Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24 h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5 min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety.     

Strain-dependent involvement of D1 and D2 dopamine receptors in muscarinic cholinergic influences on memory storage

These experiments examined the interaction of muscarinic and dopaminergic systems in influencing memory for one-trial inhibitory avoidance training in mice of the C57BL/6 and DBA/2 strains. In both strains, immediate post-training systemic administration of the muscarinic cholinergic agonist oxotremorine enhanced retention and the cholinergic antagonist atropine impaired retention. No effects were seen with injections 2 h post-training. Furthermore, the drugs did not affect retention performance of animals that received no footshock on the training trial. These results confirm previous findings indicating that muscarinic cholinergic drugs affect memory by influencing memory consolidation. In C57 mice, pretreatment with selective D1 or D2 dopamine (DA) receptor agonists (SKF 38393 or LY 171555, respectively) in otherwise non-effective doses (5 and 0.25 mg/kg, respectively) potentiated the effects of oxotremorine (0.04 mg/kg). Furthermore, in C57 mice pretreatment with selective D1 or D2 receptor antagonists (SCH 23390 or (-)-sulpiride) in otherwise non-effective doses (0.025 and 6 mg/kg, respectively) blocked the memory enhancing effects of oxotremorine. The memory impairing effects of atropine (3 mg/kg) were blocked by the D1 and D2 selective agonists and potentiated by the selective D1 or D2 antagonists. In contrast, in DBA mice, the D1 and D2 selective agonists antagonised the memory enhancing effects of oxotremorine (0.02 mg/kg) and potentiated the effects of atropine (2 mg/kg). Furthermore, the D1 and D2 antagonists potentiated the effects of oxotremorine and antagonised those of atropine. These findings indicate that although muscarinic cholinergic influences on memory storage are comparable in mice of these two strains, the cholinergic-dopaminergic interactions are opposite in the two strains. These results have implications for hypotheses of cholinergic and dopaminergic regulation of memory storage.     

Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy

Memory function after olfactory bulbectomy (OBX) was examined in two tasks, namely, step-through passive avoidance task and elevated plus-maze task. OBX mice showed a significant impairment of learning and memory-related behavior on the 7th and 14th day, as measured by passive avoidance task but not elevated plus maze task. The impairment of learning and memory-related behavior on the 14th day was improved by administration of the cholinesterase inhibitor physostigmine (0.1 mg/kg, i.p.), the non-selective muscarinic agonist oxotremorine (0.1 mg/kg, i.p.) or the selective muscarinic M(1) agonist McN-A-343 (10 microg/mouse, i.c.v.). In contrast, administration of the nicotinic agonist lobeline (5-9.8 mg/kg, i.p.) or the selective muscarinic M(2) antagonist methoctramine (2.25-18 microg/mouse, i.c.v.) has no effect on the impairment of learning and memory-related behavior induced by OBX. In addition, we have demonstrated that the intensity of choline acetyltransferase (ChAT) fluorescence is significantly decreased in the cortex, hippocampus and amygdala on the 14th day after OBX. These results suggest that the impairment of learning and memory-related behavior induced by OBX may be caused by degeneration of cholinergic neurons and muscarinic M(1) receptors play an important role in the improvement process.     

Concurrent muscarinic and beta-adrenergic blockade in rats impairs place-learning in a water maze and retention of inhibitory avoidance

These experiments examined the effects of separate and concurrent muscarinic cholinergic and beta-adrenergic blockade on inhibitory (passive) avoidance performance and spatial learning in the Morris water maze. Pretraining systemic administration of either scopolamine (0.3 or 1.0 mg/kg) or propranolol (3.0 or 10.0 mg/kg) had no significant effect on one-day retention of step-through inhibitory avoidance training. Similarly, pretraining administration of either 0.3 mg/kg scopolamine or 10 mg/kg propranolol did not affect spatial learning in the Morris water maze. However, combined administration of scopolamine and 10.0 mg/kg of propranolol impaired performance on these tasks. These findings further support a role for interactions between norepinephrine and acetylcholine in the modulation of learning and memory and implicate the participation of beta-adrenergic mechanisms in this interaction. Because cholinergic and noradrenergic deterioration is found in aging and Alzheimer's disease, these results also have implications regarding the role of age-related noradrenergic and cholinergic dysfunction in cognitive decline.     

Are the effects of the antidepressants amitriptyline, maprotiline, and fluoxetine on inhibitory avoidance state-dependent?

State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 x 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.     

Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects and facilitates cognitive amelioration of rivastigmine

Rivastigmine is a potent acetyl- and butyrylcholinesterase inhibitor widely used for cognitive improvement in Alzheimer’s disease (AD) therapy. However, dose-limiting adverse effects restrict its tolerability and clinical outcomes. This study explored new combined therapy, in which peripheral cholinergic adverse effects and central cognitive amelioration of rivastigmine were differentiated by a peripheral cholinoceptor antagonist anisodamine. The results demonstrated that rivastigmine (0.75 and 2.0 mg/kg) could significantly reverse the scopolamine-induced cognitive deficit in mice through passive avoidance test. Nevertheless, a high dose of rivastigmine (3.25 mg/kg) would compromise cognitive amelioration and produce obvious adverse effects, including hypersalivation, intestinal hyperperistalsis and muscle cramp. Interestingly, concomitant administration of anisodamine (10 mg/kg) effectively counteracted both the muscarinergic and nicotinergic adverse effects, while facilitating cognitive amelioration of rivastigmine (3.25 mg/kg). These findings provide an insight into the feasibility of combined therapy with cholinesterase inhibitors and peripheral cholinoceptor antagonists for the treatment of AD.     

Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze

The elevated T-maze (ETM) is an animal model of anxiety-like behavior that assesses two different defensive behavioral tasks in the same animal—acquisition of inhibitory avoidance and latency to escape from an open and elevated arm. In rats, cute and chronic treatments with anxiolytic-like drugs impair avoidance acquisition while only chronic administration of panicolytic-like drugs impairs open arm withdrawal. To date, only the acute effects of anxiolytic/anxiogenic or panicolytic/panicogenic drugs have been tested in the mouse ETM and the results have partially corroborated those found in the rat ETM. This study investigated the effects of acute (a single intraperitoneal injection 30 min before testing) and chronic (daily i.p. injections for 15 consecutive days) treatment with imipramine or fluoxetine, non-selective and selective serotonin reuptake inhibitors, respectively, on inhibitory avoidance and escape tasks in the mouse ETM. Neither acute nor chronic treatment with imipramine (0, 1, 5 or 10 mg/kg, i.p.) significantly changed the behavioral profile of mice in the two ETM tasks. Interestingly, while acute fluoxetine (0, 5, 10, 20 or 40 mg/kg, i.p.) facilitated inhibitory avoidance and impaired escape latency, chronic treatment (0, 5, 20 or 40 mg/kg, i.p.) with this selective serotonin reuptake inhibitor (SSRI) produced an opposite effect, i.e., it impaired inhibitory avoidance acquisition and facilitated open arm withdrawal. Importantly, acute or chronic treatment with imipramine (except at the highest dose that increased locomotion when given acutely) or fluoxetine failed to alter general locomotor activity in mice as assessed in an ETM in which all arms were enclosed by lateral walls (eETM). These results suggest that inhibitory avoidance acquisition is a useful task for the evaluation of acute and chronic effects of SSRI treatment on anxiety in mice. However, as open arm latency was actually increased and reduced by acute and chronic fluoxetine, respectively, this does not seem to be a useful measure of escape from a proximal threat in this species.     

Role of state-dependency in memory impairment induced by acute administration of midazolam in mice

Although the memory deficits produced by pre-training benzodiazepines administration have been extensively demonstrated both in humans and in animal studies, there is considerable controversy about the involvement of the state-dependency phenomenon on benzodiazepines-induced anterograde amnesia. The present study aimed to characterize the role of state-dependency on memory deficits induced by the benzodiazepine midazolam (MID) in mice submitted to the plus-maze discriminative avoidance task (PM-DAT). This animal model concomitantly evaluates learning and retention of discriminative avoidance task, exploratory habituation as well as anxiety-like behavior and motor activity. Mice received 2mg/kg MID before training and/or before testing in the PM-DAT. Pre-training (but not pre-test) MID administration impaired the retention of the discriminative avoidance task, which was not counteracted by a subsequent pre-test administration of this drug, thus refuting the role of state-dependency. Conversely, the pre-training administration of MID also led to an impairment of the habituation of exploration in the PM-DAT (an animal model of non-associative memory). This habituation deficit was state-dependent since it was absent in pre-training plus pre-test MID treated mice. Concomitantly, MID pre-training administration induced anxiolytic effects and diminished the aversive effectiveness of the aversive stimuli of the task, leading to an impairment of the acquisition of the discriminative avoidance task. Our findings suggest that pre-training benzodiazepine administration can impair the retention of different types of memory by producing specific deleterious effects on learning or by inducing state-dependent memory deficits.     

Effects of neonatal clomipramine on cholinergic receptor sensitivity and passive avoidance behavior in adult rats

Summary The effects of neonatal treatment with clomipramine on the sensitivity of cholinergic receptor and passive avoidance behavior were studied to examine the activity of the central cholinergic system. Rat pups were treated twice daily from postnatal day 5 to 21 with clomipramine (15mg/kg, s.c.) and at 3 months of age the thermic responses to three different doses of oxotremorine were measured. One day following oxotremorine challenge study, the animals were subjected to passive avoidance training and retention was measured 24-hr later. Clomipramine treated animals showed an enhanced cholinomimetic — induced hypothermia and an increased latency in passive avoidance test. These findings may reflect an altered sensitivity of central cholinergic system in rats given clomipramine as neonates. The results were compared to other animal models of depression.     

Discrepancy between effects of milligram and nanogram doses of a COX-2 inhibitor (celecoxib) on morphine state-dependent memory of passive avoidance in mice

This experiment examined and compared the effects of pre-test administration of a selective COX-2 inhibitor (celecoxib), at the doses in the range of mg/kg and ng/kg on morphine state-dependent learning in step-down passive avoidance task in mice. Pre-training administration of 5mg/kg of morphine-impaired memory retrieval tested 24h later, which was restored by pre-test administration of the same dose of the drug. Pre-test administration of celecoxib (12.5, 25 and 50mg/kg), alone or in combination with morphine (1mg/kg) prevents morphine-induced memory impairment. Ultra-low doses (ULDs) of celecoxib (2, 10 and 50 ng/kg) produced no change in morphine-induced memory impairment. However, co-administration of nanogram doses of celecoxib with 5mg/kg of morphine in the test day prevented morphine-induced memory improvement, an action different from mg/kg doses. These findings implicate the involvement of COX-2 in memory retrieval and demonstrate that the effect of celecoxib ULD is different from that of mg/kg doses.     

Influence of acute and sub-chronic nicotine pretreatment on morphine state-dependent learning

In the present study, the effects of acute and sub-chronic pretreatment of nicotine on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pre-training administration of morphine (5mg/kg) decreased the learning of a one-trial passive avoidance task, which was reversed by pre-test administration of the same dose of morphine. Amnesia induced by pre-training morphine was also significantly reversed in nicotine (0.001, 0.01 and 0.1 mg/kg)-treated animals on the test day. Morphine induced amnesia was also reversed in animals which had previously received sub-chronic injections of nicotine, once daily for 3 days followed by 14 days of no drug treatment. The restoration of memory by pre-test morphine was also reduced in animals which had previously received once daily injections of atropine (0.25, 0.5 and 1 mg/kg, i.p.) for 3 days after 14 of being days drug free. In the animals, restoration of memory by sub-chronic nicotine administration, was also decreased by once daily administration of atropine (0.25, 0.5 and 1 mg/kg) 10 min prior to injection of nicotine (0.1 microg/kg/day, for 3 days) but not with SCH 23390; R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (0.01, 0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) during 3-days of treatment with nicotine. The results suggest that nicotine may induce sensitization which affects the impairment of memory formation via cholinergic but not dopaminergic systems.     

The cannabinoid CB1 receptor antagonist rimonabant dose-dependently inhibits memory recall in the passive avoidance task in domestic chicks (Gallus domesticus)

The effect of endocannabinoids on synaptic plasticity has been demonstrated in a variety of species and brain regions. Relatively little is known about the localization and significance of cannabinoid (CB) receptors in the avian brain. The objective of the present study was to investigate the effect of a specific CB₁ receptor antagonist upon the acquisition and consolidation of memory in young domestic chicks. One-day-old domestic chicks (Gallus domesticus) were trained and tested by the passive avoidance paradigm. Systemic (i.p.) administration of the CB₁ receptor antagonist rimonabant in a dose of 1 mg/kg 30 min before the training failed to affect learning, but a similar treatment 30 min before the recall (5.5 h after training) attenuated the retention in 60% of animals. In another set of animals, a dose of 0.01 mg/kg produced no significant impairment, whereas doses 0.1 mg/kg and 1.0 mg/kg resulted in significant attenuation in passive avoidance performance when tested 30 min prior to recall. The results are discussed in terms of a putative mediating role of CB receptors in the consolidation of memory.     

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Pre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.     

Brain-derived neurotrophic factor signaling plays a role in resilience to stress promoted by isoquinoline in defeated mice

Certain stressful life events have been associated with the onset of depression. This study aims to investigate if 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) is effective against social avoidance induced by social defeat stress model in mice. Furthermore, it was investigated the effects of FDPI in the mouse prefrontal cortical plasticity-related proteins and some parameters of toxicity. Adult Swiss mice were subjected to social defeat stress for 10 days. Two protocols with FDPI were carried out: 1- FDPI (25 mg/kg, intragastric) was administered to mice 24 h after the last social defeat stress episode; 2- FDPI (1–25 mg/kg, intragastric) was administered to mice once a day for 10 days concomitant with the social defeat stress. The mice performed social avoidance and locomotor tests. The prefrontal cortical protein contents of kinase B (Akt), extracellular signal-regulated kinase (ERK), cAMP-response element binding protein (CREB), pro-brain-derived neurotrophic factor (proBDNF), p75^NTR, neuronal nuclear protein (NeuN) and nuclear factor-κB (NF-κB) were determined in mice. A single administration of FDPI (25 mg/kg) partially protected against social avoidance induced by stress in mice. Repeated administration of FDPI (25 mg/kg) protected against social avoidance induced by stress in mice. Social defeat stress decreased the protein contents of p75^NTR, NeuN and the pERK/ERK ratio but increased those of proBDNF and the pCREB/CREB ratio, without changing that of NF-κB. Repeated administration of FDPI modulated signaling pathways altered by social defeat stress in mice. The present findings demonstrate that FDPI promoted resilience to stress in mice.     

Amygdala and dorsal hippocampus lesions block the effects of GABAergic drugs on memory storage

These experiments examined the effects of posttraining systemic administration of the GABAergic agonist muscimol and the GABAergic antagonist bicuculline on retention in mice with bilateral lesions of the amygdala, dorsal hippocampus or caudate nucleus. Unoperated male CD1 mice and mice with either sham lesions or electrolytically induced lesions of these 3 brain regions were trained in a one-trial inhibitory avoidance task and, immediately after training, received i.p. injections of either muscimol, (1.0, 2.0 or 3.0 mg/kg), bicuculline, (0.25, 0.5 or 1.0 mg/kg), or control solutions. Retention was tested 24 h after training. Lesions of the 3 brain regions produced comparable impairment of retention. In the unoperated controls and sham controls muscimol and bicuculline produced dose-dependent impairment and enhancement, respectively, of retention. The drug effects on retention were blocked by lesions of the amygdala and hippocampus, but were not blocked by lesions of the caudate nucleus. These findings are consistent with other recent evidence suggesting that the amygdala and hippocampus are involved in mediating posttraining neuromodulatory influences on memory storage.     

Amantadine antagonism of oxotremorine effects

Summary Administration of oxotremorine to mice produced centrally-mediated effects, such as catalepsy and tremor, and peripheral muscarinic actions, such as diarrhoea and lachrymation. Pretreatment with amantadine (25–200 mg/kg) prevented these oxotremorine-induced effects in mice. Catalepsy was most susceptible and tremor most resistant to the administration of amantadine. The possible mechanisms involved are discussed.Our results validate the use of the oxotremorine model in the search for novel antiparkinsonian drugs.     

Effect of ethanol on memory consolidation in mice: antagonism by the imidazobenzodiazepine Ro 15-4513 and decrement by familiarization with the environment

Three sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. In a first set of experiments the posttraining administration of ethanol (1 or 2 g/kg) impaired, while that of the imidazobenzodiazepine Ro 15-4513 (5 or 10, but not 2.5 mg/kg) improved the retention performance of the animals. In a second set of experiments a by itself ineffective dose of Ro 15-4513 (2.5 mg/kg) antagonized the effect of ethanol (1 and 2 kg/kg). These results are discussed on the basis of the interaction of these drugs with the GABAergic system. In a third set of experiments, in which the performances of mice familiarized with the apparatus were compared with those of non-familiarized mice, ethanol was less effective in impairing memory processes of the experienced subjects. These results are discussed in terms of attenuation of emotionality, resulting in impaired retention, following posttraining ethanol administration.     

Developmental differences of antinociceptive effects of oxotremorine in two inbred strains of mice

During development the C57BL/6 and DBA/2 mouse strains present morphological variations in cholinergic forebrain structures correlated with different behavioral reactivities to cholinergic agents. The present research assessed that these strain-dependent differences are also present in cholinergic-mediated analgesia. The administration of oxotremorine (0.0025, 0.005 and 0.01 mg/kg) to 30- and 60-day-old C57 and DBA mice resulted in dose- age- and strain-dependent analgesia. In particular oxotremorine is more effective in DBA/2 than in C57BL/6 mice and the latter strain showed a significant decrease of analgesic response in adulthood.     

Effects of concurrent manipulations of cholinergic and noradrenergic function on learning and retention in mice

Interactions between the neuromodulators acetylcholine and norepinephrine (NE) have been reported in both developmental neural plasticity and learning and memory. In a test of the generality of this phenomenon, we assessed the amnestic effects of the muscarinic antagonist scopolamine in normal and NE-depleted mice. Pretraining administration of scopolamine impaired 24-h retention of inhibitory (passive) avoidance training (at doses of 0.1, 0.3 and 1.0 mg/kg) and the acquisition of place-training in a water maze (at a dose of 1.0 mg/kg). NE depletion resulting from systemic administration of DSP-4 did not affect performance on these tasks and did not significantly alter the effects of scopolamine. NE depletion did, however, impair the retention of place learning when mice were retested 16 days after initial training; and this impairment in the retest was additive with one observed in mice originally trained under scopolamine. Normal acquisition but rapid forgetting has also been reported in aged rodents, who display deterioration of the noradrenergic system. Thus, observation of a similar pattern of performance consequent to experimental NE depletion suggests a role for noradrenergic dysfunction in age-related memory decline.     

Blockade of adenosine A(1) receptors prevents methylphenidate-induced impairment of object recognition task in adult mice

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A₁ receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A₁ receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5 mg/kg, i.p.), or an acute overdosage (50 mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5 mg/kg improved whereas 50 mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A₁ receptors immunocontent in the frontal cortex. The selective adenosine A₁ receptor antagonist, (DPCPX 1 mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A₁ receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.