Benzodiazepines alter acquisition and retention of an inhibitory avoidance response in mice

These experiments were performed to examine the effects of graded doses of diazepam, flurazepam, or lorazepam given to Swiss-Webster mice either 30 min prior to training or immediately after training in a one-trial inhibitory (passive) avoidance task. A 350 A footshock was administered following entry into a darkened compartment and retention was tested three days later. Doses of 10.0 mg/kg diazepam and 20.0 mg/kg lorazepam given before training significantly impaired acquisition, while 1.0 mg/kg flurazepam, given immediately after training, produced retrograde amnesia. These results indicate that benzodiazepines affect memory processes and that various drugs of the benzodiazepine family differentially affect acquisition and memory consolidation.     

Intrahippocampal infusion of ebselen impairs retention of an inhibitory avoidance task in rats

Ebselen is a seleno-compound used in the treatment of neurological disorders involving the glutamatergic system. Although ebselen is currently used in clinical trials, the physiological effects of this seleno-compound are poorly known. In this study, we investigated the effects of intrahippocampal infusion of ebselen (0.1-3 nmol) in rats submitted to an inhibitory avoidance task. Ebselen (1-3 nmol) infused after the training session impaired retention of inhibitory avoidance, tested 90 min or 24 h after the training session. Moreover, ebselen also impaired the retention when infused 30 min prior to training or 10 min prior to test sessions. In summary, ebselen impaired memory consolidation, acquisition and retrieval. This amnesic effect of ebselen could be related to oxidant activity at N-methyl-D-aspartate (NMDA) receptors. Our results indicate that more studies must be performed to investigate the mechanisms of this amnesic effect and whether ebselen has a cognition-impairing effect when administered chronically.     

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.     

Enhancement by secoverine and physostigmine of retention of passive avoidance response in mice

A one-trial passive avoidance test in the mouse, in which drugs were injected intraperitoneally immediately after the shocked acquisition trial, was used. The effects of enhancing central cholinergic transmission on retention of passive avoidance was investigated using secoverine, which blocks muscarinic autoreceptor-mediated inhibition of acetylcholine release, and using physostigmine, an acetylcholinesterase inhibitor. Secoverine (1.0–5.0 mg/kg) and physostigmine (0.1–0.4 mg/kg) were found to improve retention of the avoidance response measured 24 h after acquisition. These effects were augmented when the two drugs were given in combination. In contrast, atropine (5.0 mg/kg) tended to impair retention of passive avoidance and blocked the facilitatory effects of physostigmine. The results support the hypothesis of a novel approach to treatment of memory disorders based on blockade of muscarinic autoreceptors, to augment central cholinergic activity.     

Effects of endogenous morphine deprivation on memory retention of passive avoidance learning in mice

Memory and the processes of learning in mammals are well known to be affected by opioid agonists such as morphine, which has been proven to interfere and cause amnesia. The presence of endogenous morphine has been demonstrated in various tissues from mammals to invertebrates. In this study, we have investigated the effects caused by in-vivo immunodepletion of endogenous morphine on working memory under different experimental conditions. When mice were submitted to fasting, a stress condition, acquisition and consolidation of memory were significantly impaired compared to controls. This was demonstrated by a decrease in entry latency into the dark room in the retention session of the passive avoidance test. This effect was significantly reversed to baseline values when endogenous morphine was depleted from the extracellular brain space. These findings support a role for endogenous morphine in weakening memory processes under stress conditions.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

Facilitating effects of chlordiazepoxide on the performance of mice in an inhibitory avoidance task

Inhibitory avoidance behaviour of mice was studied by using an automated procedure. Animals were subjected to five 15-min sessions. Facilitation of the inhibitory avoidance behaviour was observed following the administration of chlordiazepoxide at doses which did not produce significant effects on spontaneous locomotor activity.     

Effects of post-training infusions of a mitogen-activated protein kinase kinase inhibitor into the hippocampus or entorhinal cortex on short- and long-term retention of inhibitory avoidance

We recently demonstrated the time-dependent impairment of long-term retention of a step-down inhibitory avoidance task in rats induced by post-training infusion of the specific MAPKK (mitogen-activated protein kinase kinase) inhibitor PD 098059 into the hippocampus (HIP), amygdala (AMY), entorhinal cortex (EC) and posterior parietal cortex (PPC). Here we investigate the role of the MAPK cascade in the HIP and the EC on both short- and long-term retention of inhibitory avoidance in rats, using three different doses of the MAPKK inhibitor PD 098059. Adult male Wistar rats were trained and tested in inhibitory avoidance and given an infusion of PD 098059 (0.5, 5.0 or 50.0 microM) at 0, 30, 90, 120, 180, 270 or 360 min after training. A retention test session was carried out at 90, 180 or 270 min after training (short-term memory, STM) and/ or 24 h after training (long-term memory, LTM). When infused into the HIP at 0 min, but not at 30, 90, 120 or 180 min after training, PD 098059 impaired STM. Intrahippocampal PD 098059 impaired LTM when infused at 180 min, but not at 0, 30, 90, 120 or 270 min after training. When infused into the EC, PD 098059 enhanced STM when given at 0 min after training and had no effect when given at 30, 90, 120 or 180 min after training. In this structure, PD 098059 impaired LTM when given at 180 or 270 min, but not at 30, 90, 120 or 360 min after training. All effects were dose-dependent. These findings indicate that the MAPK cascade in the HIP and EC is differentially involved in short- and long-term retention of inhibitory avoidance in rats.     

Effects of scopolamine on operant avoidance acquisition and retention

Summary Three experiments demonstraced that i.p. doses of 0.1 mg/kg scopolamine resulted in higher response rates and lower shock rates than normal during acquisition of lever pressing Sidman avoidance responses by rats. A fourth experiment confirmed previous reports that well-trained rats were not affected by such low doses of the drug. The scopolamine-induced acquisition performance changes were a function of baseline shock rate. Maintained savings of the higher response rates, but not of the lower shock rates, were, nevertheless, found in subsequent undrugged sessions after initial acquisition with scopolamine.A preliminary report of these studies was presented at the 1965 Meeting of the Federated American Societies for Experimental Biology.     

Effects of amiridin on ambulatory activity and the discrete shuttle avoidance response in mice

Behavioral effects of amiridin, [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta (b)-quinoline monohydrate hydrochloride] were investigated by observing ambulatory activity and the discrete shuttle avoidance response in mice. In addition, the in vivo effects of 4-amino-pyridine and physostigmine, which have inhibitory effects similar to those of amiridin on acetylcholine esterase in vitro, were compared with those of amiridin. Single doses of amiridin (0.3-10 mg/kg, s.c.) or 4-aminopyridine (0.3-3 mg/kg, s.c.) failed to produce marked changes in ambulatory activity, nor did these drugs exhibit any antagonistic effect on the ambulation-increasing effect of scopolamine (0.5 mg/kg, s.c.). However, single doses of physostigmine (0.03-0.1 mg/kg, s.c.) suppressed the ambulatory activity and antagonized with scopolamine. Amiridin (1-3 mg/kg, s.c. and 0.3-1 mg/kg, p.o.) and 4-aminopyridine (1-3 mg/kg, s.c.) administered to mice immediately before the training start of the discrete shuttle avoidance response facilitated the acquisition process. Furthermore, amiridin, but not 4-aminopyridine, elicited a good retention of the avoidance response after 24 hr. Although amiridin and 4-aminopyridine facilitated acquisition of the avoidance response, they failed to affect an avoidance response which had been established by sufficient previous training. On the other hand, physostigmine (0.1 mg/kg, s.c.) not only retarded acquisition of the avoidance response, but also suppressed established avoidance responses. The present results suggest that amiridin facilitates both acquisition and memory processes of mice in the discrete shuttle avoidance situation without eliciting a marked change in general activity level.     

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.     

The role of trazodone metabolism in its inhibitory action on avoidance response

To assess the role of trazodone metabolism in its depressant action on conditioned avoidance response we investigated whether in the mouse brain 3-chlorophenylpiperazine (CPP) is formed from trazodone, whether trazodone metabolism is affected by a drug metabolism inhibitor, proadifen, and how trazodone, CPP and their combinations act on avoidance responses in proadifen-pretreated mice. It was found that CPP is formed from trazodone in mice, that proadifen inhibits trazodone metabolism, and that the moderate and transient inhibitory effect of trazodone on avoidance responses is dramatically potentiated and prolonged in proadifen-pretreated mice. This effect, and inhibition of unconditioned escape response observed in mice receiving lower doses of trazodone after proadifen pretreatment, were counteracted by CPP. The results indicate that the inhibitory action of trazodone on avoidance response is caused by the parent compound, and that it is brief and moderate because of the rapid metabolism of the drug with formation of CPP which counteracts the depressant effect of the parent compound.     

Effect of an inhibitor of dopamine-beta-hydroxylase on the acquisition and retention of four different avoidance tasks in mice

The effect of [bis-(4-methyl-1-homopiperazinylthiocarbonyl)-disulfide] (FLA-63) (40 mg/kg, i.p.) on acquisition and retention in four different avoidance tasks was evaluated in mice. In all tasks animals were submitted to a training session on one day and to a retest session 24 h later. The drug or its vehicle were given either 2 h prior to training and/or retest (pretrial treatments) or immediately after the end of the training session (posttrial treatments). Two hours after injection, FLA-63 was found to lower brain norepinephrine (NE) levels by 51% without affecting those of dopamine (DA). Pretrial administration of the drug resulted in poorer performance of step-through and step-down passive avoidance as well as of step-up active avoidance in retest sessions. There was no apparent posttrial effect of the drug nor any effect on acquisition in these tasks. The drug was without influence on either acquisition or retention in an any-way passive avoidance task in which the response required from the animals was immobility. No evidence for statedependent learning was detected in any of the tasks. The data are consistent with the hypothesis of an involvement of NE either in memory processes or in events parallel and related to memory processes. The present results rule out, however, several such possible parallel events (effects on acquisition, motor disturbances, and effects on reactivity to shocks).Work carried out at the Department of Psychology, Carleton University, Ottawa, supported by grants from the National Research Council (A9845) and the Medical Research Council (MA6486) of Canada to H. Anisman.     

Effects of the novel compound NIK-247 on impairment of passive avoidance response in mice

The effects of NIK-247 [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate hydrochloride] were studied on a model involving various types of drug- and electroconvulsive shock (ECS)-induced amnesia. The step-down type passive avoidance task in mice was used for comparison of the effects with those of tacrine, a 4-aminopyridine derivative which has an antiamnesic action. NIK-247 administered pre- and post-training or pre-retention test (24 h after training) prevented the disruption of memory induced by cycloheximide administered immediately after training. In addition, NIK-247 protected from the amnesia induced by treatment with ECS, phencyclidine and picrotoxin immediately after training. Tacrine failed to protect from ECS- and PCP-induced amnesia at the doses effective on cycloheximide-induced amnesia. The results indicate that NIK-247 improves cognitive functions at different phases of the learning and memory processes such as acquisition, consolidation, and retrieval in drug- and ECS-induced amnesia. NIK-247 may produce its antiamnesic effects via the cholinergic and GABAergic neuronal systems.     

The effects of chlorpromazine on the expression of an acquired passive avoidance response in mice

Mice given one-trial passive avoidance training were examined 24 hours later for retention of the acquired response. Testing was carried out with subjects given either chlorpromazine or saline injections before the test session. Three chlorpromazine doses (0.5, 2.0, and 3.5 mg/kg) were used, and three injection times (10, 90, or 180 min before testing). Chlorpromazine was found to impair the expression of the acquired response, both by depressing its initial elicitation and also by apparently facilitating extinction. A second experiment confirmed that extinction rate was indeed increased. A clear dosage effect was observed but injection time was not important in determining the drug's effect. Further experiments were undertaken to clarify the interpretation of the drug's action; in particular, the possibility that the effects might have been caused by a dissociation of learning between the training and test situations was examined. It is suggested that the elevated extinction rates observed during testing when subjects were given chlorpromazine represents a temporary effect resulting from the reduced stimulus control of behaviour. Permanent effects of pre-test drug administration were noted on the initial expression of the learned response.     

Effects of oxotremorine on inhibitory avoidance behaviour in two inbred strains of mice: interaction with 5-methoxy-NN-dimethyltriptamine

The effects of the cholinergic muscarinic agonist, oxotremorine (0.005, 0.01, 0.02 and 0.04 mg/kg), the serotonergic agonist, 5-methoxy-NN-dimethyltriptamine (5-MeODMT) (0.5, 1 and 2 mg/kg), and their combination, were investigated in C57BL/6 and DBA/2 mice using a one-trial inhibitory avoidance task, drug treatment being given immediately after the acquisition trial. Post-trial administration of oxotremorine facilitated, while post-trial administration of 5-MeODMT inhibited memory retention of both strains in a dose-dependent fashion. The DBA/2 strain was more affected by oxotremorine than the C57BL/6 mice; no strain-dependent sensitivity to serotonergic agonist administration was observed. In both strains, the combination of oxotremorine plus 5-MeODMT inhibited the performance improvement shown by the administration of the cholinergic agonist alone. The facilitatory role of cholinergic stimulation on retention performance was confirmed and an inhibitory action of the serotonergic system on memory processes was suggested. Moreover, the present results support a functional interaction between cholinergic and serotonergic systems on memory consolidation.     

Passive avoidance retention in mice tolerant to the organophosphorus insecticide disulfoton

Male mice were administered the organophosphorus insecticide disulfoton (O,O-diethyl S-[2-(ethylthio)ethyl] phosphorodithioate) daily for 14 days at a dosage rate of 10 mg/kg/day. Signs of poisoning disappeared after 5 to 8 days of treatment indicating that the animals had developed tolerance to disulfoton toxicity. Acetylcholinesterase activity was inhibited 75 to 93% in hippocampus, cerebral cortex, striatum, and cerebellum of tolerant animals. Binding of the muscarinic cholinergic antagonist [³H]quinuclidinyl benzilate was significantly decreased in all these brain areas. The decrease was due to a decrease in the number of receptors (B max) without any change in the affinity constant K_d. Sodium-dependent high-affinity choline uptake was unchanged in the hippocampus of tolerant animals. When tested in a single trial passive avoidance task, mice tolerant to disulfoton did not show any difference from controls in 24-hr retention. These results indicate that the decreased number of muscarinic receptors in brain of disulfoton-tolerant animals does not affect their response latencies in a passive avoidance task.     

Effects of chlorpromazine on continuous avoidance behavior in mice

Previous reports have indicated that self-trained appetitive operant schedules of reinforcement can be acquired readily by mice using an apparatus which detects head movement responses. Using a similar apparatus, suitably modified, the utility of this methodology has been extended to an operant schedule of reinforcement in which behavior is maintained by an aversive shock stimulus. As previously demonsrated with various other CNS active drugs in the appetitive mouse procedures, the effects of chlorpromazine in the mouse continuous avoidance procedure described here were similar to those obtained in analogous standard rat procedures. These results increase the opportunities for experimenters to avail themselves of the advantages offered by the use of mice, rather than rats, in operant behavioral pharmacology.     

Effects of (-)3-PPP on acquisition and retention of a conditioned avoidance response in the rat

The administration of (-)3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) was found to partially, but significantly, suppress the acquisition (4–8 mg/kg IP) and performance (8–16 mg/kg IP) of a conditioned avoidance response (CAR) in male Sprague-Dawley rats. All statistically significant effects were observed within 2 h of injection. Furthermore, using a situation in which the CAR was dependent on a visual successive discrimination, it was shown that discriminative performance was unaffected, and that (-)3-PPP (12.5–25 mg/kg IP) but not (+)3-PPP, suppressed the CAR. When (-)3-PPP (6.25 mg/kg IP) was combined with haloperidol (0.1–0.4 mg/kg IP), additive effects on the CAR performance were observed. Considering these effects, and the doses of (-)3-PPP required to suppress the CAR performance, it is concluded that the effects obtained in the present experiments are primarily due to a blockade of postsynaptic DA receptors.     

Effects of scopolamine and D-amphetamine on one-way, shuttle and inhibitory avoidance: a diallel analysis in mice.

The effects of scopolamine (2.0 mg/kg) and d-amphetamine (3.0 mg/kg) on one-way, shuttle and inhibitory avoidance performance were evaluated in 3 strains of mice (A/J, DBA/2J and C57BL/6J) and their 6 reciprocal F1 hybrids. In the saline condition, intermediate inheritance was observed in the inhibitory task, complete dominance for superior avoidance in the one-way task, and hybrid superiority in the shuttle situation. Administration of d-amphetamine disrupted inhibitory performance in all strains. In the shuttle task no amphetamine effect was observed in C57BL/6J mice, while improvement was seen in A/J and DBA/2J mice, as well as in all the hybrid corsses. No drug effect was seen in the one-way task. As with d-amphetamine, scopolamine disrupged performance in the inhibitory task among the inbreds, but had negligible effects in the hybrids. In the shuttle task, only the A/J mice exhibited improved performance, while a small decline in response rate was seen in one-way avoidance. Results were interpreted in terms of tha role of scopolamine and d-amphetamine in modifying non-associative factors involved in avoidance, and the interaction between associative and non-associative factors in modulating avoidance response rate.