Intrahippocampal spermidine administration improves inhibitory avoidance performance in rats

Polyamines are polycations present at high concentrations in the mammalian brain. We investigated the effect of an intrahippocampal infusion of spermidine, a polyamine agonist, immediately post-training on the inhibitory avoidance learning paradigm in rats. Bilateral intrahippocampal microinjection of spermidine (0.02-20 nmol) caused an increase in test step-down latencies at low concentrations. Administration of arcaine (0.002-0.2 nmol), an antagonist of the N-methyl-D-aspartate (NMDA) receptor polyamine binding site, did not modify the test step-down latencies. In contrast, co-administration of arcaine and spermidine completely reversed the facilitatory effect of spermidine on the test step-down latencies. These results provide evidence that polyamines may be involved in learning and memory modulation.     

Intra-amygdala spermidine administration improves inhibitory avoidance performance in rats.

In the present study, we investigated the effect of immediate post-training bilateral infusion of spermidine, a polyamine agonist, into the amygdala on inhibitory avoidance learning of rats. Bilateral microinjection of spermidine (0.02--20 nmol) caused an increase in test step-down latencies at high concentrations. Administration of arcaine (0.002--0.2 nmol), an antagonist of the NMDA receptor polyamine binding site, decreased test step-down latencies. On the other hand, co-administration of arcaine and spermidine completely reversed the spermidine-induced increase of test step-down latencies. These results provide evidence that polyamines may be involved in learning and memory modulation in the amygdala.     

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.     

Nitric oxide in the nucleus accumbens is involved in retrieval of inhibitory avoidance memory by nicotine

In the present study, the possible effect of nitric oxide agents injected into the nucleus accumbens (NAc) in the presence or absence of nicotine on morphine state-dependent memory in adult male Wistar rats was investigated. As a model of memory, a step-through type inhibitory avoidance task was used. Post-training injection of morphine (4 and 6 mg/kg) dose dependently induced the impairment of memory retention. Administration of morphine (4 and 6 mg/kg) before retention induced state-dependent retrieval of the memory acquired under post-training morphine (6 mg/kg) influence. Injection of nicotine before retention (0.25 and 0.5 mg/kg) alone and nicotine (0.1, 0.25 and 0.5 mg/kg) plus an ineffective dose of morphine (2 mg/kg) reversed the post-training morphine-induced memory impairment. The amnesia elicited by morphine (6 mg/kg) was also prevented by pre-retention intra-NAc administration of a nitric oxide synthase (NOS) inhibitor, l-NAME (0.24 μg/rat, intra-NAc). Interestingly, an ineffective dose of nicotine (0.1 mg/kg) in combination with low doses of l-NAME (0.06 and 0.12 μg/rat, intra-NAc) synergistically improved memory performance impaired by morphine given after training. It is important to note that intra-NAc administration of l-NAME before retention impaired memory retrieval by itself. In contrast, pre-retention administration of l-arginine, a nitric oxide (NO) precursor (0.25 and 0.5 μg/rat, intra-NAc), which had no effect alone, prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of nucleus accumbens in the improving effect of nicotine on the morphine-induced amnesia and morphine state-dependent memory.     

Nitric oxide modulates state dependency induced by lithium in an inhibitory avoidance task in mice

The effect of intracerebroventricular (i.c.v.) injections of L-arginine, a nitric oxide (NO) precursor and L-NAME, an inhibitor of NO synthase, on retrieval of state-dependent memory induced by LiCl (lithium) was investigated. A one-trial step-down inhibitory avoidance task was used for memory assessment in adult male NMRI mice. Intraperitoneal administration of lithium (10 mg/kg), immediately after training, impaired memory on the test day. Pretest administration of different doses of lithium (5, 10 and 20 mg/kg) reversed the impairment of memory caused by posttraining lithium (10 mg/kg). In addition, pretest administration of L-arginine (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) or L-NAME (0.001, 0.01 and 0.1 microg/mouse, i.c.v.) also reversed amnesia induced by posttraining lithium. Furthermore, pretest coadministration with lithium of a dose of L-arginine (0.0001 microg/mouse, i.c.v.) or L-NAME (0.0001 microg/mouse, i.c.v.) that had no effects when administered alone, increased the effect of lithium on retrieval of inhibitory avoidance memory. The results suggest that NO may have a modulatory role on state-dependent retrieval of inhibitory avoidance memory induced by lithium.     

Possible involvement of mu-opioid receptors in effect of lithium on inhibitory avoidance response in mice

In the present study, effects of intracerebroventricular (i.c.v.) injections of mu-opioid receptor agonist and antagonist on lithium state-dependency were investigated. For memory assessment, a one-trial step-down inhibitory avoidance task was used in adult male NMRI mice. Intraperitoneal (i.p.) administration of lithium (10 mg/kg) after training impaired memory when retrieval was tested 24 h later. The memory impairment was reversed by pretest administration of the same dose of lithium, suggesting state-dependency induced by lithium. In addition, i.c.v. administration of both lithium (2 and 4 microg/mouse, i.c.v.) and morphine (3 and 6 microg/mouse, i.c.v.) before the test reversed memory impairment induced by post-training lithium (10 mg/kg, i.p.). On the other hand, pretest administration of naloxone (1 and 2 mg/kg) which had no effects alone on inhibitory avoidance response, prevented the improving effects of both morphine (3 microg/mouse, i.c.v.) and lithium (2 microg/mouse, i.c.v.) on memory retrieval. The results suggest that the mu-opioid receptors in the central nervous system may be involved in the retrieval of lithium state-dependent learning.     

Influence of ATP-sensitive potassium channels on lithium state-dependent memory of passive avoidance in mice

The effects of ATP-sensitive potassium channels on lithium induced state-dependent memory of passive avoidance task were examined in mice. The pre-training (5 mg/kg) and pre-test (5 mg/kg) injection of lithium impaired memory retrieval on the test day. Impairment of pre-training lithium was restored by pre-test administration of lithium (5 mg/kg), diazoxide, an ATP-sensitive potassium channel opener, (15, 30 and 60 mg/kg) or glibenclamide, an ATP-sensitive potassium channel blocker, (6 and 18 mg/kg). Pre-test administration of inactive doses of lithium (2.5 and 10 mg/kg) plus lower and inactive dose of glibenclamide (2 mg/kg) or diazoxide (1.5 mg/kg) also reversed the amnesia induced by pre-training lithium (5 mg/kg). In conclusion, the ATP-sensitive potassium channel opener or blocker not only mimicked the effect of lithium in state-dependent learning in the absence of lithium on the test day, but also potentiated the effect of low dose of lithium in restoration of memory. Therefore, ATP-sensitive potassium channels may have a modulatory influence on lithium response.     

Chronic administration of fluoxetine or venlafaxine induces memory deterioration in an inhibitory avoidance task in rats

Antidepressants inhibiting the reuptake of both serotonin and norepinephrine may exhibit efficacy superior to that of selective serotonin reuptake inhibitors (SSRIs). Since the clinical effects of antidepressants appear gradually following weeks of treatment, the present study was designed to investigate if there is a benefit to long‐term administration of the SSRI, fluoxetine, in comparison with venlafaxine, a 5‐HT/norepinephrine (5‐HT/NE) reuptake inhibitor (SNRI; both 20 mg/kg ip, once a day for 14 days) in a one‐trial step‐through passive avoidance task in rats. Locomotor activity was evaluated to assess the effects of the drugs on the motility of the animals. The comparison of training latencies versus test latencies showed inhibition of passive avoidance learning in fluoxetine‐ or venlafaxine‐treated rats (e.g., no significant difference between training and test latencies) in a step‐through test. There was no significant difference between fluoxetine‐ and venlafaxine‐induced reduction of latency in rats in this test. Drug Dev. Res. 67:456–461, 2006. © 2006 Wiley‐Liss, Inc.     

Facilitation of memory retrieval by pre-test morphine and its state dependency in the step-through type passive avoidance learning test in mice

Amnesia produced by scopolamine and cycloheximide were reversed by morphine given 30 min before the test trial (pre-test), and pre-test morphine also facilitated the memory retrieval in the animals administered naloxone during the training trial. Similarly, pre-test scopolamine partially reversed the scopolamine-induced amnesia, but not significantly; and pre-test cycloheximide failed to reverse the cycloheximide-induced amnesia. These results suggest that the facilitation of memory retrieval by pre-test morphine might be the direct action of morphine rather than a state dependent effect.     

Chronic administration of sulbutiamine improves long term memory formation in mice: possible cholinergic mediation

Thiamine deficiency in both man and animals is known to produce memory dysfunction and cognitive disorders which have been related to an impairment of cholinergic activity. The present experiment was aimed at testing whether, inversely, chronic administration of large doses of sulbutiamine would have a facilitative effect on memory and would induce changes in central cholinergic activity. Accordingly mice received 300 mg/kg of sulbutiamine daily for 10 days. They were then submitted to an appetitive operant level press conditioning test. When compared to control subjects, sulbutiamine treated mice learned the task at the same rate in a single session but showed greatly improved performance when tested 24 hr after partial acquisition of the same task. Parallel neurochemical investigations showed that the treatment induced a slight (+ 10%) but significant increase in hippocampal sodium-dependent high affinity choline uptake. The present findings and previous results suggest that sulbutiamine improves memory formation and that this behavioral effect could be mediated by an increase in hippocampal cholinergic activity.     

Cilostazol improves hippocampus-dependent long-term memory in mice

Rationale

Phosphodiesterases (PDEs) play an important role in the regulation of intracellular signaling mediated by cyclic adenosine monophosphate (cAMP). Recently, several PDE inhibitors were assessed for their possible cognitive enhancing properties. However, little is known about the effect of PDE3 inhibitors on memory function.

Objectives

We examined how the PDE3 inhibitor cilostazol affects C57BL/6 J mice as they perform various behavioral tasks. After behavioral assessment, brains of the mice were analyzed immunohistochemically to quantify the phosphorylation of cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway.

Results

Oral administration of cilostazol significantly enhanced recollection of the exact platform location in the Morris water maze probe test. Cilostazol also improved context-dependent long-term fear memory, without affecting short-term memory. No apparent effect was observed in cue-dependent fear memory. The results suggest that cilostazol selectively improves hippocampus-dependent long-term memory in these tasks. Cilostazol also significantly increased the number of phosphorylated-CREB-positive cells in hippocampal dentate gyrus.

Conclusions

These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity.     

CP55,940 attenuates spatial memory retrieval in mice

BackgroundCannabinoids constitute a varied group of lipophilic substances able to infiltrate the blood–brain barrier and influence neuronal processes. Clinical observations supported by experimental data have revealed that these compounds exert a deleterious effect on cognitive processes. The present study was carried out to determine the influence of a single systemic administration of CP55,940, a potent synthetic agonist of cannabinoid receptors, on spatial memory retrieval assessed in a Morris water maze.MethodsC57BL/6J male mice were submitted to three consecutive days of training to find a hidden platform in the water maze. CP55,940 was given intraperitoneally once, at doses of 0.025, 0.125 or 0.25 mg/kg on the fourth day, 30 min before testing memory retrieval, and in separate groups before testing psychomotor activity and anxiety level in a hole-board test.ResultsCP55,940 only at the highest dose of 0.25 mg/kg significantly altered all parameters used to assess spatial memory. It increased the latency in the first crossing of the former platform location (target area), decreased the number of target area crossings and shortened the time spent in the target quadrant. Moreover, CP55,940 at doses of 0.25 and 0.125 mg/kg attenuated motor and exploratory activity in hole-board test.ConclusionSince the attenuated psychomotor activity after a dose of 0.125 mg/kg did not interfere with memory retrieval, we assume that the impairment of spatial memory observed after the highest dose of CP55,940 (0.25 mg/kg) was exerted by its influence on cognitive processes, however, the impact on locomotion could not be excluded.     

Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline

The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline.     

Anseculin improves passive avoidance learning of aged mice.

Anseculin is a new coumarine derivative with promising cognition improving properties. We investigated its possible effects on passive avoidance learning in young and aged mice and the possible relationship to its alpha(1)-antagonistic properties.A single dose of anseculin did not affect long-term memory of young and aged mice. Moreover, in young mice, subchronic treatment with anseculin had no effect on cognitive functions, whereas aged, cognitively impaired mice clearly showed improved long-term memory with no effects on short-term memory.Further biochemical studies of aged control mice showed in comparison to the young mice a significant decrease of central alpha(1)-adrenoceptors density, but unchanged alpha(1)-adrenoceptor-mediated IP hydrolysis. Subchronic treatment with anseculin had no effect on the density of central alpha(1)-adrenoceptors in young adult mice and only a small although not significant effect on the density of cognitively-impaired aged mice. Furthermore, anseculin has no effects on alpha(1)-adrenoceptor-mediated IP hydrolysis.     

State dependent and/or direct memory retrieval by morphine in mice

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.     

Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task

Dehydroepiandrosterone (DHEA) exerts multiple effects in the rodent central nervous system (CNS), mediated through its nongenomic actions on several neurotransmitter systems, increasing neuronal excitability, modulating neuronal plasticity and presenting neuroprotective properties. It has been demonstrated that DHEA is a potent modulator of GABA(A), NMDA and Sigma receptors. In the present study, we investigated the effect of DHEA on (i) basal- and K(+)-stimulated l-[(3)H]glutamate release from synaptosomes (both in vitro and ex vivo), (ii) synaptosomal l-[(3)H]glutamate uptake (in vitro), and (iii) an inhibitory avoidance task (in vivo). The results indicated that DHEA in vitro increased glutamate release by 57%, and its intracerebroventricular infusion increased the basal-[(3)H]glutamate release by 15%. After 30 min of intraperitoneal administration, DHEA levels in the serum or CSF increased 33 and 21 times, respectively. Additionally, DHEA, intraperitoneally administrated 30 min before training, improved memory for inhibitory avoidance task. Concluding, DHEA could improve memory on an inhibitory avoidance task, perhaps due to its ability to physiologically strength the glutamatergic tonus by increasing glutamate release.     

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