Pierre Etienne

The N-methyl-d-aspartate antagonists CGS 19755 and CPP reduce ischemic brain damage in gerbils

N-Methyl-D-aspartate (NMDA) antagonists reduce ischemic brain damage and associated hypermotility. Two potent, selective and competitive NMDA antagonists, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) and 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP), were characterized in the gerbil ischemia model with respect to dose-response and time course effects. Both drugs were effective in reducing ischemia-induced hippocampal brain damage as well as hypermotility. In this model, CGS 19755 was more potent than CPP, and had protective effects when given after longer delays between ischemia and drug administration.

Neurotransmitter and receptor deficits in senile dementia of the Alzheimer type.

Multiple neurotransmitter systems are affected in senile dementia of the Alzheimers type (SDAT). Among them, acetylcholine has been most studied. It is now well accepted that the activity of the enzyme, choline acetyltransferase (ChAT) is much decreased in various brain regions including the frontal and temporal cortices, hippocampus and nucleus basalis of Meynert (nbm) in SDAT. Cortical M2-muscarinic and nicotinic cholinergic receptors are also decreased but only in a certain proportion (30-40%) of SDAT patients. For other systems, it appears that cortical serotonin (5-HT)-type 2 receptor binding sites are decreased in SDAT. This diminution in 5-HT2 receptors correlates well with the decreased levels of somatostatin-like immunoreactive materials found in the cortex of SDAT patients. Cortical somatostatin receptor binding sites are decreased in about one third of SDAT patients. Finally, neuropeptide Y and neuropeptide Y receptor binding sites are distributed in areas enriched in cholinergic cell bodies and nerve fiber terminals and it would be of interest to determine possible involvement of this peptide in SDAT. Thus, it appears that multi-drug clinical trials should be considered for the treatment of SDAT.

Acute tryptophan depletion blocks morphine analgesia in the cold-pressor test in humans

The effects of depletion of the serotonin precursor,l-tryptophan, on the threshold and tolerance to cold pressor pain, and the analgesic effect of morphine (10 mg intramuscularly), were tested in a double blind trial on human volunteers. Effects on mood were also assessed using the Profile of Mood States and the Addiction Research Center Inventory (ARCI) Scales. To deplete tryptophan, subjects were fed a tryptophan-deficient amino acid mixture 4.5 h before morphine was administered. Controls received the mixture with tryptophan, which is equivalent to a nutritionally balanced protein. The tryptophan-deficient meal reduced plasma tryptophan more than 70% but had no effect on threshold or tolerance to cold pressor pain. After morphine, tolerance to cold pressor pain increased in controls. Tryptophan depletion abolished this analgesic effect. Pain threshold was not altered by morphine. In subjects with normal tryptophan, the analgesic effect of morphine was predicted by the level of plasma morphine-6-glucuronide, but not by the level of morphine. Morphine increased scores on the LSD scale of the ARCI, but had no effect on other measures of mood. Tryptophan depletion also failed to alter mood in these subjects, who had unusually low depression scores before tryptophan depletion.

Calcium dependent aspects of synaptic plasticity, excitatory amino acid neurotransmission, brain aging and schizophrenia: A unifying hypothesis

(1) The functional and structural reorganization of dendritic spines by calcium activated proteases is postulated to play a causal role in the production of the phenomenology of brain aging and in particular in the development of pathology and degeneration. Excitatory neurotransmission appears to be essential for the development of irreversible synaptic changes. (2) One of the genes modified in schizophrenia is postulated to be directly or indirectly linked to the control of excitatory neurotransmission; possibly the normal switching on of the expression of the adult form of the NMDA receptor is altered, resulting in an inappropriate functioning of this receptor. This genetic characteristic might explain the apparent resistance of schizophrenic brains to aging.

Nootropic effects of ACE inhibitors in mice.

The angiotensin converting enzyme (ACE) inhibitors captopril and enalapril and the nootropic piracetam reduced the amnesiogenic effects of cerebral electroshock treatment in mice. These compounds also directly improved passive-avoidance learning if administered before the learning trial. When given immediately after the learning trial, captopril and piracetam were active, but not enalapril. Captopril, but neither enalapril nor piracetam, facilitated memory retrieval after a 2-month retention interval. Unlike those of piracetam, the memory-improving effects of captopril and enalapril are not established by aldosterone-receptor blockade, suggesting that the two types of drug act via different mechanisms of action.

A pilot study of magnesium aspartate hydrochloride (Magnesiocard®) as a mood stabilizer for rapid cycling bipolar affective disorder patients

1. Nine severe rapid cycling manic-depressive patients were treated with a magnesium preparation, Magnesiocard 40 mEq/day in an open label study for a period up to 32 weeks. 2. Magnesiocard was found to have clinical results at least equivalent to those of lithium in about 50% of these patients. These results were obtained in an exploratory study and should be interpreted with caution. 3. The possibility that Magnesiocard could replace or improve the efficacy of lithium as a preventive treatment of manic-depressive illness merits further clinical investigation.

Effect of domperidone on apomorphine-induced growth hormone secretion in normal men

Domperidone, a peripheral dopamine (DA) receptor blocker which poorly crosses the blood-brain barrier and which is inactive towards dop-amine-sensitive adenylate cyclase, in a dose (100μg/kg) sufficient to increase serum prolactin levels at least 5-fold, decreased the growth hormone (GH) response to the DA receptor agonist, apomorphine HC1 (Apo) (0.5 mg s.c.) in each of six normal men examined. The mean GH increment at 30,45, 60 and 75 min following Apo injection, the mean individual peak increment and the mean individual GH secretion (ng min) was significantly decreased by domperidone pretreatment (p<0.05–p<0.02). These results indicate that in man Apo stimulates GH secretion by an effect on DA receptors which are not linked to adenylate cyclase and which are situated at a locus in the hypothalamic-pituitary axis that lies outside the blood-brain barrier.

CSF acetylcholinesterase in dementia and in sequential samples of lumbar CSF

Acetylcholinesterase (AchE) activity (nmol/ml/min) was measured in lumbar CSF from 11 patients with dementia of the Alzheimer type (DAT), 8 patients with Korsakoff psychosis and 33 patients with low back pain who were undergoing myelography (controls). There was no significant difference in enzyme activity between the three groups. There was no significant correlation between age and AchE activity. AchE was also measured in 20 two-ml samples of CSF collected sequentially by lumbar puncture in two neurosurgical patients who had been recumbent for at least 8 hours. Variations in AchE between samples were small. In neither patient was there an increase in AchE activity with progressive sampling. These data indicate that (1) AchE is unchanged in Korsakoff psychosis (2) decreases in brain AchE which are found in DAT are not readily reflected in lumbar CSF (3) AchE in lumbar CSF has a diffuse origin including spinal cord (4) CSF AchE activity is unlikely to be a useful clinical marker for DAT.

Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons

The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release. At high doses, sulpiride increases both dopamine metabolism and release. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent.

CCK-33 antagonizes apomorphine-induced growth hormone secretion and increases basal prolactin levels in man

Cholecystokinin (CCK-33) (225 Ivy Dog Units intravenously) had no effect on basal growth hormone (GH) secretion but antagonized the GH response to the dopamine receptor agonist, apomorphine HCl (0.5 mg sc) (N = 7), and induced a transient increase in basal prolactin (PRL) secretion (N = 8) in normal men. These findings are similar to those described with neuroleptics and are compatible with an inhibitory effect of CCK-33, or fragments, on dopamine function in man, at least in the hypothalamic-pituitary axis. However, an inhibitory effect of CCK-33 on the release of GH and a stress-induced increase in PRL secretion cannot be excluded.