Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1).

The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.

Psychopharmacological profile of salsolinol.

SAL is a tetraisoquinolein (T.I.Q.), resulting from the condensation of acetaldehyde and dopamine. SAL, injected intraperitoneally, is active in tests commonly used to screen potential antidepressants. This effect is especially studied by using antagonism of apomorphine, reserpine, oxotremorine-induced hypothermia. The noradrenergic system seems to be involved in the mechanism of action.

Chronic beta-adrenergic stimulation increases in mice the sensitivity to methysergide and the number of cerebral high affinity serotonin binding sites (5-HT-1).

Reserpine administration in mice causes, among other effects an akinesia which can be reversed by the serotonin agonist-antagonist methysergide. The effect of methysergide is potentiated by clenbuterol, a beta-adrenergic agonist, which itself causes hypomotility. Potentiation is weak after a single injection of clenbuterol, but becomes much stronger after repeated administration for 12 days. This treatment also causes a 50% increase in the number of high affinity 5-HT-1 binding sites in the brain. This increase would explain the increased potency of methysergide against reserpine-induced akinesia. These results show that: a beta-adrenergic drug, clenbuterol modulates the serotoninergic system; this modulation takes its importance after chronic treatment only; this interrelation may be important in depressive illness since it is observed on a test used in the screening of antidepressant drugs.

[Antidepressive effects of 3 endogenous monoamines: psychopharmacologic profiles of noradrenaline, octopamine and phenethylamine]. / Effet "antidépresseur" de 3 monoamines endogènes: profils psychopharmacologiques de la noradrénaline, de l'octopamine et de la phényléthylamine.

Norepinephrine (NE), octopamine (OA) and phenethylamine (PEA) are easily destroyed by M.A.O. but we could show, even injected intraperitoneally that they are active upon tests used generally to reveal an "antidepressant" effect. This effect is especially studied by using antagonism of apomorphine, reserpine, oxotremorine-induced hypothermia. The psychopharmacological spectra of NE and OA are close to the one of salbutamol and the observed effects correspond to alpha- and beta-adrenergic stimulations. The PEA spectrum is similar to the one of amphetamine and the observed effects correspond to adrenergic stimulations and to a dopaminergic stimulation. The mechanisms involved in the tests realized to show an "antidepressant" effect could reflect an activity not only through endogeneous NA but also possibly through endogeneous OA and PEA.

[Brain rat histoenzymological changes induced by microsphere injection during ischemia (author's transl)]. / Modifications histoenzymologiqes du cerveau de rat au cours de l'ischémie provoquée par injection de microsphères.

The cerebral thrombosis of the rat with 35 micrometer labeled microspheres gives infarcted areas easily seen. After 15 min, in these areas, there is no change in NADH diaphorase-, succinic-dehydrogenase-, mono-amino-oxidase-, glucose-6-phosphate-dehydrogenase-, isocitric dehydrogenase-, lactic-dehydrogenase-, ATPase, alpha galactosidase-, acid phospatase activity. After 2, 4, 6 h all these activities diminish in the neuropil but they are preserved in the neurones for diaphorase, succinic-dehydrogenase and mono-amino-oxidase. The margin of infarcted areas shows a strong staining for acid phosphatase. Before 2 h there is not enzymatic changes neither oedema. This experimental model seems trustly and could be developped.