Effects of systemic administration of beta-casomorphin-5 on learning and memory in mice

The effects of systemic administration of bovine beta-casomorphin-5 (Tyr-Pro-Phe-Pro-Gly), a mu-opioid receptor agonist derived from milk beta-casein, on spontaneous alternation behavior in the Y-maze (spatial short-term memory) and step-down-type passive avoidance response (non-spatial long-term memory) were investigated in mice. Intraperitoneal (i.p.) administration of beta-casomorphin-5 (0.1-20 mg/kg) did not have a significant effect on either spontaneous alternation behavior or passive avoidance response. However, a low dose (1 mg/kg, i.p.) of beta-casomorphin-5 improved scopolamine (1 mg/kg, s.c.)-induced impairment of spontaneous alternation behavior and passive avoidance response. Pretreatment with intracerebroventricular injections of beta-funaltrexamine (a mu-opioid receptor antagonist, 0.1 microg/mouse) and naloxonazine (a mu(1)-opioid antagonist, 5 microg/mouse), which did not improve scopolamine-induced impairment, prevented the ameliorating effect of beta-casomorphin-5 on scopolamine-induced impairment of passive avoidance response. These results indicated that systemic administration of a low dose (1 mg/kg, i.p.) of beta-casomorphin-5 improves the disturbance of learning and memory resulting from cholinergic dysfunction through central mediation involving mu(1)-opioid receptors.     

Improvement by low doses of nociceptin on scopolamine-induced impairment of learning and/or memory

The effects of fmol doses of nociceptin/orphanin FQ on scopolamine-induced impairment of learning and/or memory were examined using spontaneous alternation of Y-maze and step-down type passive avoidance tasks. While fmol doses of nociceptin alone had no effect on spontaneous alternation or passive avoidance behavior in normal mice, administration of nociceptin (10 and/or 100 fmol/mouse) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, significantly improved the scopolamine-induced impairment of spontaneous alternation and passive avoidance behavior. This ameliorating effect was not antagonized by nocistatin (0.5 and 5.0 nmol/mouse, i.c.v.), naloxone benzoylhydrazone (2.3, 11.2, and 56.1 micromol/kg, s.c.) or nor-binaltorphimine (4.9 nmol/mouse, i.c.v.). These results indicated that very low doses of nociceptin ameliorate impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that this peptide has bidirectional modulatory effects on learning and memory; impairment at high doses and amelioration at low doses.     

Effect of acetyl-L-carnitine on conditioned reflex learning rate and retention in laboratory animals

The aim of the study was to evaluate the effects of acetyl-L-carnitine on learning and/or memory processes in laboratory animals. In the water maze test, acetyl-L-carnitine, given intraperitoneally at doses ranging from 0.3 to 100 mg/kg, improved performances in both mice and rats. In the latter the drug also proved active when administered orally in the 3-100 mg/kg dosage range. In the pole climbing test in the rat, acetyl-L-carnitine at doses ranging from 0.03 to 10 mg/kg i.p. increased the conditioned reflex learning rate. In the passive avoidance test in the rat, significant increases in retention were observed after treatment with acetyl-L-carnitine at doses ranging from 1 to 30 mg/kg i.p. In the passive avoidance plus electroconvulsive shock test in the mouse, acetyl-L-carnitine antagonized amnesia at doses ranging from 0.1 to 3 mg/kg i.p.     

Effects of selective inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) on mice in learning and memory tasks

The purpose of the present study was to examine the effects of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a selective inhibitor of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, glutamate carboxypeptidase II), an enzyme catalyzing the cleavage of glutamate from the neuropeptide N-acetyl-aspartyl-glutamate (NAAG), on memory processes in mice. Long-term memory was evaluated in step-through passive avoidance task while alternation behavior, as a measure involving spatial working memory, was assessed in Y-maze task. Additionally, horizontal activity was evaluated by means of electronically monitored locomotor activity system. The mice were treated with either 2-PMPA (50, 100 and 150 mg/kg i.p.) or N-methyl-d-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) at doses of: 0.05, 0.1, 0.15 and 0.2 mg/kg i.p., as a comparator. In the passive avoidance task, the drugs were administered once before or immediately after training, and before retention test. 2-PMPA at the doses used did not affect retention of passive avoidance; however, it increased the latency to enter the dark box during the training day. In the Y-maze task, 2-PMPA (150 mg/kg i.p.) impaired spontaneous alternation and reduced locomotion while the lower dose of 100 mg/kg was ineffective. In the locomotor activity test, 2-PMPA (100 and 150 mg/kg i.p.) did not significantly affect horizontal activity. MK-801 (0.2 mg/kg i.p.) injected before training reduced retention in the passive avoidance task. In the Y-maze task, MK-801 (0.1 mg/kg i.p.) impaired alternation behavior and considerably increased locomotion in the Y-maze and locomotor activity test. These results indicate that NAALADase inhibition may impair alternation behavior.     

Stimulation of D1-receptors improves passive avoidance learning of female rats during ovary cycle

The involvement of D1-receptors in learning/memory processes during ovary cycle was assessed in the adult female rats. SKF-38393 (0,1 mg/kg, i.p.), D1-receptor agonist and SCH-23390 (0,1 mg/kg, i.p.), D1-receptor antagonist were injected chronically to adult female rats. Learning of these animals was assessed in different models: passive avoidance performance and Morris water maze. Chronic SKF-3839 administration to females resulted in the appearance of the passive avoidance performance in proestrous and estrous, as distinct from the control animals, but failed to change the dynamics of spatial learning in Morris water maze. Chronic SCH-23390 administration similarly impaired non-spatial and spatial learning in females during all phases of ovary cycle. The results of the study suggest modulating role of D1-receptors in learning/memory processes during ovary cycle in the adult female rats.     

Effects of cadmium on memory processes in mice exposed to transient cerebral oligemia

The purpose of the present study was to examine whether the effects of chronic or acute exposure to cadmium on memory processes in mice could be exacerbated by transiently reducing cerebral oxygen supply. Adult mice were subjected to bilateral clamping of the carotid artery (BCCA) for 30 min under anesthesia. Cadmium chloride was administered intraperitoneally after surgery at single doses of: 0.7 mg/kg (low dose), 1.4 mg/kg (high dose), or at a prolonged dose of 0.7 mg/kg for up to 10 days. Long-term memory was evaluated in a step-through passive avoidance task while spatial working memory was evaluated using a Y-maze spontaneous alternation task. BCCA mice injected with the 1.4 mg/kg dose of cadmium exhibited recall deficits in the step-through passive avoidance task. Combined treatment at either dose had no effect on the acquisition of passive avoidance. In the Y-maze task, spontaneous alternation behavior was only impaired in BCCA mice treated with the prolonged cadmium dose. These results indicate that cerebral oligemic hypoxia may alter cadmium neurotoxicity and potentiate the tendency for cadmium-induced memory impairments in the passive avoidance task and spontaneous alternation deficits.     

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.     

Characteristics of learning and memory impairment induced by delta9-tetrahydrocannabinol in rats

We investigated the characteristics of delta9-tetrahydrocannabinol (THC)-induced impairment of learning and memory using an 8-arm radial maze task, a water maze, a visual discrimination task with 2 figures and a passive avoidance test in rats. THC (6 mg/kg, i.p.) impaired spatial memory in the standard task of the 8-arm radial maze. THC (4-6 mg/kg, i.p.) selectively impaired working memory in a reference and working memory task of the 8-arm radial maze. Even at a dose of 10 mg/kg, THC did not impair spatial memory in the water maze. In addition, THC at a dose of 6 mg/kg, which had inhibitory effects in the 8-arm radial maze, did not affect performance in the visual discrimination task. These results indicate that at low doses (2-6 mg/kg), THC may not produce visual function abnormalities. THC impaired retrieval (6 mg/kg, i.p.) as well as acquisition (10 mg/kg, i.p.) in the passive avoidance test. The consolidation process was also impaired by i.c.v. injection (100 microg), but not i.p. injection (6-10 mg/kg) of THC. These results suggest that THC-induced impairment of spatial memory is based on the selective impairment of working memory through its effects on acquisition and retrieval processes.     

Rivastigmine reverses aluminum-induced behavioral changes in rats

Aluminum, a known neurotoxin, has long been implicated in the pathogenesis of Alzheimer's disease. Its exposure is associated with impairment in the cholinergic system in the brain. In this study we investigated the behavioral effects of aluminum in rats and the possible effect of rivastigmine, a cholinesterase inhibitor, on the aluminum-induced behavioral changes. Rats were exposed to aluminum chloride (100 mg/kg/day i.p.) for 60 days before the start of behavioral tests. Rivastigmine was given in doses of 0.5, 1, 1.5 and 2.5 mg/kg i.p. 60 min before the behavioral tests. Five tests were investigated; open field test, Morris water maze, radial arm maze, passive avoidance test and rota-rod test. Results showed that aluminum exposure was associated with significant reductions in spontaneous locomotor and exploratory activities in open field test and significant impairments in learning and memory in Morris water maze, radial arm maze and passive avoidance tests. The behavioral impairments caused by aluminum were significantly improved by rivastigmine. Neither aluminum alone nor co-treatment with rivastigmine caused any significant alteration of the animals' performance in rota-rod test. The improvements in activity, learning and memory caused by rivastigmine were found to be dose-dependent, and the maximal improvement was encountered with its large dose (2.5 mg/kg). From these results we can conclude that rivastigmine can reverse behavioral deficits caused by aluminum intoxication.     

Effects of the novel 5-HT(6) receptor antagonist RO4368554 in rat models for cognition and sensorimotor gating.

Serotonin(6) (5-HT(6)) receptors are almost exclusively located in the central nervous system. High expression in the hippocampus, nucleus accumbens and striatum is consistent with a potential role in cognition and psychosis. The availability of potent, selective and brain-penetrating 5-HT(6) antagonists such as RO4368554 allows further characterization of the role of the 5-HT(6) receptor in these processes. Herein, we tested RO4368554 in several cognition tasks, as well as sensorimotor gating tests. Using scopolamine-impaired and unimpaired adult male rats, RO4368554 was given in novel object discrimination, social recognition, social discrimination, Morris water maze, passive avoidance and autoshaping procedures. RO4368554 reversed the effects of scopolamine in novel object discrimination (active doses in mg/kg, i.p., 3, 10), social recognition (3, 10), social discrimination (1, 3, 10) and passive avoidance (10, 30 i.p. and 100 p.o.) tasks. In unimpaired rats, RO4368554 enhanced object discrimination (3, 10; 4-h forgetting interval) and autoshaping learning (3), but was inactive in a water maze task (doses tested: 1-10 mg/kg, i.p.). In tests sensitive to antipsychotics, RO4368554 did not reverse sensorimotor gating deficits induced by the psychostimulants dizocilpine and amphetamine (doses tested: 1-30 mg/kg, i.p.) or neonatal lesion of the ventral hippocampus (1-10 mg/kg, i.p.). In conclusion, RO4368554 enhanced learning and memory processes in unimpaired and scopolamine-impaired rats, supporting the notion that the cognitive enhancing effects of 5-HT(6) receptor antagonists involve modulation of cholinergic neurotransmission.     

Nootropic activity of Celastrus paniculatus seed

The effect of Celastrus paniculatus Willd. (Celastraceae) seed aqueous extract on learning and memory was studied using elevated plus maze and passive avoidance test (sodium nitrite induced amnesia rodent model). The aqueous seed extract was administered orally in two different doses to rats (350 and 1050?mg/kg) and to mice (500 and 1500?mg/kg). The results were compared to piracetam (100?mg/kg, p.o.) used as a standard drug. Chemical hypoxia was induced by subcutaneous administration of sodium nitrite (35?mg/kg), immediately after acquisition training. In elevated plus maze and sodium nitrite-induced amnesia model, Celastrus paniculatus extract has showed statistically significant improvement in memory process when compared to control. The estimation of acetylcholinesterase enzyme in rat brain supports the plus maze and passive avoidance test by reducing acetylcholinesterase activity which helps in memory performance. The study reveals that the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain.     

Clove oil reverses learning and memory deficits in scopolamine-treated mice

The present study was performed to examine the effect of Eugenia caryophyllata (Myrtaceae) on learning and memory, and also evaluate whether it can modulate oxidative stress in mice. Passive avoidance step-down task and elevated plus-maze were used to assess learning and memory in scopolamine-treated mice. Oxidative stress parameters were also assessed in brain samples by estimating the malondialdehyde (MDA) and reduced glutathione (GSH) levels at the end of the study. Scopolamine (0.3 mg/kg, i. p.) produced impairment of acquisition memory as evidenced by a decrease in step-down latency and an increase in transfer latency on day 1, and also impairment of retention of memory on day 2. Pretreatment with clove oil (0.05 mL/kg and 0.1 mL/kg) for 3 weeks significantly reversed the increase in acquisition latency and all the doses (0.025, 0.05, 0.1 mL/kg, i. p.) reversed the increase in retention latency induced by scopolamine (0.3 mg/kg, i. p.) in elevated plus-maze. However, 0.05 mL/kg clove oil attenuated memory deficits in the passive avoidance step-down task. Brain samples showed a significant decrease in MDA levels in the group treated with clove oil (0.05 and 0.025 mL/kg). GSH levels were also increased in clove oil-treated mice though the results were not significant. Thus, it can be concluded that clove oil can reverse the short-term and long-term memory deficits induced by scopolamine (0.3 mg/kg, i. p.) and this effect can, to some extent, be attributed to decreased oxidative stress.     

Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice

The effects of systemic administration of tianeptine, a new psychotropic agent with antidepressant properties, were investigated on spontaneous alternation behavior, and on simple and concurrent spatial discrimination, in normal mice of the BALB/c strain. Tianeptine increased rates of spontaneous T-maze alternation, facilitated retention of a T-maze left-right discrimination, and speeded up acquisition of concurrent discrimination in a radial maze. These effects were consistent across successive experiments with a dose of 10mg/kg; lower doses (2.5 and 5.0mg/kg) had less or no effect depending on the task. These results, together with theoretical considerations, led us to investigate the effect of tianeptine on the sequential-specific alternation deficit induced by long-term ethanol administration in the same strain of mice. Results showed that, at the dose of 10mg/kg, the drug completely alleviated the alcohol-induced deficit. Unlike tianeptine, fluoxetine impaired discrimination performance in the radial maze. These data are discussed in light of the effects of tianeptine on serotonergic transmission and of the role of serotonin and acetylcholine in learning and memory processes.     

Improvement of cognitive functions by the acetylcholine releaser SM 21

The effect of administration of SM 21 on memory processes was evaluated in the mouse passive avoidance and in the rat social learning tests. SM 21 (10–20 mg kg⁻¹ i.p.) prevented amnesia induced by scopolamine and dicyclomine as tested by the mouse passive avoidance test and prevented memory disruption by AF‐64A and benehexol ascertained by the rat passive avoidance test. Both SM 21 enantiomers were able to abolish dicyclomine‐induced amnesia in mice. SM 21, starting from the dose of 10 mg kg⁻¹ i.p., antagonized the memory impairment produced by mecamylamine, baclofen, and diphenhydramine in mice, as well as amnesia induced by diazepam in rats. SM 21, at doses ranging between 10 and 30 mg kg⁻¹ i.p., prevented memory reduction in mice by hypoxia in the passive avoidance test. In the social learning test, SM 21 (10 mg kg⁻¹ i.p.) injected in adult rats reduced the duration of active exploration of a familiar partner in the second session of the test. SM 21 prevented amnesia in both mice and rats comparable to that of the cholinesterase inhibitor physostigmine (0.2 mg kg⁻¹ i.p.), the M1 selective agonist AF‐102B (10 mg kg⁻¹ i.p.), and the nootropic drug piracetam (30 mg kg⁻¹ i.p.). These results demonstrated the ability of SM 21 to modulate memory functions and suggests that SM 21 could be useful in the treatment of cognitive deficits. Drug Dev. Res. 47:118–126, 1999. © 1999 Wiley‐Liss, Inc.     

Administration of midazolam in infancy does not affect learning and memory of adult mice

• 1 Midazolam is a common fast‐acting GABA_A receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long‐term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood.
• 2 An open‐field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open‐field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water‐maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age).
• 3 The results of open‐field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water‐maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long‐term effects on the learning and memory behaviours of adult mice compared with the saline control.
• 4 Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

     

Nociceptin/orphanin FQ and nocistatin on learning and memory impairment induced by scopolamine in mice.

1. Nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid receptor-like receptor 1 (ORL1) and involves in various functions in the central nervous system (CNS). On the other hand, nocistatin is recently isolated from the same precursor as nociceptin and blocks nociceptin-induced allodynia and hyperalgesia. 2. Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus, little is known regarding their role in learning and memory. 3. The present study was designed to investigate whether nociceptin/orphanin FQ and nocistatin could modulate impairment of learning and memory induced by scopolamine, a muscarinic cholinergic receptor antagonist, using spontaneous alternation of Y-maze and step-down type passive avoidance tasks in mice. 4. While nocistatin (0.5-5.0 nmol mouse-1, i.c.v.) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task, had no effect on spontaneous alternation or passive avoidance behaviours, a lower per cent alternation and shorter median step-down latency in the retention test were obtained in nociceptin (1.5 and/or 5.0 nmol mouse-1, i.c.v.)-treated normal mice. 5. Administration of nocistatin (1.5 and/or 5.0 nmol mouse-1, i.c.v.) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, attenuated the scopolamine-induced impairment of spontaneous alternation and passive avoidance behaviours. 6. These results indicated that nocistatin, a new biologically active peptide, ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that these peptides play opposite roles in learning and memory.     

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.     

Pharmacological evidence for the potential of Daucus carota in the management of cognitive dysfunctions

The present study was aimed at investigating the effects of Daucus carota seeds on cognitive functions, total serum cholesterol levels and brain cholinesterase activity in mice. The ethanolic extract of Daucus carota seeds (DCE) was administered orally in three doses (100, 200, 400 mg/kg) for seven successive days to different groups of young and aged mice. Elevated plus maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam-, scopolamine- and ageing-induced amnesia served as the interoceptive behavioral models. DCE (200, 400 mg/kg, p.o.) showed significant improvement in memory scores of young and aged mice. The extent of memory improvement evoked by DCE was 23% at the dose of 200 mg/kg and 35% at the dose of 400 mg/kg in young mice using elevated plus maze. Similarly, significant improvements in memory scores were observed using passive avoidance apparatus and aged mice. Furthermore, DCE reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.). Daucus carota extract (200, 400 mg/kg, p.o.) reduced significantly the brain acetylcholinesterase activity and cholesterol levels in young and aged mice. The extent of inhibition of brain cholinesterase activity evoked by DCE at the dose of 400 mg/kg was 22% in young and 19% in aged mice. There was a remarkable reduction in total cholesterol level as well, to the extent of 23% in young and 21% in aged animals with this dose of DCE. Therefore, DCE may prove to be a useful remedy for the management of cognitive dysfunctions on account of its multifarious beneficial effects such as, memory improving property, cholesterol lowering property and anticholinesterase activity.     

Differential effects of pimozide and SCH 23390 on acquisition of learning in mice

Our main purpose was to clarify the differences between the effects of dopamine D-1 (SCH 23390) and D-2 (pimozide) antagonists on memory acquisition in a water-finding and a one-trial passive avoidance task with ddY mice. In the water-finding task, pimozide (0.1 and 0.2 mg/kg i.p.) enhanced the acquisition of latent learning of mice although it suppressed exploratory behavior. In contrast, SCH 23390 (0.1 mg/kg i.p.) attenuated the acquisition of latent learning and suppressed exploratory behavior. In the passive avoidance task, pimozide (0.1 and 0.2 mg/kg i.p.) enhanced the acquisition of the passive avoidance response of mice. SCH 23390 (0.05 and 0.1 mg/kg i.p.) failed to enhance the acquisition of the passive avoidance response. These results could suggest that a moderate block of D-2 receptors enhances memory acquisition but blocking D-1 receptors affects it in an opposite way.     

The dopaminergic system plays a role in the effect of lithium on inhibitory avoidance memory in mice

The effects of dopaminergic drugs on the inhibitory avoidance memory affected by lithium were examined in the Naval Medical Research Institute (NMRI) mice using a single-trial step-down inhibitory (passive) avoidance task. The results showed that post-training administration of lithium (10 mg/kg, i.p.) decreased the step-down latency on the test day, which was fully or partly reversed by pre-test administration of the same dose of the drug; suggesting state-dependent learning induced by lithium. Our results also showed that pre-test (i.p.) administration of the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole by themselves and in combination with ineffective doses of lithium (0.3, 0.6 and 1.25 mg/kg) reversed the decrease of the step-down latency induced by post-training lithium. In contrast, pre-test administration of the dopamine D1 receptor antagonist SCH23390 (0.025, 0.05 and 0.1 mg/kg, i.p.) and the dopamine D2 receptor antagonist sulpiride (6.25 and 12.5 mg/kg, i.p.) alone or in combination with pre-test lithium (10 mg/kg), did not significantly alter the step-down latency on the test day, except for a higher dose of sulpiride (25 mg/kg) which by itself increased the step-down latency. Furthermore, pre-test administration of a lower dose of sulpiride (3 mg/kg) in combination with ineffective doses of lithium (03, 0.6 and 1.25 mg/kg) also reversed the decrease in the step-down latency induced by post-training lithium. In conclusion, the dopamine D1 and D2 receptor mechanism(s) may be involved, at least partly, in the effect of lithium on retrieval of the inhibitory avoidance memory influenced by the drug.