (4–15 years) were quantified for these staining profiles of Gallyas-positive GCIs. Although most of GCIs were positive for Ub and variably positive for S, they were consistently negative for TR. The result was opposite in LBs in Lewy body disease with variable affinity to TR, suggesting that the construction of GCIs is different from that of LBs. These four staining features (S, Ub, TR and Gallyas) alone failed to exhibit apparent correlation with disease duration, lesion site or severity of degeneration as reported previously. The fraction of S-negative and Ub-positive GCIs, however, linearly increased along the disease progression, while that of S-positive and Ub-negative GCIs decreased in contrast. This reciprocal change suggests that S immunoreactivity in GCIs is being replaced by Ub immunoreactivity during the disease progression, which resulted in the ultimate predominance of S-negative and Ub-positive GCIs in the most advanced case. Interestingly, this predominance of S-negative and Ub-positive GCIs was a feature of motor cortex, where degeneration usually remains mild in spite of robust appearance of Gallyas-positive GCIs. Another fraction, S-positive and Ub-positive GCIs were frequent in cerebellar white matter, suggesting that GCI evolution is heterogeneous and dependent also on area examined. Progressive accumulation of Ub with concomitant disappearance of S epitope and their colocalization, partly shared with LBs, may represent a process of GCI formation, possibly linked to an aspect of degeneration in MSA.     

Immunohistochemical study on the distribution of α and β subunits of S-100 protein in brain tumors

Summary The immunohistochemical distribution of and subunits of S-100 protein (S-100, S-100, respectively) in 138 cases of human brain tumors was investigated by the avidin-biotin immunoperoxidase method. Brain tumors can be divided into four groups: group 1 [S-100 (+) and/or S-100 (+)]; astrocytoma, glioblastoma, ependymoma, subependymoma, oligodendroglioma, choroid plexus papilloma, gangliocytoma, meningioma, chordoma, malignant melanoma. Group 2 [S-100 (+) and S-100 (-)]; pineoblastoma, pituitary adenoma, craniopharyngioma, rhabdomyosarcoma. Group 3 [S-100 (-) and S-100 (+)]; acoustic Schwannoma. Group 4 [S-100 (-) and S-100 (-)]; medulloblastoma, malignant lymphoma, germinoma. The S-100 immunoreactivity pattern in brain tumors was similar to those obtained using conventional anti-S-100 protein sera. In the first group of brain tumors both the number of positively stained tumor cells and the staining intensity were generally greater for S-100 than for S-100 with a few exceptions including one gemistocytic astrocytoma, one subependymoma, one malignant melanoma, and some cases of glioblastomas. As to the relationship between malignancy and S-100 protein in glioma, S-100 immunoreactivity decreased according to degree of malignancy, while that of S-100 varied, suggesting a heterogeneity of tumor cells in glioblastomas. Immunostaining for S-100 and S-100 might become a useful diagnostic procedure in brain tumors and may give us more detailed and precise data of S-100 protein in brain tumors.     

Antipsychotic treatment withα-methyltyrosine in combination with thioridazine: Prolactin response and interaction with dopaminergic precursor pools

Summary The antipsychotic effect of-methyltyrosine (-MT) in combination with thioridazine was investigated by means of rating scales for social behaviour and mental symptoms The clinical effect was also evaluated in relation to the serum concentrations of-MT and thioridazine and to the increase in prolactin secretion in response to the interaction with hypothalamic dopaminergic mechanisms. The interactions between the serum levels of-MT and those of the transmitter precursors phenylalanine and tyrosine were analysed. The results confirmed the ability of-MT (2g/day) to potentiate the antipsychotic effect of thioridazine, whereby the dose of neuroleptic drug required to control psychotic symptoms may be markedly reduced. None of the four patients who completed the trial showed side effects that could be ascribed to-MT. The antipsychotic effect of thioridazine, alone or in combination with-MT, correlated well with the prolactin response in the individual patient. No important interference with serum phenylalanine or tyrosine levels was noted during treatment with-MT.