The effect of two nootropic drugs, oxiracetam and aniracetam, on cholinergic neurotransmission in vivo was investigated in the rat b y means of the transversal microdialysis technique. The basal release of acetylcholine (ACh) from the hippocampus and parietal cortex was 2.93 ? 0.17 and 3.10 c 0.18 pmol/20 min (mean * s.e.m.), respectively, and remained stable for at least 3 h, while the initial efflux of choline was 51.9 I+_ 2.6 and 42.8 I+_ 6.4 pmolRO min (mean 2 s.e.m.), respectively, and decreased by about 50% during the first 60 min of collection. Oxiracetam, tested at doses of 50,100, and 300 mg/kg ip, elicted a 63% increase in ACh release from the hippocampus at the dose of 100 mg/kg only. This effect of oxiracetam was inhibited by perfusion with tetrodotoxin (TTX), 5 x lo-' M. In oxiracetam-treated rats the decrease in choline efflux was less pronounced than in controls (-23% of the initial value) at the dose o f 100 mg/kg. Aniracetam (100 mg/kg, orally) elicited a sustained increase of ACh release from the hippocampus (+58%, 120 min after the administration), without affecting choline efflux. Doses of 50 and 300 mg/kg, orally, o f aniracetam were ineffective. Oxiracetam and aniracetam (50 and 100 mg/kg) neither modified the output of ACh or choline from the parietal cortex nor induced gross behavioral changes. These results indicate that oxiracetam and aniracetarn could act on cognitive processes by stimulating the hippocampal cholinergic pathways. o 1993 WiIey-Liss, Inc.
1 The effects of 4-aminopyridine (4AP) on the output of acetylcholine (ACh) from the cerebral cortex were investigated in unanaesthetized freely moving rats and in anaesthetized rats by means of the 'cup technique'. ACh was determined by bioassay on the dorsal muscle of the leech. 2 In unanaesthetized rats intraperitoneal injection of 4AP (3 mg/kg) had no effect on the cortical output of ACh.3 After injection of morphine (10 mg/kg s.c.), which depressed the spontaneous output of ACh, 4AP increased the cortical output to a level significantly higher than that determined before morphine injection. 4 In rats anaesthetized with either urethane or pentobarbitone, drugs known to decrease cortical output of ACh, 4AP (i.v. or i.p.) elicited a significant increase in the output of ACh. The time-courses of the 4AP-induced effects were different depending on the anaesthetic drug used: an immediate increase slowly fading in urethane anaesthesia and a gradual increase after delayed onset in pentobarbitone-anaesthetized rats. 5 In some urethane-anaesthetized rats, respiratory frequency was kept constant (tracheotomy, connection to respirator, bilateral vagotomy) and prazosin (1 mg/kg i.v.) was administered to reduce the 4AP-induced increase of blood pressure. Cortical output of ACh was not related to changes in blood pressure. Moreover, the 4AP-induced increase in cortical ACh output was not related to changes in respiratory frequency.6 In summary systemic administration of 4AP in subconvulsive doses (1 and 3 mg/kg) increased cortical output of ACh in rats anaesthetized with urethane or pentobarbitone or after injection of morphine, but not in untreated freely moving rats. It is suggested that the anaesthetic agents and morphine may cause an imbalance between excitatory and inhibitory central pathways, and that this imbalance may play a role in their depressant effect on cortical output of ACh and/or in the 4AP-induced facilitation described in this paper.
The effect of bromocriptine on acetylcholine (ACh) output from the cerebral cortex was investigated in anaesthetized rats. Bromocriptine caused a brief decrease in ACh output at the dose of 0.1 mg/kg i.p. and a dose-related long-lasting increase at doses from 1.25 to 10 mg/kg i.p. Apomorphine elicited an increase in ACh output when injected intraperitoneally at doses from 0.1 to 10 mg/kg. When bromocriptine was administered to rats in which a septal lesion had been made 12 days prior to the test, no increase in ACh output was observed. Bromocriptine seems therefore to stimulate a cortical cholinergic pathway originating from or passing through the septum.
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