The 5-hydroxytryptamine-releasing properties of two epimer quinoline derivatives.

Two epimer quinoline derivatives, PK 5078 and PK 7059, have been shown to be potent at releasing 5-HT from blood platelets. Moreover PK 5078 was also a potent and selective inhibitor of the uptake of 5-HT, being about 20 times as active as clomipramine. Both drugs, like p-chloroamphetamine, released 5-HT but did not inhibit MAO-A. Whilst p-chloroamphetamine seemed to be active on the cytoplasmic pool of 5-HT and reserpine on the vesicular pool, PK 5078 and PK 7059 were effective first on the vesicular pool and then on the cytoplasmic pool. The quinoline derivatives were devoid of the typical side-effects of amphetamine-like drugs, i.e. hyperactivity, anorexia and group toxicity. For these reasons PK 5078 and PK 7059 can be considered to be a new type of selective 5.HT-releasing drug.

2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission--II. Biochemical properties.

Two models have been chosen to study the effect of 2-amino-6-trifluoromethoxy benzothiazole (PK 26124) on excitatory amino acid neurotransmission: the pool of cyclic guanosine monophosphate (cGMP) in the cerebellum and the release of acetylcholine in the striatum and olfactory tubercles. The release of acetylcholine induced by N-methyl-DL-aspartate in the striatum and olfactory tubercles was antagonized by PK 26124 which was less potent on the release of acetylcholine induced electrically. The increase in levels of cGMP in the cerebellum induced by excitatory amino acids such as glutamate and quisqualate was antagonized by PK 26124, but the drug was inactive against N-methyl-DL-aspartate, L-aspartate, kainate and cysteine sulphinate. In vivo it antagonized the increases of cGMP in the cerebellum elicited by all these excitatory compounds. All these results are compatible with a possible antagonism by PK 26124 of the excitatory amino acid neurotransmission and may explain its anticonvulsant properties.

Central dopaminergic neurons during development of genetic and DOCA-salt hypertension in the rat.

The in vivo binding of [3H]spiroperidol was measured in discrete areas of the brain in 7-, 9- and 16-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto (WKY) controls. An increase in the [3H]spiroperidol binding in the striatum, tuberculum olfactorium and frontal cortex but not in the cerebellum was detected at all ages in SHR. The increase was more pronounced in 7- than in 9- or 16-week-old SHR. In vitro data indicated an increase in Bmax but no variation in Kd in the striatum of 7-week-old SHR. Moreover no difference was detectable in the dopaminergic cell bodies (A9, A10). This increase was specific to [3H]spiroperidol binding sites since no difference was observed in the in vivo binding of [3H]QNB and [3H]LSD in the same brain regions. No variation in dopamine level or dopamine utilization, as estimated by measuring the disappearance of the amine induced by alpha-methyl-p-tyrosine, was observed. The DOPA accumulation after injection of the DOPA decarboxylase inhibitor NSD 1015 was greater in the tuberculum olfactorium from 7-week-old SHR. An increase in [3H]spiroperidol binding sites was also observed in the striatum and tuberculum olfactorium after 7 weeks of DOCA-salt treatment. These results suggest that dopaminergic neurons might be implicated in the onset of hypertension in the rat.

A subacute treatment of L-methionine induces an increase in the number of [3H]spiperone binding sites in the striatum of the rat.

A subacute treatment, 500 mg/kg I.P. twice daily during 5 days, by L-methionine provoked an increase in the Bmax of [3H]-spiperone binding in the striatum of the rat. This increase was associated to a decrease in membrane microviscosity. However in these conditions no changes were found in the [3H]-DHA, [3H]QNB bindings or in the brain dopamine sensitive adenylate cyclase activity. L-methionine treatment reduced the accumulation of Dopa after NSD 1015 and antagonized the decrease in striatal acetylcholine provoked by haloperidol. Thus L-methionine might be a new potential drug for Parkinson's disease treatment.

[Platelet monoamine oxidase and sex hormones in a population of depressed patients]. / Monoamine oxydase plaquettaire et hormones sexuelles dans une population de déprimés.

The association between changes in platelet MAO activity and Major Depressive Episode have been demonstrated. Cyclical changes in sex hormones serum levels had never been related with changes of MAO activity in depressed patients. Platelet MAO activity, oestrogen serum levels, progesterone serum levels and testosterone serum levels, have been measured in drug free depressed patients: 22 men and 42 women. This study demonstrates no relationship between serum levels hormons and platelet MAO activity, measured in men and in women. If young women are separated from menopaused women, platelet MAO activity is negatively correlated with oestrogen serum levels, in non menopaused women. Significance of this variation in studies about the use of MAO as a biochemical marker in depression is discussed.

Platelet MAO activity in clinical subtypes of depression and DST suppression.

Platelet MAO activity was measured in 75 hospitalized depressed patients and in 31 healthy subjects. Plasmas post dexamethasone cortisol levels were examined in 73 patients. Results indicate that higher platelet MAO activity does not occur in all, but only in male major depressed patients. No relationship between changes of MAO activity and specific clinical subtypes was found. Platelet MAO activity is not different between DST suppressors and DST non suppressors. The authors suggest that platelet MAO activity may be related to non specific factors such as sex, age, but not to diagnosis of depression.

Relationships between plasma corticosteroids and benzodiazepines in stress.

Forcing a rat to swim in a situation from which there is no escape results in an increase in plasma corticosteroid level. This rise was selectively inhibited by benzodiazepines, phenobarbital and meprobamate but not by other psychotropic drugs like trycyclic antidepressants, monoamine oxidase inhibitors, neuroleptics and amphetamines. This effect of benzodiazepines is of central origin since diazepam did not block the rise in plasma corticosteroid level produced by adrenocorticotrophic hormone. Diazepam also had no effect on plasma corticosteroid levels in hypophysectomized rats or in rats treated with betamethasone. Brief stress did not alter binding of [3H]diazepam in vitro nor binding of [3H]flunitrazepam in vivo.