Showing papers in "Journal of Neural Transmission in 1989"

The NMDA antagonist MK-801 causes marked locomotor stimulation in monoamine-depleted mice

Abstract: It was shown in the present study that the selective non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] caused a pronounced and dose-dependent increase in locomotion in mice pretreated with a combination of reserpine and alpha-methyl-para-tyrosine. Haloperidol pretreatment did not antagonize the MK-801-induced stimulation of locomotion. The findings are discussed in relation to the concept of a corticostriatothalamocortical negative feedback loop serving to protect the cortex from an overload of information and hyperarousal. Such a feedback loop would encompass i.a. corticostriatal glutamatergic neurons and it would be modulated by mesencephalostriatal dopaminergic neurons.

[3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients

Abstract: [3H]MK-801 binding was used as a marker for the NMDA receptorion channel complex in postmortem brain samples from the frontal cortex, hippocampus, putamen, entorhinal region, and amygdala of schizophrenic patients and controls. In schizophrenia [3H]MK-801 binding levels were increased in all brain regions investigated reaching significance in the putamen.

3H-spiperone binding sites in post-mortem brains from schizophrenic patients: relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms.

Abstract: In post-mortem putamen samples from 27 schizophrenics and 27 controls D2 receptors were measured by Scatchard analysis using 3H-spiperone as a ligand. Maximum number of binding sites (Bmax) and apparent dissociation constant (KD) were significantly increased only in patients in whom neuroleptic medication had been given within a three-month period before death. When the neuroleptic medication had been withdrawn at least 3 month before death, there was a slight, but not significant, reduction in Bmax values and unchanged KD values. Withdrawal of neuroleptic drugs was followed by a normalization of the KD values within 2 weeks and a slower reduction of Bmax values. There were 6 schizophrenic patients with mainly positive schizophrenic symptoms and 17 patients with mainly negative symptoms; positive schizophrenic symptoms were not related to higher Bmax values. There was no difference in 3H-spiperone binding between patients with and without movement disorders (tardive dyskinesia or extrapyramidal symptoms).

Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulatory effect in monoamine-depleted mice

Abstract: The present study corroborates previous findings showing that the selective, non-competitive N-methyl-D-aspartate (NMDA) antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5 H-dibenzo(a,d)-cyclohepten-5,10-imine] produces a dose-dependent increase in locomotion in mice pretreated with a combination of the monoamine-depleter reserpine and the catecholamine synthesis inhibitor α-methyl-para-tyrosine. Moreover, the present investigation demonstrates a synergistic interaction between MK-801 and the α-adrenergic agonist clonidine in monoamine-depleted mice: MK-803 in a dose of 1 mg/kg and clonidine in a dose of 2 mg/kg hardly affected locomotion when given separately, but when the two drugs were combined a dramatic enhancement of motor activity was observed. This effect was effectively antagonized by the α2-adrenergic blockers idazoxan and yohimbine, as well as by the “atypical” neuroleptic clozapine.

Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type.

Abstract: A massive cerebral release of amino acids and ammonia was found in early-onset dementia of Alzheimer type. Aspartate and glycine were liberated in high concentrations, whereas glutamate remained rather unchanged. This excess cerebral protein catabolism is due to a 44% reduction in cerebral glucose metabolism. Whereas glutamate and other glucoplastic amino acids may substitute glucose, elevated aspartate may contribute to neuronal damage. The results are discussed with respect to a possible neuronal insulin/insulin receptor deficiency.

Effects of melatonin on spontaneous electrical activity of neurons in rat suprachiasmatic nuclei: an in vitro iontophoretic study.

Abstract: Circadian rhythms, endogenously generated in suprachiasmatic nuclei (SCN), seem to be under the direct influence of melatonin. Therefore, the effect of iontophoretically applied melatonin on electrical activity of SCN neurons was investigated in vitro. Usually, melatonin had an inhibitory effect. In the 3-h periods before (2.00-5.00 p.m.) or after (5.00-8.00 p.m.) the light-dark transition the percentage of SCN neurons sensitive to melatonin was very high (80% and 100%, respectively). However, efficacy of melatonin was low in the periods preceeding (20%) and following (33%) this 6-h time interval.

PHysical exercise: evidence for differential consequences of tryptophan on 5-HT synthesis and metabolism in central serotonergic cell bodies and terminals.

Abstract: The aim of the present study was to investigate the effects of physical exercise (running) on serotonin (5-hydroxytryptamine, 5-HT) synthesis and metabolism in midbrain on the one hand, and in striatum and hippocampus on the other hand. To address such a question, tryptophan (TRP) and 5-hydroxytryptophan (5-HTP) were measured in running rats pretreated with an inhibitor of aromatic amino acid decarboxylase, namely NSD 1015. In another series of experiments, the consequences of a TRP load on TRP, 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were compared in resting and running rats. Although running triggered a 30% increase in TRP levels in the three brain regions examined, inhibition of 5-HT synthesis by NSD 1015 was found to promote increased (midbrain), unchanged (striatum) or decreased (hippocampus) 5-HTP accumulation in the running situation, respectively compared to that measured in the resting situation. Inasmuch as running-induced elevation in TRP was not associated with an increased 5-HTP accumulation in the striatum and the hippocampus, the consequences of running on regional TRP, 5-HT and 5-HIAA levels were analyzed in saline- and TRP-injected rats. Indeed, running, per se, was found to increase central TRP, 5-HT and 5-HIAA levels. On the other hand, a TRP load that promoted identical increases in central TRP levels in running and resting rats revealed that running, according to the region examined, differentially affected TRP utilization in the 5-HT synthesis pathway. Thus, in the midbrains of the resting and running rats, respective 210-250% increases in TRP led to identical 25% increases in 5-HT and 90% increases in 5-HIAA levels. Conversely, in hippocampus, TRP loads triggered marked increases in TRP levels that were similar in the controls and the runners, but the rise in 5-HIAA promoted by such a precursor load was found to be significantly minored in the runners, compared to the resting rats. Moreover, such a running-induced impairment in 5-HT synthesis and metabolism was even more observable in the striatum; thus, TRP loads which promoted identical increases in striatal TRP levels in the resting and the running rats respectively triggered a 50% and a 32% increase in 5-HT levels and a 76% and a 47% increase in 5-HIAA levels. The results presented herein indicate that under certain pharmacological conditions, TRP utilization into the 5-HT synthesis pathway is altered in serotonergic nerve terminals, but not in the cell bodies of the running rat.

Astrocytes as a primary locus for the conversion MPTP into MPP

Abstract: The enzymatic conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion by monoamine oxidase-B is an essential step mediating the dopaminergic neurotoxicity. Since monoamine oxidase-B is located primarily in serotonergic neurons and astrocytes, the production of 1-methyl-4-phenylpyridinium ion is thought to be extra-dopaminergic. This study provides evidence in support of this conclusion. Pretreating mice with fluoxetine (a serotonergic uptake inhibitor) before the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine attenuated the dopaminergic neurotoxicity. This was not the result of a nonspecific inhibition of dopaminergic uptake, as fluoxetine pretreatment did not attenuate the dopaminergic neurotoxicity resulting from the intrastriatal administration of the 1-methyl-4-phenylpyridinium ion. Further localization of the primary site of 1-methyl-4-phenylpyridinium ion production as being astrocytes was provided by the failure of 5,7-dihydroxytryptamine-induced serotonergic lesions to attenuate the neurotoxicity produced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, whereas, fluoxetine pretreatment in similarly lesioned subjects, continued to attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. These results are consistent with the hypothesis that astrocytes are a principle site of 1-methyl-4-phenylpyridinium ion production.

A marked rise in 5-S-cysteinyl-dopamine levels in guinea-pig striatum following reserpine treatment.

Abstract: Reserpine administration (5 mg/kg, i.p.) to guinea pigs resulted in marked and long lasting dopamine (DA) depletion and a rapid, short lasting, increase of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. A marked and sustained increase of the level of 5-S-cysteinyl-dopamine, which is an adduct presumably formed following autoxidation of DA, started 3–4 h following the DA and DOPAC changes. Only small changes in the levels of the 5-S-cysteinyl adducts of DOPAC and 3,4-dihydroxyphenylalanine (DOPA) were found.

The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects.

Abstract: Nineteen obese female subjects with body mass index ranging between 30 and 40 were included in a double-blind crossover study aimed at evaluating the effects of oral 5-hydroxytryptophan administration on feeding behavior, mood state and weight loss. Either 5-hydroxytryptophan (8 mg/kg/day) or placebo was administered for five weeks during which patients were not prescribed any dietary restrictions. Feeding behavior was investigated by means of a questionnaire designed to establish the onset of anorexia and related symptoms. Food intake was evaluated using a three-day diet diary. BDI, SI, STAI-T, and STAI-S were used to assess mood state. The administration of 5-hydroxytryptophan resulted in no changes in mood state but promoted typical anorexia-related symptoms, decreased food intake and weight loss during the period of observation.

Ratio of the R and S enantiomers of salsolinol in food and human urine

Abstract: Salsolinol is present in human fluids and tissues as well as in some foods and beverages. It was found previously that the R enantiomer of salsolinol predominates in human urine whereas the S enantiomer predominates in Port wine. In this study a new methodology for measuring the proportion of the R and S salsolinol enantiomers in dried banana and human urine is described. In dried banana, a food particularly rich in salsolinol, the R/S ratio was found to be very near to 1. In urine from additional healthy volunteers, the presence of only the R enantiomer was detected. The origin of urinary salsolinol and its enantiomeric composition are discussed with respect to exogenous salsolinol.

Elevated plasma prostaglandin E2 levels in schizophrenia.

Abstract: Plasma levels of prostaglandin E2 (PGE2) were determined with radioimmunoassay in 40 DSM-III schizophrenics, 15 patients with other mental disorders, and 23 normal controls. The mean value of plasma immunoreactivity of PGE2 was significantly higher in the schizophrenic patients than in the normal controls. Schizophrenic patients with high plasma PGE2 levels had more guilt feelings and hallucinatory behavior on BPRS, relatively successful heterosexual relations, and a higher incidence of birth complications.

Dopamine in the rabbit retina and striatum: diurnal rhythm and effect of light stimulation.

Abstract: In rabbits, dopamine levels in the retina, but not in the caudate nucleus, showed clear diurnal rhythm, with high values seen in the light phase. Thirty min exposition of dark-adapted rabbits to day-light produced no changes in dopamine levels in the retina. In rabbits treated with alpha-methyl-p-tyrosine, the same light exposition decreased the retinal amine level by 18%, while stimulation with intensive, flickering light significantly decreased the retinal dopamine content by 36%. Experiments performed at noon and midnight, under light or dark conditions, showed the retinal dopamine levels to be very similar in groups kept either at light or dark, irrespective of the time of the day, although in animals deprived of light the amine levels were clearly lower than in those exposed to light, both at noon and midnight. Under all experimental conditions there were no significant changes in dopamine level and utilization in the caudate nucleus. The isolated and superfused retina (preloaded with [3H]-dopamine), when stimulated with flashes of white light (2 Hz, 10 min), released [3H]-radioactivity in a Ca2+-dependent manner. It is concluded that in rabbits, light enhances dopamine levels and utilization selectively in the retina, and the observed diurnal changes in the amine metabolism are dependent on the presence or absence of light, and not on the time of the day. The proposed physiological role(s) of the retinal dopaminergic mechanisms is discussed.

Dysbalance of neuronal second messenger function in the aetiology of affective disorders: a pathophysiological concept hypothesising defects beyond first messenger receptors.

Abstract: It is suggested that affective disorders arise from the dysbalance of the two major intraneuronal signal amplification systems, the adenylate cyclase and the phospholipase C system, with depression resulting from underfunction of cyclic adenosine 3′,5′-monophosphate-mediated effector cell responses associated with an absolute or relative dominance of the inositoltriphosphate/ diacylglycerol-mediated responses and mania resulting from the converse. The usefulness of this hypothesis is discussed with respect to (a) the mechanism of action of current therapeutic agents and (b) the development of novel therapeutic approaches.

Dopamine and sexual behavior in the male rat: a reevaluation

Abstract: In castrated male rats treated with a low dose of testosterone propionate (0.40 mg/kg per week), the dopamine agonists amphetamine and amfonelic acid reduced mount latency without affecting other aspects of sexual behavior. Apomorphine, in doses between 0.05 and 0.15 mg/kg, and 1-DOPA 5 –45 mg/kg + carbidopa 50 mg/kg, lacked effect on sexual behavior. Both amphetamine and amfonelic acid increased locomotor activity in a dose-dependent manner. Apomorphine, in the lowest dose, produced a reduction whereas the higher doses of this drug as well as all doses of 1-DOPA lacked effect on this behavior. In castrated animals implanted with a testosterone-filled Silastic capsule, showing a level of sexual activity indistinguishable from that of intact animals, amphetamine and amfonelic acid did not affect sexual behavior. The dopamine receptor antagonists haloperidol and cis(Z)-flupentixol reduced sexual behavior, whereas pimozide was without effect in the dose range used. The doses of haloperidol and fiupentixol that were required to reduce sexual activity were such that they also affected motor execution measured in a treadmill test. It is suggested that increased dopaminergic neurotransmission may stimulate sexual behavior in an indirect way, augmenting behavioral arousal. The inhibitory effects of dopamine antagonists could be explaned either by a reduced arousal level or by motor deficiencies.

Reciprocal interactions between α2-adrenoceptor agonist and neuropeptide Y binding sites in the nucleus tractus solitarius of the rat. A biochemic and autoradiographic analysis

Abstract: Interactions between a α2-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; α2-adrenoceptor agonist), idazoxan (3H-IDA; α2-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 KD 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 μg 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 α2-adrenoreceptor antagonist idazoxan.

Different regulation of serotonin receptors following adrenal hormone imbalance in the rat hippocampus and hypothalamus.

Abstract: Adrenal influence on serotonin (5-HT) transmission in the hippocampal and hypothalamic areas was studied in adrenalectomized rats receiving or not corticosterone replacement. After adrenalectomy, the 5-HT presynaptic receptors were desensitized both in hippocampus and hypothalamus: a significant increase in 5-HT 1 and 5-HT 2 receptor binding numbers took place in membranes from the hippocampus, but not in hypothalamus, while no changes in affinity of receptors to radioligands were observed in either brain area. Corticosterone treatment restored the adrenalectomy-impaired 5-HT autoreceptor sensitivity in hippocampus and hypothalamus and 5-HT density receptor sites in the hippocampus. Serotonin autoreceptor down-regulation following adrenalectomy may increase 5-HT release to maintain the constancy of serotonergic transmission in the brain and 5-HT modulated CRH-ACTH release to compensate the plasma corticosteroid drop. Corticosterone seems to display a distinct tonic control on serotonin transmission in both hippocampus and hypothalamus, the diversity being due to the different roles played by the hormone in these brain regions.

The influence of repeated treatment with imipramine, (+)- and (-)-oxaprotiline on behavioural effects of dopamine D-1 and D-2 agonists.

Abstract: The paper examined the action of imipramine, (+)- and (−)-oxaprotiline, administered repeatedly to rats, on the behavioural effects of the dopamine D-1 and D-2 agonists, SKF 38393 and quinpirole, respectively. The three antidepressants studied, given in the single dose or repeatedly, attenuate the enhanced grooming evoked by SKF 38393. The locomotor hyperactivity, evoked by quinpirole administered s.c., is increased by repeated but not single-dose treatment with imipramine and (+)-oxaprotiline [but not with (−)-oxaprotiline]. Quinpirole at a low dose produces the locomotor hypoactivity which is attenuated by repeated, but not single-dose, treatment with the antidepressants studied here. Repeated imipramine and (+)-oxaprotiline [but not (−)-oxaprotiline] increase the locomotor activity effect of quinpirole injected into the nucleus accumbens.

Influence of food intake on the enantiomeric composition of urinary salsolinol in man.

Abstract: Salsolinol is present in human fluids and tissues as well as in foods and beverages. It was shown previously that the R enantiomer of salsolinol predominates in human urine, whereas the S enantiomer predominates in Port wine. An R/S ratio very near to 1 was found in dried banana, a food particularly rich in salsolinol.

Regionally-specific alterations in mesotelencephalic dopamine synthesis in diabetic rats: association with precursor tyrosine

Abstract: The effect of diabetes-induced chronic tyrosine (Tyr) deficiency on dopamine (DA) synthesis in different areas of the mesotelencephalic DA system was examined. Diabetes was induced using streptozotocin. In vivo Tyr hydroxylation was used as an index of DA synthesis. The brain areas examined were prefrontal cortex (PFC), pyriform cortex (PYR), olfactory tubercle (OT), caudate-putamen (CP), substantia nigra (SN), and ventral tegmental area (VTA). Significant decreases in Tyr hydroxylation were observed in PFC, CP, and PYR. The largest decrease was seen in the PFC. Variations in tissue Tyr levels were shown to account for 62% of the variability in Tyr hydroxylation in the PFC, and 23% of the variability in the CP; a significant correlation between Tyr levels and Tyr hydroxylation was not seen in the other brain areas. The mechanisms underlying this regionally selective effect, and possible clinical relevance are discussed.

Different effects of the calcium antagonists nimodipine and flunarizine on dopamine metabolism in the rat brain.

Abstract: The effect of two calcium antagonists, nimodipine and flunarizine, on striatal dopamine (DA) metabolism in rats was compared. Flunarizine (5–20 mg/kg i.p.) caused a dose-dependent increase in the DA metabolite, 3,4-dihydroxyphenilacetic acid (DOPAC) in the caudate nucleus. Following the 20 mg/kg dose, DOPAC levels were maximally elevated by about 50% from 2 to 12 hrs after treatment.

Chronic immobilization stress: evidence for decreases of 5-hydroxy-tryptamine immunoreactivity and for increases of glucocorticoid receptor immunoreactivity in various brain regions of the male rat.

Abstract: Male rats were exposed to severe 14 day immobilization stress. Body weight, body temperature, food and water intake, behavioral parameters, and serum corticosterone levels were measured during and after the stress period. On the 7th day after cessation of stress the experimental animals together with the control rats were taken to immunocytochemical analysis involving morphometry and microdensitometry of tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT), various neuropeptide, and glucocorticoid receptor (GR) immunoreactivities (IRs) in a large number of regions of the central nervous system. In addition, adrenocorticotropic hormone (ACTH) IR was analyzed in the pituitary gland. Seven days following cessation of the chronic stress food intake, total locomotion and forward locomotion had been restored to normal. Serum corticosterone levels appeared to remain increased even 6 days following cessation of the chronic immobilization stress, probably caused by increased release of ACTH. Paraventricular corticotropin releasing hormone (CRF) IR was negatively correlated with the pituitary ACTH IR, indicating that the increase in ACTH release was produced by an increased release of CRF from the hypothalamus. The major immunocytochemical change observed 7 days after cessation of stress was a disappearance of 5-HT IR in the 5-HT cell groups B 1, B 2, B 3, and B 7. 5-HT IR in nerve terminals was only affected in the dorsal horn, where 5-HT IR was increased in the substantia gelatinosa. GR IR was found to be significantly increaed in monoaminergic cell groups: serotoninergic B 7, dopaminergic A 12, and noradrenergic A 1, A 2, and A 6. A trend for a reduction of TH IR was observed in nigral DA cells associated with significant reductions in TH IR in striatal DA nerve terminals. Finally, increases in 5-HT and substance P (SP) IR were found in the nerve terminals of the substantia gelatinosa of the cervical spinal cord in the stress group. In the present experimental model evidence has been obtained for a maintained activation of the hypothalamic-pituitary-adrenal axis as evaluated 7 days after cessation of severe chronic immobilization stress. The reduction of 5-HT IR in various 5-HT cell groups indicates a reduction of 5-HT synthesis, which may also be associated with reduced 5-HT release from the nerve terminals, since no depletion was observed in terminal regions and in one case an increase in 5-HT IR was noted (substantia gelatinosa). The increase in GR IR, demonstrated in the NA and 5-HT cell groups in the presence of a maintained hypersecretion of corticosterone may represent signs of an upregulation of GR synthesis and/or increased translocation, which take place in the presence of maintained hypersecretion of corticosterone. Thus, 5-HT and NA neurons may respond more effectively to circulating glucocorticoids after severe chronic stress. In this way glucocorticoids may protect against stress-induced exhaustion of neurons leading to impairment of transmission. Studies on TH IR suggest a deficit in the DA transmission line of the nigrostriatal DA neurons, but of no other CA neurons studied. Such effects may contribute to behavioral suppression. Finally, the stress-induced increases in 5-HT and SP IR in the substantia gelatinosa may in part underlie the phenomenon of stress-induced analgesia.

Antidepressants given repeatedly increase the behavioural effect of dopamine D-2 agonist.

Abstract: The effects of single or repeated doses of antidepressant drugs (imipramine, amitriptyline, citalopram, mianserin) on rat locomotor hyperactivity induced by quinpirole, a dopamine D-2 receptor agonist, was investigated. Single doses of antidepressants do not change the effect of quinpirole, but enhance it when they are administered repeatedly. This enhancement is inhibited by (±)-sulpiride, a dopamine D-2 receptor antagonist. The results obtained indicate that the enhancement of dopaminergically-stimulated hyperactivity induced by repeated doses of antidepressants is mediated by dopamine D-2 receptors.

Antagonism by pindolol, but not betaxolol, of 8-OH-DPAT-induced facilitation of male rat sexual behavior.

Abstract: 8-OH-DPAT (0.25 mg/kg s.c.) produced a facilitation of the male rat sexual behavior, characterized by a decrease in the number of intromissions preceding ejaculation and in the time to ejaculation. This facilitation of the sexual behavior was antagonized by administration of the 5-HT and β-adrenoceptor antagonist pindolol (4mg/kg i.p.), but not by the selective β-adrenoceptor antagonist betaxolol (4 mg/kg i.p.). Neither pindolol (2–8 mg/kg), nor betaxolol (2–8 mg/kg), produced any statistically significant effects per se on the male rat sexual behavior, as observed here (mounts, intromissions, ejaculation latency or the post-ejaculatory interval). A higher dose (16mg/kg) of betaxolol produced a statistically significant reduction in the number of intromissions preceding ejaculation and in the ejaculation latency. The antagonism by pindolol of 8-OH-DPAT-induced effects on male rat sexual behavior suggests an involvement of 5-HT1A receptors in the facilitation of this behavior produced by 8-OH-DPAT.

Does the PCPA induced anticonflict effect involve activation of the GABAA/benzodiazepine chloride ionophore receptor complex?

Abstract: The effects of the benzodiazepine (BDZ) receptor antagonist flumazenil (Ro 15-1788) and the GABAA receptor antagonist bicucuiline on the anticonflict effect observed after depletion of brain serotonin (5-HT), were examined in a modified Vogel's punished drinking conflict model. Pretreatment with para-chlorophenylalanine (PCPA; 300 mg/kg/day for three days, last injection −24 h) markedly decreased brain 5-HT levels and produced clearcut anticonflict effects. The anticonflict effect, but not the biochemical effect, of PCPA pretreatment was completely counteracted by both flumazenil (10 mg/ kg, −30 min) and bicuculline (2.0 mg/kg, −10 min), in doses not altering the behavior per se. The findings suggest a behavioral interaction between 5-HT systems and the GABAA/BDZ chloride ionophore receptor complex, possibly involving a direct neuronal interaction, neuromodulation or hormonal alterations.

Cholinesterases in the cerebrospinal fluid, plasma, and erythrocytes of patients with Alzheimer's disease

Abstract: In patients with probable Alzheimer's disease and in controls, acetyl- and butyrylcholinesterase activities were studied in cerebrospinal fluid (CSF) and plasma, and acetylcholinesterase activity of erythrocytes was determined. In addition, the molecular forms of acetylcholinesterase were measured in CSF. Severely demented patients had significantly lower acetylcholinesterase (p<0.01) and butyrylcholinesterase (p<0.05) activities in CSF than the controls had, but the activities of these enzymes in plasma and erythrocytes were within the same range in both groups. Acetylcholinesterase and butyrylcholinesterase activities in the CSF of mildly demented patients did not differ from control values. The ratio of the intermediate molecular form of acetylcholinesterase to the light molecular form of the enzyme did not differ significantly between patients with Alzheimer's disease and controls. According to our results, AChE levels were lower in the CSF of severely demented patients, but both light and intermediate molecular forms were affected.

Localization of monoamine oxidase B in human brain by autoradiographical use of 11C-labelled L-deprenyl.

Abstract: 11C-labelled L-deprenyl in vitro autoradiography was used to study the regional distribution of MAO-B in human brain. 80 μm thick cryosections from two human brains, a 67 years old female and a 58 years old male, were taken on tape/paper and transferred on to a gelatinized glass plate. The sections were then incubated with 34 and 54 nM11C-L-deprenyl for 15 min and exposed to a film sensitive to high energy radiation for 2 hours. The autoradiograms obtained were analyzed by computerized densiotometry. High11C-deprenyl binding was found in the caudate nucleus, putamen, thalamus, substantia nigra, medial and lateral geniculate bodies, hippocampus and periaqueductal gray. Moderate to low binding was observed in cerebral cortex. Cerebral cortex and white matter showed the lowest binding. The autoradiographic technique described proved to be a fast and reliable method to investigate the topographic localization of MAO-B in large cryosections of human brain.

A metabolite of buspirone increases locus coeruleus activity via alpha2-receptor blockade

Abstract: Extracellular single unit recording techniques was used to pharmacologically analyze the excitatory action of buspirone on locus coeruleus (LC) noradrenergic neurons. Intravenously administered buspirone (0.5–8 mg/kg) dose-dependently increased LC firing rate. Furthermore, pretreatment with buspirone (8 mg/kg, i.p.) caused a parallel shift to the right of the dose-response curve for the inhibitory action of the alpha2-receptor agonist clonidine on LC neurons. The inhibitory effect of microiontophoretically applied noradrenaline on LC neurons was not altered by the simultaneous application of buspirone. but almost totally blocked by its major metabolite 1-(2-pyrimidinyl-piperazine) (1-PP). The results indicate that buspirone causes activation of LC neurons via an alpha2-receptor antagonistic action of its metabolite, 1-PP.

Oral aspartame and plasma phenylalanine: pharmacokinetic difference between rodents and man, and relevance to CNS effects of phenylalanine

Abstract: The ingestion of aspartame, a phenylalanine-containing dipeptide, raises plasma phenylalanine levels. These increments are much greater in humans than rats, because the rat hydroxylates phenylalanine five times faster than man. Accordingly, dose comparisons of aspartame (or phenylalanine) between humans and rats have usually been corrected by a factor of five. Recently, a correction factor of sixty has been proposed (Wurtman and Maher, 1987); the rationale is based on a novel calculation of competitive phenylalanine transport into brain. An analysis of the logic behind this postulation reveals there to be no basis for accepting the higher dose conversion of 60 between rat and man.

Synthetic peptides corresponding to the sequence of noxiustoxin indicate that the active site of this K+ channel blocker is located on its amino-terminal portion

Abstract: A nonapeptide Thr-Ile-Ile-Asn-Val-Lys-Cys-Thr-Ser (NTX1–9) and a decapeptide Met-Asn-Gly-Lys-Cys-Lys-Cys-Tyr-Asn-Asn (NTX30–39) corresponding to the N-terminal and C-terminal sequences respectively of Noxiustoxin (NTX) were synthesized by the solid phase method of Merrifield (1963). The first synthetic peptide (NTX1–9) was shown to be toxic to mice independently of the route of administration: intraperitoneally, subcutaneously or intraventricularly (100–200 μg/20 g mouse weight). The second (NTX30–39) was not toxic even at higher dose (400 μg/20 g mouse). When the effects of the peptide NTX1–9 and of the authentic toxin (Noxiustoxin) were studied on the liberation of [3H] 4-aminobutyric acid (3H-GABA) from mouse synaptosomes, both gave essentially the same results, except that peptide NTX1–9 was needed at higher concentration. Synthetic peptide NTX30–39 had no effect in the same preparation at even higher doses. The GABA release produced by toxic peptide NTX1–9 was not affected by tetrodotoxin but was completely abolished by the presence of the K+ ionophore valinomycin, mimicking the effect of native NTX in the same system (Sitges et al., 1986). These results indicate that the toxic active site of Noxiustoxin is possibly located in or near the N-terminal amino acid portion of the molecule.