The GABA-B antagonist CGP 36742 prevent PTZ-kindling-provoked amnesia in rats.

Deficit in active and inhibitory avoidance behaviour has been found in pentylenetetrazole (PTZ)-kindled rats. This supports the view that memory deficit is an integral part of epilepsy. In the present study we examined the effect of the GABA B antagonist CGP 36742 on memory deficit induced by PTZ-kindling in shuttle-box- and step-down-trained rats. The retention in CGP 36742-treated animals was significantly improved compared to the kindled controls. The mechanisms of action of CGP 36742 is considered. The favourable effect of the GABA B antagonist in cases of amnesia provoked by PTZ-kindling might be of interest in clinical practice.     

Effect of scopolamine and nootropic drugs on rewarded alternation in a T-maze.

The effects of different doses of scopolamine, and of the nootropic drugs oxiracetam and aniracetam, were investigated on the performance of male Wistar rats in a T-maze requiring a spatial discrimination in the stem (reference memory) and an alternate discrimination in the arms (working memory). Criterion (90% correct responses) was reached within 3 days of daily training for stem and 9 days for arm discrimination. Scopolamine (0.1, 0.2, 0.6, and 1.0 mg/kg, SC, 60 min before session) significantly impaired working memory, as shown by a decrease in the number of correct alternations, without affecting reference memory. Both nootropic drugs (25-50 and 100 mg/kg PO) 30 min before scopolamine) attenuated the working memory impairment induced by scopolamine.     

Memory effects of the new derivative of the p-chlorophenoxyacetic acid adafenoxate compared to the effects of some cognition-enhancing drugs in rats

In experiments on male rats the effects of adafenoxate (Adf), meclofenoxate (Mf), piracetam (Pc) and citicholine (CCh) on learning and memory were studied using the maze active avoidance method with punishment reinforcement. The drugs tested were administered twice daily for seven days at doses of 10 and 50 mg/kg body weight for Adf, Mf and CCh and only at a dose of 50 mg/kg body weight for Pc. The effects of these drugs on scopolamine-treated and scopolamine-untreated rats were also studied using the step-through method. Retention tests were given 24 h and 7 days after the end of the training session in the punishment-reinforcement active avoidance and 3 and 24 h after training in the passive avoidance situation. With the maze method statistically significant results about the favourable effects of the four drugs were obtained by most of the indices for learning and memory. However, the effects of the drugs tested were differently pronounced depending on the dose utilized. With the step-through method all four drugs prevented the scopolamine-induced amnesia. Comparing the present results with other data previously obtained about the effects of the drugs tested and of other nootropic drugs on brain biogenic monoamines, it is suggested that induced changes in biogenic monoamines are responsible for the similarities and the differences in the effects of nootropic drugs on learning and memory.     

Influence of nootropic drugs on the memory-impairing effect of clonidine in albino rats

The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on cognitive functions impaired by the antihypertensive drug clonidine were investigated in albino rats. The changes in learning and memory were studied by two-way active avoidance with punishment reinforcement (shuttle box). Clonidine injected intraperitoneally at a dose of 0.1 mg/kg immediately after a one-day shuttle box training significantly impaired retention. A 5-day treatment before the training session with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the memory-impairing effect of clonidine. The role of the NAergic neurotransmitter system in the clonidine-induced disturbances of cognition, as well as in the protective effects of nootropic drugs, was discussed.     

Influence of nootropic drugs on the learning- and memory-impairing effect of diethyldithiocarbamate in albino rats

The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on the impaired cognitive functions by the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDC) were investigated in albino rats. The changes in learning and memory were studied by the two-way active avoidance with punishment reinforcement (shuttle box). DDC injected intraperitoneally at a dose of 300 mg/kg in the course of the 5-day shuttle box training significantly impaired learning and retention. The 10-day treatment (5 days before and 5 days during training) with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the learning- and memory-impairing effect of DDC. The role of the NA-ergic neurotransmitter system for the DDC-induced disturbances in cognition as well as for the protective effects of nootropic drugs was discussed.     

Memory impairments induced by peripherally administered cholecystokinin a-type receptor antagonists in rats

Intraperitoneal injection of cholecystokinin (CCK) A-type receptor antagonists, L-364,718 and CR 1409, caused dose-dependent memory impairments in passive and active avoidance responses and in Morris water pool test in rats. These antagonist effects were significant at a dose of 1 mg/kg, while with proglumide, 50–100 mg/kg were required to produce a similar memory deficit. The results suggest that loss of biologically active CCK octapeptide (CCK-8), not only in the brain but also in the peripheral tissues, causes memory impairmets in rats. © 1992 Wiley-Liss, Inc.     

Can nootropic drugs be effective against the impact of ethanol teratogenicity on cognitive performance?

Rats exposed pre- (PA) and postnatally (PNA) to ethanol at a dose of 1 g/kg for 24 h developed fetal alcohol effects (FAE). This was measured using a condition-reflex method for active avoidance with punishment reinforcement (shuttle-box) in which pronounced learning and memory deficits in 3-month-old rats were found after ethanol exposure (Vaglenova and Petkov, 1998. Fetal alcohol effects in rats exposed pre- and postnatally to a low dose of ethanol. Alcohol. Clin. Exp. Res. 22(3), 697--703). In the present study the effects of piracetam (Pyramem) at a dose of 600 mg/kg body weight, aniracetam at 50 mg/kg, and meclophenoxate (Centrophenoxine) at 100 mg/kg were studied. The drugs were administered orally during 10 days to separate groups of naive and pre- and postnatally exposed to ethanol rats. All the investigated nootropic drugs showed a significant possibility to alleviate learning and memory disability of rats with FAE. Aniracetam was administered to 1-month-old rats, demonstrating a prolonged (2 months) therapeutic effect, observed in rats aged 3 months. As previously reported (Vaglenova and Petkov, 1998), between male rats with FAE and controls, 66 and 33% were 'poor learners', respectively. In all nootropic treatment groups the percentage of 'poor learners' dropped to 28%. The positive effects of piracetam, aniracetam and meclophenoxate suggest that these drugs could be used for both treatment and prophylactic of FAE-connected disturbances of cognition.     

Impaired memory following repeated pentylenetetrazol treatments in kindled mice

Epilepsy is characterized by recurrent seizures, which are caused by excessive discharges from cerebral neurons. Currently, antiepileptic drugs that possess sodium channel blocking activities and also mediate GABA-ergic systems are primarily used to prevent epileptic seizure. However, approximately 40% of patients with epilepsy suffer from interictal psychiatric comorbidities in clinical practice. Furthermore, it is unclear whether epilepsy is associated with psychic function. The aim of the present study was to clarify the effects of kindling-induced epileptic seizures on psychic functioning using behavioral pharmacological tests. Pentylenetetrazol (PTZ)-kindled mice demonstrated no significant differences in locomotor activity and muscle relaxation compared with na?ve mice. PTZ-kindled mice also demonstrated cognitive impairment in the objective location test, but no significant effects of PTZ-kindling were observed in the Y-maze test. These findings suggested that PTZ-kindling impairs reference memory, but not working memory. These results suggest that, with respect to their psychic functioning, PTZ-kindled mice have specific characteristics.     

Learning and memory in rats exposed pre- and postnatally to alcohol. An attempt at pharmacological control

Using conditioned-reflex methods for active and passive avoidance with punishment reinforcement, we found pronounced memory deficits in 12-week old rats exposed perinatally to alcohol (FAS rats). Impairment of memory was observed not only with the high dose of 9 g ethanol/kg body weight (ingested with tap water in a 6% solution) to which dams were exposed during pregnancy and lactation, but also with the ten-fold lower dose of 1 g ethanol/kg body weight (0.6% ethanol). The nootropic drugs citicholine, piracetam and meclofenoxate administered orally for five days before the training session were effective in decreasing memory deficits; particularly pronounced was the effect of piracetam and meclofenoxate. The benzodiazepine tranquilizer diazepam additionally impaired learning and memory in FAS rats. It is suggested that nootropics could be used to decrease the cognitive disturbances in some humans born to alcoholic mothers.     

Nootropic drugs: Animal models for studying effects on cognition

The term “nootropic” refers to compounds that act on cognitive functions. These drugs should facilitate learning and memory and prevent impairment of cognitive functions induced by diseases and brain insults. In animal models of impaired cognitive functions, the effects of several nootropic substances were investigated. Learning and retention in passive avoidance, and positive reinforcement paradigms were disrupted by hypoxia, cerebral ischemia and amnesia-inducing agents. Piracetam and several other novel nootropic compounds were shown to improve performance in these animal models. These results indicate that experimentally induced cognitive dysfunction in animals can be attenuated with drug treatment.     

A decrease in brain catecholamines prevents oxiracetam antagonism of the effects of scopolamine on memory and brain acetylcholine

The effect of oxiracetam on passive avoidance conditioned response and acetylcholine (ACh) levels in rats with selective lesions of the central monoaminergic pathways was investigated. The lesions were followed by a marked decrease in cortical serotonin (-88%), noradrenaline (-54%) and striatal dopamine (-57%) levels, while neither the performance of a passive avoidance conditioned response nor brain ACh levels were affected. Scopolamine (hyoscine) administration (0.63 mg/kg, s.c.) to lesioned rats exerted the expected amnesic effect, associated with a decrease in hippocampal, cortical and striatal ACh levels. In the rats with degeneration of dopaminergic and noradrenergic but not serotoninergic pathways, oxiracetam (50 and 100 mg/kg, s.c.) was unable to prevent both amnesia and the decrease in brain ACh levels caused by scopolamine. The effect of oxiracetam was prevented by haloperidol (0.2 mg/kg, s.c.). Our findings support the hypothesis that an interaction between monoaminergic and cholinergic neurotransmitter systems may be involved in the actions of nootropic drugs on cognitive functions.     

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

The favorable pharmacological profile exhibited by piracetam stimulated the synthesis of related compounds potentially endowed with a higher nootropic potency. The antiamnesic and procognitive activity of DM232 (unifiram), a new compound structurally related to piracetam, was investigated. Mouse passive avoidance and rat Morris water maze and Social learning tests were employed. DM232 (0.001–1 mg kg^?1 i.p. – 0.01–0.1 1 mg kg^?1 p.o.) prevented amnesia induced by scopolamine (1.5 mg kg^?1 i.p.), mecamylamine (20 mg kg^?1 i.p.), baclofen (2 mg kg^?1 i.p.), and clonidine (0.125 mg kg^?1 i.p.). Furthermore, The antiamnesic effect of the investigated compound was comparable to that exerted by well‐known nootropic drugs such as piracetam (30–100 mg kg^?1 i.p.), aniracetam (100 mg kg^?1 p.o.), rolipram (30 mg kg^?1 p.o.), and nicotine (5 mg kg^?1 i.p). DM232 (0.1 mg kg^?1 i.p.) was also able to prevent amnesia induced by scopolamine (0.8 mg kg^?1 i.p.) in the rat Morris watermaze test. In the rat social learning test, DM232 (0.1 mg kg^?1 i.p.) injected in adults rats reduced the duration of active exploration of the familiar partner in the second session of the test. DM232, similarly to piracetam, reduced the duration of hypnosis induced by pentobarbital. At the highest effective doses, the investigated compound did not impair motor coordination (rota rod test), nor modified spontaneous (Animex). These results indicate DM232 (unifiram) as a novel cognition enhancer, strictly related to piracetam‐like compounds, able to ameliorate memory impairment at doses about 1,000 times lower than the most active available nootropic compounds. Drug Dev. Res. 56:23–32, 2002. © 2002 Wiley‐Liss, Inc.     

Effects of MK-801 and nicotine combinations on memory consolidation in CD1 mice

RATIONALE: Recent experiments have shown that pre-trial administrations of nicotine to rats tested in a 16-arm radial maze attenuated the MK-801-induced deficit in both working and reference memory performance. Memory consolidation can be influenced in laboratory animals, by post-training administration of drugs. OBJECTIVE: In the present study we have investigated the effects on memory consolidation of CD1 mice exerted by: a) the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten-5, 10-imine-maleate] b) nicotine, and c) combinations of MK-801 and nicotine. METHODS: Different groups of mice were injected intraperitoneally (IP) with the single drugs and with their combinations, immediately after training in a passive avoidance task. Additional groups of animals were also injected 2 h post-training with the highest effective dose of MK-801 (0.3 mg/kg), with the highest effective dose of nicotine (0.5 mg/kg) or with the combination of an otherwise ineffective dose of MK-801 (0.1 mg/kg) with the highest effective dose of nicotine, respectively. Their performances were compared with those of mice injected with saline, with the vehicle of nicotine and with the other treatment combinations, respectively RESULTS: The results showed that MK-801 exerted deleterious effects, while nicotine exerted facilitatory effects on mice performances. Further, an otherwise ineffective dose of MK-801 (0.1 mg/kg) antagonized the facilitatory effects of nicotine (0.25 and 0.5 mg/kg). In the 2 h post-training injected groups the treatments were ineffective, showing that the immediate post-training drug administrations affected memory consolidation processes. CONCLUSIONS: In conclusion, from the present research, it is evident that NMDA glutamate and nicotinic acetylcholine receptor systems interact in modulating memory consolidation in CD I mice.     

Cholinergic drugs reverse AF64A-induced impairment of passive avoidance learning in rats

The cholinergic neurotoxin AF64A was administered to rats in order to produce learning impairment to test the effect of cholinergic drugs. Seven days after receiving an intracerebroventricular injection of AF64A (2.5–7.5 nmol), rats were subjected to one-trial passive avoidance acquisition and tested 24 h later. Learning was significantly impaired at 3.75 nmol AF64A, a dose at which significant reduction in acetylcholine level and choline acetyltransferase and acetylcholinesterase activity in the hippocampus was observed but changes in monoamine levels in the hippocampus, general behavior, or sensory sensitivity were not observed. Arecoline (4 mg/kg, IP) and physostigmine (0.1 mg/kg, IP) significantly decreased the learning impairment produced by AF64A (3.75 nmol) when given before the acquisition of passive avoidance learning but not when given after the acquisition or before the 24 h retention test. These drugs and oxotremorine (0.1 mg/kg, IP) given immediately after the acquisition, however, improved passive avoidance retention when the interval between the acquisition and the test was shortened to 1 h. These results indicate that the impairment of learning in AF64A-treated rats is caused by a memory retention deficit and suggest that such impairment can be effectively ameliorated by cholinergic drugs.     

Impairment of contextual fear conditioning in rats by Group I mGluRs: reversal by the nootropic nefiracetam

The blockade of Group I metabotropic glutamate receptors (mGluRs) may be a potential strategy for prevention therapy of neurotoxicity. We here confirm previous reports that systemic application of the Group I antagonist, 1-aminoindan-1,5-dicarboxylic acid (AIDA), causes amnesia in a contextual fear conditioning paradigm in rats. This deficit was fully reversed by long-term pretreatment with the nootropic nefiracetam, which in fact obtained supranormal performance. Our data suggest that application of Group I antagonists to prevent neurotoxicity, combined with nootropic treatment to prevent cognitive deficits, may be a therapeutic strategy for the development of novel antineurotoxic treatments.     

Memory effects of the Ca2+ and 5-HT antagonists dotarizine and flunarizine

In experiments on Wistar and Long Evans rats, using behavioral methods for passive (step-down and step-through) and active (shuttle-box two-way avoidance with punishment reinforcement) the newly synthesized diphenyl-methyl-piperazine derivative with Ca2+ and 5-HT antagonistic action dotarizine (DOT) administered repeatedly at oral doses of 50 and 10 mg/kg in some cases improve memory process. Under the same experimental conditions the chemically related to dotarizine Ca2+ antagonist flunarizine significantly facilitated retention. In old (Long Evans and Wistar) rats DOT in large dose decreases values of learning criterion. Probably this is a manifestation of the inherent to drugs with nootropic action "therapeutic window". Earlier investigations of the same and other authors suggest the participation of serotonergic neurotransmission in the mechanism of the memory effects of the drug DOT.     

Characterization of the transcallosal response in aged rats and its susceptibility to nootropic drugs.

The transcallosal response in aged rats was recorded and its susceptibility to certain nootropic drugs was compared with adult animals, under urethane-anesthesia. The transcallosal response in 24-month old rats was significantly reduced in the amplitude of both positive and negative waves, as compared with 5-month old animals. In adult rats, intravenous administration of 100 mg/kg of calcium hopantenate augmented the amplitude of both the positive and the negative waves. Intraperitoneal administration of 300 mg/kg of calcium hopantenate or 10-100 mg/kg of aniracetam increased the amplitude of the negative wave by 20-30% above the control level but had no effect on the positive one. In aged rats, these drugs, given intraperitoneally, also increased the negative wave without affecting the positive one and the degree of augmentation was more prominent; both drugs increased the amplitude of the negative wave by about 190% of the control. These results suggest that the susceptibility to the nootropic drugs became even more striking in older animals, the function in the brain of which are reduced by the natural ageing process.     

Testosterone reverses ethanol-induced deficit in spatial reference memory in castrated rats

The present study was designed to evaluate the effects of ethanol, testosterone and combination of ethanol and testosterone, on spatial reference memory and beta-endorphin (beta-EN) levels in castrated rats. Male Sprague-Dawley rats (120-150 g) were used in this study, Animals were castrated and ethanol, testosterone or combination of the drugs were administered to rats at 09:00 h. The drugs were administered after a training period of 5 days and spatial reference memory was evaluated for 7 days using the Morris water maze. One hour after the last injection, animals were sacrificed, their brains removed and dissected into cortex, hypothalamus, hippocampus and midbrain. The beta-EN levels in these brain regions were determined by radioimmunoassay. The time to find the platform (latency period) was significantly increased in ethanol-treated rats, indicating that ethanol induces deficit in spatial reference memory. On the other hand, testosterone administration improved spatial reference memory by significantly decreasing the latency period. In addition, there was a significant decrease in latency period in the animals treated with combination of ethanol and testosterone. Results also indicate that administration of ethanol resulted in a significant increase in beta-EN levels in the hippocampus and in the cortex while concurrent administration with testosterone abolished this increase. These findings clearly indicate that administration of testosterone did not only improve memory but also abolished the spatial memory deficit induced by ethanol in castrated rats.     

Chronic phosphatidylserine treatment improves spatial memory and passive avoidance in aged rats

Learning/memory deficits in senescent animals are widely used as a tool to evaluate the therapeutic potential of agents for treatment of age-associated cognitive dysfunction. As assessed in the Morris water maze test, aged (21–24 months) rats showed a variable loss of spatial memory. Aged non-impaired rats performed as well as young subjects, while aged impaired rats exhibited a severe and persistent place-navigation, deficit. Passive avoidance retention was similarly affected in the two aged subpopulations. Chronic oral administration of phosphatidylserine (50 mg/kg/day for up to 12 weeks), a pharmacologically active phospholipid, was found to improve both the spatial memory and the passive avoidance retention of aged impaired rats. Results are discussed with reference to the phosphatidylserine-induced improvement of age-associated deterioration of brain functions in rats.We are grieved to record the unexpected, death of Professor L. Valzelli. He was a scientist of merit and a great humanitarian     

Pharmacotherapy of memory loss in the geriatric patient

Memory loss is a common problem with advancing age and a prominent symptom in dementia. Categories of drugs used to reverse memory loss and enhance recall are reviewed. Positive results have been observed with cholinergic drugs, acetylcholine precursors, and the newer category of cerebral metabolic enhancers and nootropic agents. Combinations of these classes of drugs are being tried in current research.