Methylazoxymethanol microencephaly in rats: neurochemical characterization and behavioral studies with the nootropic oxiracetam.

The administration of methylazoxymethanol (MAM) to pregnant rats induced a marked reduction in the weight of the offspring's brain. This reduction was due to aplasia of the cortex and hippocampus, whose thicknesses were 50% of those of control animals. A significant reduction was also observed in the striatum. This aplasia could be ascribed to the antimitotic effect of MAM, which, when given at gestational day 15, prevented the development of neurons in the three brain areas mentioned. Indeed, we infer here that the total number of GABA-receptor complexes, as measured by [3H]muscimol and [3H]flunitrazepam binding, was reduced to the same degree as was the weight of the cortex. Similarly, total [3H]haloperidol binding sites were reduced in the striatum. From the behavioral point of view, offspring of MAM-treated rats (MAM rats) showed impaired acquisition in the water-maze and pole-climbing tests, indicating that this brain aplasia had disrupted cognitive processes. In contrast, these animals showed normal growth, and grossly their behavior appeared normal. Oxiracetam, a new compound that belongs to the recently described class of nootropic drugs, was able to restore acquisition processes in MAM rats. We propose therefore that MAM rats might become an interesting and quite simple animal model for evaluation of new acquisition-enhancing drugs. Moreover, this model could also be useful to study the neurochemical correlates of cognitive processes.

Toxicological evaluation in rats and mice of the ingestion of a cheese made from milk with added formaldehyde.

Male Swiss albino mice (CD-1) and male Sprague-Dawley rats were given single oral doses of 0.5 g (4.0 microCi) and 2.2 g (18 microCi) 14C-labelled grana cheese, respectively. The cheese was made by the normal process but using milk with added [14C]formaldehyde. The plasma and tissue kinetics of the radiolabelled cheese were studied by monitoring the decay of radioactivity in the plasma, gastrointestinal tract, liver, kidney, lung, testes, spleen, brain, muscle and adipose tissue. The faeces and urine of animals placed in individual metabolism cages were collected between 4 and 64 hr after dosing for rats and between 2 hr and 12 days for mice. Within 32 hr of administration 63-67% of the radioactivity had been excreted in the faeces and urine and 24-28% of the radioactivity had been exhaled as 14CO2, in both species. Maximum concentrations, corresponding to 0.07% and 0.3% of the dose per ml of blood were reached respectively within 8 hr for rats and 2 hr for mice. The toxicokinetic profile appears to be similar in mice and rats because of the similarity of the half-lives of the elimination phase, 27.8 and 26.4 hr respectively, and suggests that accumulation of the 14C-activity does not occur in any of the tissues of either species. The low levels of radioactivity still present 32 hr after the administration of 14C-grana cheese are probably due to the residues of labelled fractions of milk protein not completely metabolized.