Oxiracetam prevents the hippocampal cholinergic hypofunction induced by the NMDA receptor blocker AP7.

The intracerebroventricular injection of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-7-phosphonoheptanoic acid (AP7) induces an increase of the hippocampal levels of acetylcholine (ACh) which is dose-dependent in the range 1.5-10 micrograms. Similar doses of AP7 failed to affect the ACh content of the striatum. The effect of the i.c.v. administration of 3.5 micrograms AP7 on hippocampal ACh levels was prevented by pretreatment with oxiracetam 100 mg/kg i.p. In the passive avoidance test the i.c.v. administration of 3.5 micrograms of AP7 caused severe amnesia which was antagonized in a dose-dependent manner by the pretreatment with oxiracetam. These results show that oxiracetam prevents the imbalance of cholinergic activity and the amnesia caused by blockade of NMDA receptors. The present study suggests that the hippocampal cholinergic activity is modulated by glutamatergic neuronal pathways and that the functional integrity of both systems is essential for learning and memory processes.

Selective involvement of dopamine in the nucleus accumbens in the feeding response elicited by muscimol injection in the nucleus raphe dorsalis of sated rats.

Muscimol injection (100 ng) in the nucleus raphe dorsalis (NRD) caused intense eating in non-food-deprived rats. At a dose (10 micrograms) blocking dopamine mediated responses (examined by increased locomotion or stereotypy caused by systemically injected d-amphetamine), fluphenazine injected in the n. accumbens, but not in the striatum, significantly reduced the eating response elicited by muscimol in the NRD while food intake of deprived rats was not significantly modified by fluphenazine injected in either area. Fluphenazine (20 micrograms) in the striatum reduced eating in both conditions, but the animals showed marked sedation which obviously interfered with the feeding response. Dopamine release and synthesis, measured respectively by 3-methoxytyramine and accumulation of dihydroxyphenylalanine after aromatic amino acid decarboxylase inhibition, were significantly reduced in the n. accumbens, but not in the striatum, of muscimol treated animals. The metabolism of serotonin was reduced in both areas of muscimol treated rats. It is suggested that changes in dopamine receptor sensitivity, together with changes in serotonin function, might be involved in the feeding response caused by muscimol injection in the NRD.

Chronic treatment with iprindole reduces immobility of rats in the behavioural 'despair' test by activating dopaminergic mechanisms in the brain.

Iprindole, 10 mg kg-1 i.p., once daily for 21 days, enhanced the metabolism of dopamine in the frontal cortex and striatum of rats with no effect in the nucleus accumbens 1 h after the last injection. Noradrenaline metabolism in the brainstem and telencephalon was also increased in these conditions. No effect on dopamine or noradrenaline metabolism was seen 24 h after the last injection. The same repeated treatment schedule with iprindole markedly reduced the immobility of rats in the behavioural 'despair' test 1 h after the last injection and the effect was prevented by 0.5 mg kg-1 i.p. haloperidol and 100 mg kg-1 i.p. sulpiride but not by 3 mg kg-1 s.c. prazosin or 5 mg kg-1 i.p. (+/-)-propranolol. The data show that enhanced metabolism of brain dopamine and noradrenaline is associated with the presence of iprindole during repeated treatment and the effect on dopamine mechanism is important in iprindole's ability to reduce rats' immobility in the behavioural 'despair' test.

d- and l-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat.

Various doses of fenfluramine isomers were compared for their ability to affect monoamine levels, metabolism and synthesis in the rat brain. d-Fenfluramine was more potent than l-fenfluramine in reducing serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) at 4 h after their administration. After decarboxylase inhibition, a low dose of d-fenfluramine (2.5 mg/kg) reduced 5-HT synthesis, assessed as 5-hydroxytryptophan (5-HTP) accumulation, in the hypotalamus and lower brain-stem only, whereas a higher dose (5 mg/kg) reduced 5-HT synthesis in all brain regions examined except the striatum. A higher dose of l-fenfluramine (10 mg/kg) was required to reduce 5-HT synthesis. Metergoline, a 5-HT antagonist, did not modify the effects of fenfluramine isomers on 5-HT synthesis. One h after its administration l-fenfluramine 5-20 mg/kg significantly increased brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4), striatal homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) levels, while after 4 h only the highest dose raised HVA levels. No change of striatal HVA and DOPAC levels was seen 1 or 4 h after any dose of d-fenfluramine while the highest dose raised brain MHPG-SO4 levels. Neither l- nor d-fenfluramine changed striatal 3-methoxytyramine (3-MT) levels. The noradrenaline (NA) and dopamine (DA) levels were decreased 4 h after 10 and 20 mg/kg l-fenfluramine or 20 mg/kg d-fenfluramine. The results show that the d- and l-isomers of fenfluramine at relatively low doses have a specific action on brain 5-HT and catecholamines, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)