The anxiolytic but not the sedative properties of tracazolate are reversed by the benzodiazepine receptor antagonist, Ro 15-1788

The effects of the novel putative anxiolytic, tracazolate, were investigated in the social interaction of anxiety and the holeboard. Tracazolate (5 mg/kg) had an anxiolytic action that was no longer observed at higher doses (10-25 mg/kg); in the holeboard tracazolate produced a dose-related (5-25 mg/kg) depression of exploratory head-dipping, locomotor activity and rearing. The effects of tracazolate in the social interaction test, but not in the holeboard, could be reversed by the benzodiazepine receptor antagonist, Ro 15-1788 (10 mg/kg).     

Evidence that the beta-carboline, ZK 91296, can reduce anxiety in animals at doses well below those causing sedation

The effects of ZK 91296, a beta-carboline derivative that potently displaces [3H]benzodiazepines from their CNS binding sites, were examined in two extensively validated animal tests of anxiety and in the holeboard in rats. In the social interaction test of anxiety. ZK 91296 (5 mg/kg) had an anxiolytic effect that was no longer apparent at a higher dose (15 mg/kg). In a test using exploratory activity on an elevated plus-maze as a measure of anxiety, the effects of ZK 91296 (5-15 mg/kg) did not reach significance. In the holeboard. ZK 91296 did not significantly reduce exploratory head-dipping, locomotor activity or rearing until doses of 40 mg/kg. These data suggest that ZK 91296 can reduce anxiety as assessed by animal tests at doses at which it does not induce sedation.     

Evidence that the β-carboline, ZK 91296, can reduce anxiety in animals at doses well below those causing sedation

The effects of ZK 91296, a β-carboline derivative that potently displaces [³H]benzodiazepines from their CNS binding sites, were examined in two extensively validated animal tests of anxiety and in the holeboard in rats. In the social interaction test of anxiety, ZK 91296 (5 mg/kg) had an anxiolytic effect that was no longer apparent at a higher dose (15 mg/kg). In a test using exploratory activity on an elevated plus-maze as a measure of anxiety, the effects of ZK 91296 (5–15 mg/kg) did not reach significance. In the holeboard, ZK 91296 did not significantly reduce exploratory head-dipping, locomotor activity or rearing until doses of 40 mg/kg. These data suggest that ZK 91296 can reduce anxiety as assessed by animal tests at doses at which it does not induce sedation.     

Effect of prenatal levetiracetam exposure on motor and cognitive functions of rat offspring

Purpose. We aimed to establish the physical, motor, and cognitive teratogenic effect of levetiracetam exposure throughout pregnancy in rats. Methods. Thirty-two Sprague–Dawley pregnant female rats were divided into four groups. Groups 1–3 were treated with different doses of levetiracetam (25, 50, 100 mg/kg/d) from gestational days 1 to 18. Group 4 (control group) was treated with the same volume of saline. The day of occurrence for pinna detachment, incisor eruption, eye opening, ear opening, and fur development were also monitored. Righting reflex, negative geotaxis, and grip response were evaluated as measures of the development of reflexes. The cognitive and motor developments were established with T-maze, holeboard, Y-maze, locomotor activity, and passive avoidance test. Results. Levetiracetam exposure at 25, 50 and 100 mg/kg/d doses did not affect the timing of physical landmark developments. The dose of 100 mg/kg/d resulted in a significant delay in reaction time of the surface righting reflex compared to the control group. Two higher dose groups (50 and 100 mg/kg/d) had delay in the appearance of negative geotaxis reflex compared to the control group. Both groups maternally exposed to 50 and 100 mg/kg/d had a lower percentage of grip strength response comparing to control group on the first day of testing. On the second test day, only pups prenatally exposed to 100 mg/kg/d levetiracetam persistently had a significantly lower percentage of response. We could not find a significant difference between groups in tests for the locomotor activity, memory, and learning (T- and Y-maze, passive avoidance test), and explorative behavior (holeboard tests). Conclusion. We showed that levetiracetam had only a transient impact on reflex maturation and no impact on physical and cognitive function in offspring of rats exposed to the drug during pregnancy. Levetiracetam may become a promising candidate for the treatment of epileptic women in pregnancy.     

Sex differences in baseline and drug-induced behavioural responses in classical behavioural tests

Behavioural pharmacology relies on animal models which are primarily validated using the male laboratory rat. Many researchers solely employ male animals in studies; this is primarily due to concerns about the impact of variations in the female estrous cycle on behavioural responses. The objective of the present study therefore was to examine whether sex has any effect in some commonly employed behavioural pharmacology tests. Male and female Sprague Dawley rats were examined in the following behavioural pharmacology tests: diazepam (DZP) effects on anxiolytic behaviour in the elevated plus maze (EPM); desipramine (DMI) effects on immobility time in the forced swim test (FST); amphetamine (AMP) and apomorphine (APO) effects on locomotor activity in the homecage monitoring apparatus (HCMA). Baseline investigations revealed that females were more active than males in all three tests. DZP increased open arm time and entries for males but not for females. Similarly, significant reduction in immobility time with DMI was found for males in the FST, with no effect observed in females. There was a significant effect of AMP dose on distance moved for both sexes; the peak locomotor stimulating effects were seen following 1–2 mg kg^− 1 AMP doses for males, while 0.5 mg kg^− 1 produced the greatest effect in females. APO impaired locomotor activity in both sexes. These results demonstrate that male and female rats respond differently to psychotropic drugs. The absence of female responses to the effects of DZP and DMI in the EPM and FST respectively was due to the high baseline activity levels seen with females; thus behavioural tests must be designed to account for sex differences in baseline behaviours to allow for unambiguous extrapolation of the results.     

Are benzodiazepines really anxiolytic? Evidence from a 3D maze spatial navigation task

The effects of diazepam and chlordiazepoxide were assessed in a 3D maze which is a modification of an 8-arm radial maze. Each arm of the maze is attached to a bridge radiating from a central platform. Animals exposed for the first time to the maze do not venture beyond the line that separate a bridge from an arm. The prime criteria set for an anxiolytic effect is whether mice would increase the frequency of entries onto arms and increase arm/bridge entries ratio. C57 mice readily cross the line on first exposure and make more than 8 arm visits onto arms on second exposure, while other strains (CD-1 and Balb/c) hold back and rarely cross the line on first exposure and require more sessions to make more than 8 arm entries. An anxiolytic drug is expected to encourage intermediate (CD-1) and high (Balb/c) anxiety mice to adventure onto the arms of the maze and make more visits to the arms to comparable levels seen with low anxiety c57 mice. In the present report, administration of different doses of diazepam (0.625, 1.25, 2.5 and 5 mg kg(-1) i.p.) and chlordiazepoxide (5, 10 and 15 mg kg(-1) i.p.) did not reduce anxiety in animals, with the lowest dose of diazepam increasing motor activity in Balb/c and increasing anxiety in c57 mice while the highest doses of both diazepam (2.5 and 5 mg kg(-1) i.p.) and chlordiazepoxide (15 mg kg(-1) i.p.) induced mild sedation. Our results raise some concerns about the methodological foundations in the current assessment of anxiety and anxiolytic compounds both in animal and human studies.     

Anxiolytic-like effects of ginseng in the elevated plus-maze model: comparison of red ginseng and sun ginseng

This study was performed to investigate the anxiolytic-like effects of red ginseng (RG, steamed raw ginseng at 98-100 degrees C) and sun ginseng (SG, heat-processed ginseng at higher temperature) in mice using the elevated plus-maze model. Furthermore, the anxiolytic-like effects of RG and SG were compared to a known active anxiolytic drug (diazepam). The RG butanol fraction (100 mg/kg) significantly increased the number of open arms entries and the time spent on the open arm (indicators of anxiolytic-like effects) compared with that of the saline group. However, lower doses of the SG total extract (50 mg/kg) and the SG butanol fraction (25 and 50 mg/kg) significantly increased the number of open arms entries and the time spent on the open arms. The RG total extract (100 mg/kg) and the SG total extract at a lower dose (25 mg/kg) did not increase the number of open arm entries or the time spent on the open arm. On the other hand, the RG butanol fraction (100 mg/kg), the SG total extract (50 mg/kg), and the SG butanol fraction (50 mg/kg) decreased locomotor activity in a manner similar to diazepam. These data indicate that ginseng has anxiolytic-like effects, and the anxiolytic potential of SG is stronger than that of RG in the elevated plus-maze model. Ginseng saponins have been suggested to play an important role in the anxiolytic effects of ginseng. We provide evidence that ginseng may be useful for the treatment of anxiety.     

Use of SHIRPA and discriminant analysis to characterise marked differences in the behavioural phenotype of six inbred mouse strains

Detailed characterisation of six inbred strains of mice commonly used in transgenic and knockout research was carried out using a battery of behavioural tests (SHIRPA) followed by discriminant analysis of the data. In the primary observation screen, DBA/2 mice were relatively irritable and vocalised during handling. C57BL/6 were hyperactive as measured by transfer arousal, arena activity and touch-escape tests. By contrast, C3H were markedly hypoactive, had significantly enhanced grip strength and were also significantly impaired on the visual placing task. In the elevated plus-maze, BALB/c mice showed the highest level of open arm entries and time spent in the open arms, indicating the lowest level of anxiety. There was a clear dissociation of strains on exploratory activity, as measured in the holeboard test and spontaneous locomotor activity (LMA). DBA/2 mice were hyperactive in LMA but demonstrated relatively low levels of holeboard exploration. None of the six strains learnt the water maze spatial learning task particularly well. C57BL/6 and 129/Sv demonstrated most ability and C3H showed no evidence of having acquired the task. The SHIRPA screening battery and discriminant analysis of the data have enabled us to determine the relevant contribution of a number of behavioural measurements to the marked differences in phenotype of mouse strains. These data confirm the importance of carrying out a comprehensive profile in order to accurately characterise the phenotype of gene-targeted and transgenic mice.     

An approach to evaluate the ability of rats to discriminate different levels of illumination in the plus maze test: effects of scopolamine

Previous research has shown that the visual system is important for rats to establish the arm preference in the elevated plus maze (EPM), an animal model of anxiety. This study aims at evaluating whether a gradient of illumination between the enclosed arms of the maze (E/E(DeltaLux)) could be a reliable approach to detect drugs-induced harmful effect on visual discrimination of rats. Four EPM configurations with different E/E(DeltaLux) (8, 41 and 85lx) were used to demonstrate that as E/E(DeltaLux) increases, rats avoid to explore the light enclosed arm, which characterizes the animal ability to discriminate the most illuminated area within the protected environment of the maze. The establishment of either 41 or 85 E/E(DeltaLux) failed to alter the traditional spatial-temporal variables in the EPM. In addition, systemic treatment with midazolam (MDZ; 1.0mgkg(-1), a classical anxiolytic) induced anxiolysis in rats tested in 41 and 85 E/E(DeltaLux) EPM, with no change in the visual discrimination, when evaluated by the level of light enclosed arm exploration. Systemic treatment with scopolamine (SCP; 1.0, 2.0 and 8.0mgkg(-1)), a drug endowed with harmful properties upon the visual system, did not change either the open arm avoidance or the visual discrimination at the low doses, but induced increased light enclosed arm (visual discrimination deficit) and open arm exploration (anxiolytic like effect) at a higher dose. We propose that the incorporation of an E/E(DeltaLux) in the EPM may reinforce the predict validity of the test since it enables to evaluate whether a visual discrimination deficit can be confounded with an anxiolytic-like effect, thus establishing a false positive detection.     

The NK1 receptor antagonist NKP608 lacks anxiolytic-like activity in Swiss-Webster mice exposed to the elevated plus-maze

The selective non-peptide NK(1) receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC(50) values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003-10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15 mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001-10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK(1) receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK(1) receptor antagonists to their potency at NK(1) receptors.     

Reduction of predator odor-induced anxiety in mice by the neurosteroid 3α-hydroxy-4-pregnen-20-one (3αHP)

The effects of the centrally produced allylic neurosteroid, 3α-hydroxy-4-pregnen-20-one (3αHP), on the responses of male mice to an aversive, anxiety-inducing, predator (cat) odor were examined in an odor preference test. Control untreated mice displayed an anxiogenic response to the cat odor, spending a minimal amount of time in a Y-maze in the vicinity of the cat odor. Intracerebroventricular (i.c.v.) administrations of 3αHP had an anxiolytic action, resulting in significant dose-related (0.01–1.0 μg) increases in the amount of time spent in the proximity of the cat odor. These anxiolytic effects of 3αHP were stereospecific, with the stereoisomer, 3β-hydroxy-4-pregnen-20-one (3βHP) having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the response to cat odor indicating that the anxiolytic actions of 3αHP were unlikely to be related to any analgesic effects. The effects of 3αHP were significantly reduced by peripheral administrations of the GABA_A antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results indicate that the allylic neurosteroid 3αHP has anxiolytic actions involving interactions with the GABA_A receptor.     

Perinatal administration of PCP alters adult behaviour in female Sprague-Dawley rats

Perinatal phencyclidine (PCP) treatment leads to neuronal damage and causes long-term behavioural alterations in rodents. This study examined the effects of perinatal PCP treatment on behaviour of adult rats in holeboard, elevated plus maze, social interaction and forced swim tests. PCP-treated rats displayed hyperactivity in the holeboard and forced swim tests. These persistent behavioural changes are relevant to the study of psychiatric disorders such as schizophrenia.     

N-arachidonoyl-serotonin in the basolateral amygdala increases anxiolytic behavior in the elevated plus maze

CB(1) receptors in the amygdala have been shown to mediate learned and unlearned anxiety states, however, the role of amygdalar TRPV1 receptors remains unclear. In the present study we investigated the potential anxiolytic action of intra-basolateral amygdala (BLA) infusion of N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the endocannabinoid-inactivating enzyme, fatty acid amide hydrolase (FAAH), and a TRPV1 antagonist. Varying doses of AA-5-HT (0-0.5 nmol) were administered into the BLA prior to elevated plus maze testing. AA-5-HT significantly increased both time spent and number of entries into the open arms. Next, to determine whether the anxiolytic effects were the result of blocking FAAH, TRPV1, or whether a combined action was required, rats were given intra-BLA infusions of either 0.25 nmol AA-5-HT, 1.0 nmol capsazepine (CZP, a TRPV1 antagonist), 0.01 μg URB597 (a selective FAAH inhibitor), or vehicle. Again, AA-5-HT increased the time spent in the open arms as well as the number of open arm entries. In contrast, CZP and URB597 did not reliably alter plus maze performance. We then investigated the effects of co-administration of CZP (1.0 or 10.0 nmol) and URB597 (0.01 or 0.1 μg). At lower doses, co-injections significantly increased both open arm entries as well as the time spent in the open arms, compared to vehicle or either compound alone. While co-administration of the higher doses had no significant effect when compared to either vehicle or CZP treatment, we did observe that open arm activity was elevated in rats receiving combined CZP-URB597 treatment compared to URB597 alone. Overall, our findings indicate that simultaneous FAAH activity and TRPV1 activation are important with respect to the expression of unconditioned fear as mediated within the BLA.     

Influence of spatial and temporal manipulations on the anxiolytic efficacy of chlordiazepoxide in mice previously exposed to the elevated plus-maze

It has been widely reported that the anxiolytic efficacy of benzodiazepines in the elevated plus-maze test is abolished in subjects (rats or mice) that have been given a single prior undrugged experience of the test apparatus. The present series of experiments was designed to further characterise the key experiential determinants of this intriguing phenomenon in Swiss Webster mice. Using a standard 5 min test duration for both trials, Experiment 1 confirmed the anxiolytic efficacy of chlordiazepoxide (CDP; 5-20 mg/kg) in mice naive to the plus-maze, but a virtual elimination of drug effects in animals that had been pre-exposed to the maze 24 h earlier. Experiments 2 and 3 demonstrated that, while extending the duration of initial exposure to 10 min did not prevent the loss of CDP (10 mg/kg) efficacy in a standard-duration second trial, increasing the duration of both trials reinstated an anxiolytic profile for the compound. Finally, although trial 1 confinement to an open arm did not compromise CDP efficacy when animals were subsequently allowed to freely explore the maze (Experiment 4), closed arm confinement during initial exposure abolished the drug's anxiolytic action upon retest (Experiment 5). In contrast to previous findings in rats, these data suggest that the experientially induced loss of benzodiazepine efficacy in the mouse plus-maze depends rather critically upon prior discovery and exploration of relatively safe areas of the maze (i.e. closed arms). Results are discussed in relation to the hypothesis that the absence of an anxiolytic response to benzodiazepines in plus-maze-experienced subjects reflects the acquisition of an open arm phobia during trial 1.     

Reproductive experience reduces the sedative, but not anxiolytic effects of diazepam

Benzodiazepines are frequently prescribed to women for both their anxiolytic and hypnotic effects. Previous studies in rodents have demonstrated reproductive experience, i.e. pregnancy and lactation, can alter sensitivity to certain drugs, such as morphine. The purpose of the present study was to determine whether reproductive experience alters sensitivity to the benzodiazepine, diazepam. Two groups of subjects were generated, a primparous group (pregnancy+21 days of lactation) and an age-matched, nulliparous group. All subjects were injected with diazepam (0.0, 0.5, 2.0 or 2.5 mg/kg) at least 6 weeks after primiparous females weaned their litters. Twenty minutes post-injection, subjects were place in an activity chamber and locomotor behavior was measured. Thirty minutes post-injection, subjects were tested on an automated elevated plus maze. In addition to behavioral testing, diazepam's effects on corticosterone levels were measured. Overall, diazepam's sedative effects on locomotor activity were significantly reduced in primiparous females when compared to nulliparous controls as determined both in the activity chamber and on the elevated plus maze. There was, however, no significant effect of reproductive experience on the anxiolytic effects of diazepam in the elevated plus maze. Finally, while diazepam increased corticosterone in both groups, primiparous females were less sensitive to the effects of the drug on corticosterone secretion. These results indicate that the effects of diazepam on locomotor activity and corticosterone secretion are attenuated following reproductive experience.     

Systemic Administration of Atipamezole, a Selective Antagonist of Alpha-2 Adrenoceptors, Facilitates Behavioural Activity but does not Influence Short-term or Long-term Memory in Trimethyltin-intoxicated and Control Rats

NIITTYKOSKI M., R. LAPPALAINEN, J. JOLKKONEN, A. HAAPALINNA, P. RIEKKINEN Sr and J. SIRVIÖ. Systemic administration of atipamezole, a selective antagonist of alpha-2 adrenoceptors, facilitates behavioural activity but does not influence short-term or long-term memory in trimethyltin-intoxicated and control rats. NEUROSCI BIOBEHAV REV 22(6) 735–750, 1998.—The present study used trimethyltin (TMT)-intoxicated rats as a model for the behavioural syndrome seen after neuronal damage to the limbic system. Behavioural assessments indicated increased locomotor activity and reduced number of groomings in an open-arena task in TMT-intoxicated (6.6 mg/kg as a free base) rats, as has been found previously. A novel finding was the severe deficit in swimming to a visible platform in the water maze task, with reduced swimming speed at the beginning of the training period. During the reacquisition phase of a radial arm maze task, TMT-intoxicated rats made more short-term and long-term memory errors, and their behavioural activity was increased in comparison with controls. The administration of atipamezole (300 μg/kg), a selective antagonist of ₂-adrenoceptors, enhanced locomotor activity compared to saline-treated rats, but these effects did not differ between the TMT group and their controls. Atipamezole did not enhance short-term or long-term memory in either TMT or control groups. Taken together, the present data indicate that TMT intoxication is a model for global dementia rather than for a specific loss of relational memory. Previous studies on the neurochemical effects of TMT and the alleviation or prevention of neurotoxicity of TMT are reviewed.     

Behavioural study of the D-galactose induced aging model in C57BL/6J mice

Rodent chronically injected with D-galactose (D-gal) has been used as an animal aging model for brain aging or anti-aging pharmacology research. However, the dosage of D-gal used to establish this model in mice has been reported in a wide range. To study the dose-dependent effect of D-gal on rodent behaviour, we investigated the learning and memory ability of C57BL/6J (C57) mice after 8-week subcutaneous injection of D-gal at different doses by Morris water maze (MWM) and object recognition test (ORT). In addition, locomotor activity test (LAT) was also performed to examine the neuromuscular function. In comparison of vehicle (0.9% saline)-treated mice, D-gal-treated mice at dose of high (200 mg/kg per day) and middle (100 mg/kg per day) doses showed significant longer latency to platform and less target quadrant search time and distance in MWM In ORT, D-gal at high and middle doses reduced the discrimination index (DI) of mice more significantly than low dose (50 mg/kg per day), although all three doses of D-gal reduced the DI of mice significantly. Furthermore, D-gal at high and middle doses significantly decreased locomotor activity of the mice in LAT. Throughout three tests, D-gal induced behavioural impairments in C57 mice at high and middle doses tended to be in the same degree. These results indicate that d-gal can induce the behavioural impairment of C57 mice in a dose-dependent manner from 50 to 100 mg/kg, higher dose than 100 mg/kg cannot further deteriorate its behavioural performance.     

U-69,593 microinjection in the infralimbic cortex reduces anxiety and enhances spontaneous alternation memory in mice

The present report investigated the contributions of the ventromedial prefrontal cortex to the control of spontaneous alternation/working memory and anxiety-related behaviour. In Experiment 1, we examined the effects of microinjections of the selective kappa(1) receptor agonist, U-69,593, in the infralimbic cortex (IL) of CD-1 mice on several ethologically-derived anxiety indices in the elevated plus-maze (EPM) and defensive/withdrawal (D/W) anxiety in the open field, as well as on memory in the EPM transfer-latency (T-L) test and implicit spontaneous alternation memory (SAP) in the Y-maze. In week 1, pretreatment with one injection of vehicle, 1, 10 or 25 nmol/1.0 microliter U-69,593 in the IL dose-dependently prolonged T-L and produced a dose-dependent anxiolytic behavioural profile in the first EPM trial. Following a 24-h delay, the same mice were given a drug-free second trial in the EPM tests of T-L memory and anxiety. Whereas T-L memory was not disturbed, small but detectable carry-over effects were observed in trial-2 EPM behaviour relative to vehicle-treated animals. In week 2, the same groups of mice were again pretreated with one injection of the same doses of U-69,593 in the IL and given a D/W test in an open field, followed immediately by an 8-min SAP trial in the Y-maze. The smallest U-69,593 dose was anxiolytic in the D/W test, and SAP/working memory was dose-dependently enhanced in the Y-maze. In Experiment 2, we evaluated whether 0.5 microliter volume microinjections would produce comparable behavioural and carry-over effects in the IL of three new groups of CD-1 mice, in the event that the 1.0 microl volume injections used in Experiment 1 diffused beyond the IL and therefore may have confounded some effects. Experiment 2 procedures were carried out in the same manner as in Experiment 1, except the animals were tested in reverse order. Thus in week 1, SAP memory was tested in the Y-maze followed by D/W anxiety in the open field for half of the animals in each group, and the other half was tested in reverse order. In week 2, T/L memory and anxiety were tested in the EPM in 2 trials as described in Experiment 1. Pretreatment with one injection of vehicle, 10 or 25 nmol/0.5 microliter U-69,593 in the IL reduced D/W anxiety and enhanced SAP memory regardless of testing order in week 1. In week 2, the same groups of mice were again pretreated with one injection of the same doses of U-69,593 in 0.5 microliter volumes in the IL and tested in the EPM. In a similar fashion to Experiment 1, U-69,593 dose-dependently prolonged T/L and produced an anxiolytic behavioural profile in the first EPM trial. Following a 24-h delay, T/L recall memory was again not significantly influenced, but a robust anxiolytic behavioural profile was observed in the second drug-free anxiety trial in the EPM relative to vehicle-treated animals. Results are discussed relative to a) injection volumes and testing order, b) the possible influence kappa receptors may exert on neurochemical responsivity to anxiety-provoking environments in the IL area of the mPFC, c) the possibility that kappa-mediated anxiolysis from the IL in CD-1 mice results from interactions with neurochemical systems involved in the blunting of incoming anxiety-provoking information, d) evidence that SAP memory may be an implicit subtype of working memory, and e) the possibility that IL implicit working memory processes may modulate the induction and expression of anxiety-related behaviour.     

Negative and positive effects of intracerebroventricular scopolamine on memory in mice undergoing passive avoidance and escape tests

The effects of intracerebroventricular administration of scopolamine on memory and learning in the conscious, freely moving mouse were evaluated using step-down passive avoidance and water maze tests. A new technique was used that allows convenient injection into the cerebral ventricles without disturbing the animal's behavior. No significant changes in locomotor activity were observed after low doses of scopolamine (0.1 and 1.0 μg). However, 10 μg produced an increase in locomotor activity, while 100 μg caused an initial decrease followed by an increase in activity. In the passive avoidance test, scopolamine significantly impaired memory acquisition at doses higher than 1.0 μg, consolidation at a dose of 100 μg, and retrieval at doses of 10 and 100 μg. In contrast, a dose of 0.1 μg significantly improved consolidation and retrieval. In the water maze with a bridge, scopolamine either impaired memory acquisition, consolidation, and retrieval, or had no significant effect in the dose range tested. These results suggest that there are differences in the process of memory formation in the passive avoidance and escape tests.