Hippocampal muscarinic receptor loss following trimethyl tin administration

The effects of trimethyl tin on passive and active avoidance behavior, hippocampal muscarinic receptors and hippocampal cell destruction were examined in male rats. The animals were intubated with 18 mumoles/kg (3.5 mg/kg) of TMT hydrochloride or vehicle. When tested two weeks later treated animals exhibited marked deficits in retention of passive avoidance and extinction of active avoidance tasks. Receptor binding analysis, using 3H-QNB, revealed a significant decrease (21%) in muscarinic receptor density in the hippocampus. Histological examination of the hippocampus revealed a concomitant loss in pyramidal cells in these animals. These results suggest that muscarinic receptors reside on the hippocampal pyramidal cells and that these cells and receptors may be involved in retention of passive avoidance behavior.     

Behavioral effects of arginine in male rats

The effects of aminoacid arginine on conditioned and unconditioned behavior were studied in male rats. Arginine was administered orally at different dose levels. Both acute and subchronic (7 days) treatment schedule was performed. Exploratory behavior of the rats was studied in an open field. Acquisition of active avoidance behavior was studied in the shuttle-box test situation, and retention of passive avoidance reaction was studied in a step-through type of passive avoidance behavior. Acute administration of arginine failed to affect the acquisition and the retention of avoidance responses, and exploratory behavior of the rats. A 7-day treatment with the aminoacid caused an increase in ambulation of rats of Wistar strain, and a facilitation of acquisition and retention of avoidance responses in rats of CDR strain with poor learning capacity. It is possible that behavioral effects or arginine depend on its involvement in nucleic acid synthesis.     

Dose-related facilitation and inhibition of passive avoidance behavior by the ACTH 4-9 analog (ORG 2766)

The effects of "low" and "high" doses of the ACTH 4-9 analog (ORG 2766) were studied on passive avoidance behavior of rats compared to ACTH 4-10 and [D-Phe7] ACTH 4-10. All peptides increased avoidance latency in a dose-dependent manner. However, "high" doses of ORG 2766 (500 and 1000 ng/rat) inhibited passive avoidance retention. "High" amounts of ACTH 4-10 and [D-Phe7] ACTH 4-10 still facilitated passive avoidance behavior. "High" doses of ORG 2766 like "low" amounts of this peptide delayed extinction of active avoidance behavior. "High" doses of [D-Phe7] ACTH 4-10 like "low" amounts of this peptide facilitated extinction of active avoidance behavior. The substituted analog apparently carries a dual effect on passive avoidance behavior.     

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.     

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone (TRH) analog (IV): Effects on experimental memory impairment in mice and rats

The effects of a new TRH analog, TA-0910, orally administered, on experimental memory impairments for the one-trial passive avoidance response in anoxic mice (light-dark box), active avoidance response in basal forebrain (BF)-lesioned rats (shuttle box), and delayed alternation task in scopolamine-treated rats (T-maze) were studied. In mice, TA-0910 (3-30 mg) administered 60 min before the retention trial dose-dependently prolonged the passive avoidance response latency reduced by CO2-exposure that was given immediately after the acquisition trial, but not when it was given 60 min before the acquisition or just after the anoxic treatment. In rats, TA-0910 (0.3-3 mg/kg) administered 40-60 min before the test trial, dose-dependently prevented the reduction in mean avoidance rate caused by BF-lesioning and elevated the scopolamine (0.1 mg/kg, i.p.)-induced reduction in percent correct choice level in the alternation task. TRH (30-300 mg/kg), on the other hand, produced no improvements in any of the above tests. These results suggest that TA-0910 improves impaired memory by correcting the retrieval process of memory.     

Substance P enhancement of passive and active avoidance conditioning in mice

In a series of seven experiments we explored the effects of peripherally administered substance P on passive and active avoidance conditioning in mice of two genotypes. The peripheral post-trial administration of substance P significantly enhanced the retention of a single-trial passive avoidance task. This effect was dose dependent; 1 ng/g of substance P enhanced the retention of this habit, whereas higher and lower doses were either less effective or ineffective. In heterogeneous strain (HS) mice, substance P administered before training on an active avoidance task did not alter the rate at which these animals learned this habit. However, animals that had been trained with substance P were significantly more resistant to extinction than were animals that had been injected with vehicle. Similarly, C57Bl/6J mice that had been treated with substance P immediately after active avoidance training were more resistant to extinction than were mice that had been given control injections. The enhancement of retention of the passive avoidance habit with substance P was reversed in animals that had been pretreated with naltrexone. Substance P enhancement of the retention of the passive avoidance habit, and its reversal with naltrexone, was observed in both sham operated and adrenalectomized mice.     

Luteinizing-hormone-releasing hormone modifies retention of passive and active avoidance responses in rats

The influence of posttraining subcutaneous administration of luteinizing-hormone-releasing hormone (LHRH) was tested on the retention of either active or passive avoidance conditioning in male rats. Injection of LHRH (200/kg) immediately after the acquisition of an active avoidance response (two-way shuttle behavior) enhanced retention of the response, assessed 7 days later. When the neuropeptide was injected immediately after a passive avoidance conditioning training, the effects varied with the intensity of the footshock applied. LHRH enhanced retention of avoidance training with weak footshock (0.20 and 0.35 mA) but impaired retention of training with strong footshock (0.70 and 1.0 mA). The effects of LHRH seem to be unspecific since they are similar to those observed after treatment with several hormones. The results are discussed based on the interactions between peripherally injected hormones and endogenous substances released following footshock. A modulatory effect on the monoaminergic pathway involved in memory storage processes is postulated.     

Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats

Pretraining IP injection of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) enhanced performance during acquisition, but did not improve retention of active avoidance responses in rats. Naloxone (0.1 or 3 mg/kg) had no effect on acquisition or on retention. The combination of naloxone (0.3 mg/kg) plus amphetamine (2 mg/kg) did not produce the facilitation observed when each of the two drugs was administered alone. Pretreatment with the higher dose of naloxone (3 mg/kg) blocked the facilitative effect of amphetamine on acquisition. Post-training administration of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) improved retention. Naloxone (0.1 or 3 mg/kg) had no effect. When naloxone and amphetamine were combined, at respective doses of 0.3 mg/kg and 2 mg/kg, the improvement did not occur, i.e., the higher dose of naloxone prevented the facilitative effect of amphetamine. In addition, an ineffective dose of amphetamine (0.5 mg/kg), given either pre-or post-training together with the lower dose of naloxone (0.1 mg/kg), produced a significant enhancement of acquisition or consolidation, respectively. The results are consistent with the possibility that naloxone might exert its facilitative action on acquisition and memory consolidation through the release of catecholaminergic systems from inhibitory influences of opioids.     

The novel anticonvulsant loreclezole (R 72063) does not produce diazepam-like anterograde amnesia in a passive avoidance test in rats

Summary Rats were injected intraperitoneally with loceclezole (R 72063), diazepam, or scopolamine 60 min prior to acquisition of a passive avoidance task and tested 18 h later for retention of the learned (passive) behavior. The known impairment of performance produced by diazepam in this test is believed to be a model for the clinically observed diazepam-induced anterograde amnesia in humans. We report in this study that (1) consistent with the literature, pretreatment with diazepam (2.0 –16.0 mg/kg i.p.) or scopolamine (3.0 mg/kg i.p.) produced impairment in passive avoidance performance of rats (anterograde amnesia), but (2) pretreatment with loreclezole (R 72063) (2.0–80.0 mg/kg i.p.) did not impair the acquisition, retention, or the retrieval (tested 18 h later) of passive avoidance behavior by rats at any dose. The results suggest that the anticonvulsant activity of loreclezole is mediated by a mechanism distinct from the one coupled to diazepam-like disruption of cognitive functions involved in the acquisition or posttraining information processing of passive avoidance behavior.Send offprint requests to R. B. Raffa at the above address     

The effect of N-acetylaspartic acid on the processes of memory and learning in rats

The effects of a neurospecific substance N-acetyl-aspartic acid on memory and learning processes were investigated after intraperitoneal and oral administrations in rats. N-acetyl-aspartic acid was shown to restore the passive avoidance reaction in electroshock and scopolamine amnesias as well as in natural extinction. Chronic injections of N-acetyl-aspartic acid improved the learning in water maze but exerted no effect on the acquisition and retention of the active avoidance reaction in the shuttle box.     

Potency and duration of action of the ACTH 4-9 analog (ORG 2766) as compared to ACTH 4-10 and [D-Phe7] ACTH 4-10 on active and passive avoidance behavior of rats

Experiments were performed to examine the potency and duration of action of various ACTH analogs on active and passive avoidance behavior of rats. ACTH 4-10 and the ACTH 4-9 analog (ORG 2766) delayed extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. [D-Phe7] ACTH 4-10 facilitated extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. [D-Phe7] ACTH 4-10 facilitated extinction of pole-jumping avoidance behavior and facilitated passive avoidance responding. ORG 2766 was a thousand times more active than ACTH 4-10. The effect of ORG 2766 on extinction of pole-jumping avoidance behavior and on passive avoidance behavior was of longer duration than that of ACTH 4-10. As determined more precisely in the passive avoidance test it appeared that the action of ACTH 4-10 lasted 3 to 6 hours, while that of ORG 2766 amounted to at least 24 hours. Although [D-Phe7] ACTH 4-10 was a thousand times less active than ORG 2766 in the passive avoidance paradigm, its duration of action was of the same magnitude. In view of this, the marked increase in potency of the ACTH 4-9 analog cannot be explained only on the basis of its metabolic stability but also by an increased intrinsic activity.     

The effects of intra-amygdaloid injections of 6-hydroxy-dopamine on avoidance responding in rats.

1 The effects of bilateral intra-amygdaloid injections of 6-hydroxydopamine (6-OHDA) on shuttle box avoidance acquisition, retention, and extinction, and passive avoidance acquisition were examined in rats. 2 Intra amygdaloid 6-OHDA injections produced catecholamine depletion in and around the amygdalae but failed to reduce striatal dopamine concentrations. 3 Conditioned avoidance acquisition was markedly inhibited in 6-OHDA-treated rats whereas retention and extinction were only slightly impaired. 4 Passive avoidance acquisition was slightly but significantly improved in rats with amygdaloid 6-OHDA lesions. 5 Treated rats showed no motor abnormalities, they were not hypoactive in a photocell activity cage and they performed as well as controls on a rotating rod. 6 It is suggested that the conditioned avoidance acquisition deficit in rats with amygdaloid 6-OHDA lesions may be related to an impairment of associative learning rather than to perceptual or motor disturbances.     

Failure of dexamethasone to influence sex differences in acquisition of discriminated lever press avoidance

Discriminated lever press avoidance was used to test the hypothesis that higher plasma levels of pituitary-adrenocortical hormones in female rats can be held responsible for the superior active avoidance of female as compared to male rats. Male and female rats were administered dexamethasone (500 microg/kg body weight) during 4 days of avoidance acquisition and 1 additional day of extinction. This treatment resulted in a strong suppression of the pituitary-adrenocortical activity in both sexes. The corticosterone plasma level was very low, the adrenal weight was significantly reduced, but the pituitary weight was not affected. In other words, animals treated with dexamethasone were exposed to the lever press avoidance situation without a reactive pituitary-adrenocortical system. Under these conditions, sex differences in behavior were not affected and, therefore, the hypothesis that sex differences in pituitary-adrenocortical hormone levels contribute to sex differences in active avoidance, was not confirmed.     

Long-lasting neurotoxicity of prenatal benzene acute exposure in rats

Benzene is a common element of environmental pollution. Although this substance is not recognized as a teratogenic agent, it is not known whether prenatal exposure to benzene may induce neurobehavioral changes in the progeny. Benzene 0.1mg/kg was injected subcutaneously (s.c.) acutely at day 15 of gestation into pregnant female rats of the Sprague-Dawley strain and neurotoxicity of the substance was studied in pups and male adult animals of the same progeny. No change was found in total number of neonates, body weight and eye opening time between benzene-exposed animals and controls. No malformations were observed. At birth, neonatal reflexes (cliff aversion, forelimb placing, bar holding, forelimb grasping, startle) were scored in benzene-exposed pups and their percent appearance was found to be anticipated (more benzene-exposed pups exhibited reflexes each day) in comparison to that of control animals. Also, the completion (maximum appearance, i.e. 100% of the brood was found to exhibit each reflex) of neonatal reflexes in benzene-exposed animals preceded that of controls. Starting 2 months after birth, cognitive and motor performance was assessed only in male animals of the prenatally benzene-exposed progeny. The overall evaluation of motor activity in benzene-exposed animals in the open-field test revealed reduced ambulation in these rats as compared to control animals. Acquisition of active avoidance responses in the shuttle-box test, as assessed by the number of conditioned avoidance responses and the percent of learners, was impaired in benzene-exposed rats as compared to control animals. Prenatal exposure to benzene was also followed by reduced retention latency in a step-through passive avoidance task in two retention tests. These results suggest that acute exposure to benzene during gestational organogenesis may cause long-lasting changes in motor behavior and cognitive processes. This may be relevant for the assessment of benzene toxic profile for the progeny of pregnant subjects, although teratogenic effects are not observed.     

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     

Effects of the chronic administration of pyrithioxin on behaviour and cholinergic function in young and aged rats

Behavioural effects were assessed in both young and old rats of the pyridine derivative pyrithioxin, which has been reported to elevate acetylcholine levels in several brain regions in old rats. Pyrithioxin was administered in rats' food according to two separate dosing regimens (200 and 600 mg kg( -1)) over a 6 week period. Spontaneous locomotor activity was measured weekly in photocell cages. Two measures of memory were used: one trial step-down passive avoidance, and spatial learning and retention in the Morris water maze. Pyrithioxin had no effect on locomotor activity or swim speed, but enhanced one trial passive avoidance retention in both young and old animals. The drug also enhanced sensitivity to foot shock and retention of the water maze in old animals.     

Cognition enhancement by the acetylcholine releaser DuP 996

DuP 996, 3,3,-Bis(4-pyridinylmethyl)-1-phenylindolin-2-one, a potent in vitro and in vivo releaser of acetylcholine (ACh), dopamine (DA), and serotonin (5HT) in rat brain, significantly enhanced the performance of rats and mice in several behavioral test procedures. At doses of 0.01–0.1 mg/kg s.c. DuP 996 protected against a hypoxia-induced passive avoidance deficit in rats. In active avoidance procedures, DuP 996 enhanced acquisition of responses: in rats, at doses between 0.085 and 0.85 mg/kg s.c. and 0.25 and 0.85 mg/kg p.o.; in mice, at doses between 0.85 and 2.5 mg/kg s.c. These effects occurred without any alteration of sensitivity to foot-shock. In addition, Dup 996 prevented a CO₂-induced retention deficit of a passive avoidance response when administered prior to acquisition testing. In a test for acquisition of lever pressing for food in the rat, DuP 996 increased the proportion of animals acquiring this response. Thus, DuP 996 was active in both the shock- and appetitive-motivated procedures and was shown to enhance performance levels when administered post-training as well as before training trials. These results suggest that DuP 996 may be useful in the treatment of cognition dysfunction.     

The effects of lindane, DDT, and chlordecone on avoidance responding and seizure activity

Male adult Fischer-344 rats were given various doses of lindane (0, 15, and 30 mg/kg, po), chlordecone (0, 25, 50, or 100 mg/kg, ip), or p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) (0, 25, 50, or 100 mg/kg, po) and tested for their ability to perform a two-way shuttle box task or to learn and retain a step-through passive avoidance response. Administration of p,p'-DDT or chlordecone 3 hr prior to acquisition did not affect the number of shuttle box avoidance responses made during a 60-trial training task, while responses during the intertrial interval (ITI) were decreased. Rats receiving 15 or 30 mg/kg of lindane made fewer avoidance responses, but did not differ from controls in terms of the number of responses during the ITI. When 30 mg/kg lindane was given 3 hr prior to passive avoidance acquisition, retention was impaired 7 days later; the lower dose of lindane, and all doses of chlordecone or p,p'-DDT had no effect under these conditions. When these chemicals were given immediately after passive avoidance training, animals treated with lindane were not affected. Animals receiving 100 mg/kg of p,p'-DDT or chlordecone displayed marked signs of toxicity and animals tested 7 days after training showed an impaired retention. Pretreatment with anticonvulsants such as phenobarbital and chlordiazepoxide, which may enhance GABA-mediated responses, blocked the disruptive effects of lindane (30 mg/kg) on shuttle box avoidance. The seizure-related activity produced by a higher dose of lindane (60 mg/kg) and kainic acid, a hippocampal excitotoxin, was also blocked by phenobarbital and chlordiazepoxide. Pretreatment with phenytoin, which is thought to bind to the inactivation gates of sodium, had no effect on the effects produced by lindane or kainic acid. These data suggest that treatment with nonconvulsant doses of lindane can interfere with the ability to acquire and use new information and that these effects may be associated with alterations in GABA.     

Effects of anabaseine-related analogs on rat brain nicotinic receptor binding and on avoidance behaviors

Several novel anabaseine-derived compounds were investigated with respect to their ability to displace high affinity [³H]cytisine binding in rat brain membranes, as well as their ability to improve passive and active avoidance behaviors in nucleus basalis-lesioned rats. The relative potencies for displacement of 1 nM [³H]cytisine binding IC50 in parentheses: anabaseine (70 nM) > DMAB (140 nM) = DMXB (150 nM) > anabasine (270 nM) > DMAC (420 nM). Passive avoidance behavior in bilaterally nucleus basalis-lesioned rats was improved by each of these drugs to an extent comparable to that observed with (–)-nicotine. The relative potencies of these compounds for improving this behavior exhibited a pattern very similar to their affinities for displacing [³H]cytisine binding (nicotine > anabaseine > DMXB > DMAB = DMAC > anabasine). Acquisition of active avoidance behavior was slower in unilaterally and bilaterally nucleus basalis-lesioned rats than unlesioned controls; (?)-nicotine improved acquisition behavior only in the former group. At doses that improved passive avoidance behavior, DMXB also improved acquisition of active avoidance behavior in unilaterally lesioned rats, while DMAB and DMAC did not. (?)Nicotine and DMXB had no effect on escape behavior in the active avoidance task at doses that improved retention of avoidance behavior itself. These results suggest that anabaseine and several of its analogs bind to brain α4β2 nicotinic receptors and mimic non-spatial, memory-related behaviors in a nicotine-like manner. © 1994 Wiley-Liss, Inc.