Interactions between angiotensin II and baclofen in shuttle-box and passive avoidance performance

In experiments on male rats, we established that angiotensin-II (AT II) at a dose of 0.1 micrograms injected intracerebroventricularly immediately after training improved memory when retention tests (active and passive avoidance) were given 24 hours later. Baclofen at doses of 2, 5 and 10 mg/kg injected intraperitoneally immediately after training also improved retention in both active and passive avoidance tasks. Baclofen at a dose of 20 mg/kg was without effect on active avoidance performance. Combination of AT II and baclofen (2, 5 and 10 mg/kg) facilitated memory in active avoidance as compared to controls, but impaired retention as compared to the AT II-treated group. The impairment of the AT II-improved retention was stronger when the dose of baclofen in the combination was 20 ng/kg. Combination of AT II and baclofen (10 mg/kg) did not impair retention in passive avoidance. These data favor the view that GABA receptors may interfere with the AT II effects on memory consolidation or retention and that interactions of GABA (GABAA and GABAB) receptors with AT II receptors are of importance for memory processes.     

Interleukin-6 involvement in antidepressant action of Hypericum perforatum

Hypericum, a plant widely used as antidepressant has been shown to interact with the immune system. We studied the effects of the administration of the Hypericum perforatum extract Ph-50, a Hypericum extract, standardized to flavonoids (50%) and containing 0.3% of hypericin and 4.5% of hyperforin in a forced swimming test and tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) diencephalic content using a high performance liquid chromatography method in male interleukin-6 (IL-6) knock-out (IL-6(-/-)) and wild type (IL-6(+/+)) mice. Hypericum extract (Ph-50; 500 mg/kg) oral acute administration reduced the immobility time of wild type, but not of knockout mice. Tryptophan content was not modified by Hypericum in all the animal groups. Serotonin and 5-HIAA diencephalic content was increased by Hypericum in both wild type and knockout mice. However, the increase observed in the wild type was greater than in knockout mice. These data indicate that IL-6 could be necessary to the antidepressant action of Hypericum, and that this cytokine (probably) mediates the effects of Hypericum through activation of the serotonin system.     

Scopolamine blocks the effects of swim stress on memory retrieval in rats

Summary This study examined whether application of swim stress improved retrieval of a passive avoidance memory and if pretreatment with the anticho-linergic agent, scopolamine, blocked this effect on memory retrieval. Animals initially given a passive avoidance training session were subjected to either a two or four swim stress sessions (15 min each) with or without prior treatment of scopolamine (0.05 or 0.1 mg/kg). The retrieval performance in passive avoidance test and motor activity was assessed 24 hr after the last swim stress session. In an independent control experiment, the passive avoidance training and test were conducted respectively, 24 and 72 hr after the last of four swim stress sessions with or without prior injection of scopolamine (0.1 mg/kg). The results showed an enhanced performance for the passive avoidance task in rats subjected to four swim stress sessions in both experiments and scopolamine given 30 min prior to each stress session diminished this performance of animals in the passive avoidance test. Two swim stress sessions with or without scopolamine treatment caused no significant effects on the retrieval performance. Also, no significant difference was observed among the groups in motor activity following any of the stress treatments in the open field test. These results, thus suggested for the first time, a relationship among swim stress, cholinergic activity and avoidance memory processes.     

Pyroglutamic acid improves learning and memory capacities in old rats

The effects of the arginine salt of pyroglutamic acid (2-oxo-pyrrolidone carboxylic acid, PCA) on learning and memory capacities of old rats were studied in a subchronic treatment schedule (i.p. injection of 0.1 and 1 g/kg/day for 15 days). The acquisition and extinction of active avoidance behaviour were studied in a pole-jumping test situation. The retention of passive avoidance response was examined in a step-through passive avoidance task. PCA facilitated the rate of acquisition of pole-jumping response, and inhibited the extinction of the response. The dose of 1 g/kg was more potent than 0.1 g/kg in this respect. Also in the passive avoidance task, the treatment with PCA was followed by an improvement of avoidance retention. These results indicate that PCA is a behaviourally active compound in that it improves learning and memory capacities in old rat.     

Influence of morphine- or apomorphine-induced sensitization on histamine state-dependent learning in the step-down passive avoidance test

Effects of morphine- or apomorphine-induced sensitization on histamine state-dependent memory of passive avoidance task were examined in mice. Pre-training intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) decreased the learning of a one-trial passive avoidance task. Pre-test administration of histamine (10 and 20 microg/mouse) reversed amnesia induced by pre-training of histamine, with maximum response at 20 microg/mouse. Pre-training histamine-induced amnesia was also reversed in morphine- or apomorphine-sensitized mice that had previously received once daily injections of morphine (20 and 30 mg/kg) or apomorphine (0.5 and 1 mg/kg) for 3 days. The reversion of histamine-induced amnesia in morphine-sensitized mice was decreased by once daily administration of naloxone (0.5 and 1 mg/kg), SCH 23390 (0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) prior to injection of morphine (30 mg/kg/day, 3 days). Furthermore, once daily administration of sulpiride (50 and 100 mg/kg) but not SCH 23390 (0.01, 0.05 and 0.1 mg/kg) prior to apomorphine (1 mg/kg, for 3 days) decreased the reversion of pre-training histamine-induced amnesia by apomorphine. The results suggest that apomorphine or morphine sensitization affects the impairment of memory induced by histamine and thus it is postulated that opioid and dopamine receptors may play an important role in this effect.     

Modulation of ion channels in rat neurons by the constituents of Hypericum perforatum

Despite almost forty years of widespread use of antidepressant drugs, their mode of action is still unknown. Hyperforin, a phloroglucinol derivative, is a major pharmacologically and therapeutically active constituent of Hypericum perforatum extract that is widely used as an herbal antidepressant drug. However, the mechanism or mechanisms of action of these naturally abundant, non-toxic extracts remain unclear. Enzymatically isolated patch-clamped rat central and peripheral neurons exposed to rapid changes in the composition of external medium (concentration clamp) were used in our experiments to investigate the modulation of the various voltage- and ligand-gated channels by hyperforin, as well as by other constituents of Hypericum perforatum. At nanomolar concentrations, hyperforin induced significant inhibition of various ion channels. In the case of P-type Ca2+ channels, we established that hyperforin acts via interaction with calmodulin or through calmodulin-activated pathways involving at least one second messenger. The results presented here indicate that multiple mechanisms and extract constituents may be involved in the antidepressant action of Hypericum extracts, and that they could also possess neuroprotective and analgesic effects.     

Analysis of the avoidance learning deficit induced by the serotonin releasing compound p-chloroamphetamine

The effects of the serotonin-releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) on avoidance acquisition, retention and memory retrieval were examined in male Sprague-Dawley rats using a one-way active avoidance and a one-trial passive avoidance task. The drug was injected IP prior to training, following acquisition and prior to the retention test 24 hr after training using a state-dependent design. In the normal context situation pretraining administration of PCA markedly impaired active avoidance acquisition, but PCA-treated rats did not differ from controls in their retention performance when tested 24 hr after training. In the dark/light box test pretraining administration of PCA caused a dose-dependent impairment of both active and passive avoidance retention which could not be explained in terms of changes in locomotor activity or behavioural disinhibition at the time of testing or state-dependent retention. Post-training administration of PCA failed to affect avoidance retention in both tasks. The drug was found to impair memory retrieval in a dose- and time-dependent fashion in the one-way active but not in the passive avoidance test. Pretraining administration of PCA produced a progressive loss of passive and active avoidance performance at increasingly longer retention intervals. The present results suggest that serotonin has dual effects on processes underlying learning and memory involving effects on both associative and non-associative learning processes in the rat. The time-dependent loss of memory retention following 5-HT release indicates that serotonin has a role in the way information is processed in the brain.     

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.     

Serotonin, norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum

Hypericum perforatum is considered an effective alternative to the synthetic antidepressants in the treatment of mild-to-moderate depression. Recently, we showed that the effects on neurotransmitter contents in different brain regions of laboratory animals are more evident after administration of hypericum extracts containing a higher concentration of flavonoids, thus suggesting that these compounds are important in the antidepressant action of hypericum perforatum. We studied the effects of Ph-50, a hypericum extract standardized to flavonoids (50%) and containing 0.3% hypericin and 4.5% hyperforin on brain serotonin content, norepinephrine and dopamine by a high-performance liquid chromatography method in discrete brain areas (cortex, diencephalon and brainstem) in male Sprague-Dawley rats. Moreover, we evaluated the effects of Ph-50 alone or in association with sulpiride (a dopamine receptor antagonist), metergoline (a serotonin receptor antagonist) and 6-hydroxydopamine (6-OH-DA, destroying norepinephrine-containing neurons) using a forced-swimming test in the rat. Hypericum extract (Ph-50; 250-500 mg/kg) with acute oral administration enhanced serotonin, norepinephrine and dopamine content in the brain and reduced the immobility time of rats in the forced-swimming test. Sulpiride, metergoline and 6-OH-DA significantly increased the period of immobility in the forced-swimming test for the rats receiving hypericum extract (Ph-50). The results indicate that the neurotransmitters studied could be involved in the anti-immobility effects of hypericum, and suggest that its antidepressant action is probably mediated by serotonergic, noradrenergic and dopaminergic system activation.     

Effects of Hypericum perforatum (St. John's wort) on passive avoidance in the rat: evaluation of potential neurochemical mechanisms underlying its antidepressant activity

Along with traditional pharmacotherapies, extracts of Hypericum perforatum L. (St. John's wort) are used in the treatment of mild to moderately severe depression. Hypericum is a nonspecific inhibitor of the neuronal uptake of monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA) as well as GABA and glutamate. Hypericum extracts have been shown to be active in several different "animal models for antidepressant drugs". As one of a large number of chemical constituents, the phoroglucinol derivative hyperforin might be an important "antidepressant component" of hypericum. However, the exact role of neurochemical mechanisms underlying in vivo actions of hypericum and hyperforin are not well defined. In the present study, we compared the effects of hypericum, hyperforin and hyperforin-free hypericum and the three conventional antidepressants paroxetine, imipramine and desipramine using the passive avoidance (PA) task in the rat. The 5-HT-releasing compound p-chloroamphetamine (PCA), which operates through the 5-HT neuronal transporter, was used to reveal the potential in vivo effects on 5-HT uptake mechanisms. To examine the ability of the test-compounds to enhance noradrenaline (NA) transmission in vivo, subeffective doses of scopolamine were used. Taken together, our results suggest that (1) hypericum given at high doses can probably affect the neuronal 5-HT uptake mechanisms in a manner more reminiscent of TCAs than SSRIs; (2) similar to TCAs and SSRIs, hypericum and hyperforin are active in the scopolamine test. Hyperforin appears to play a major role in the action of hypericum in this model. Both 5-HT and NA might concomitantly contribute to the effects of different antidepressants in the "low-dose scopolamine" model; (3) hypericum might enhance both 5-HT and NA transmission in forebrain limbic brain circuits important for mood control, which could underly its antidepressant effects. However, the relative contribution of different constituents and exact mechanisms of action require further evaluation.     

In vivo neurotransmitter release in the locus coeruleus--effects of hyperforin, inescapable shock and fear

Hyperforin, the main antidepressant constituent of Hypericum perforatum, influences the extracellular concentrations of transmitters in vitro and in vivo. In vivo experiments have shown that hyperforin enhances the extracellular concentrations of dopamine, norepinephrine, serotonin and glutamate in the locus coeruleus. Hyperforin-free Hypericum extract also elevates the extracellular concentrations of dopamine and norepinephrine in the locus coeruleus, but, in contrast to hyperforin, the extracellular concentration of serotonin is diminished. The differing profiles of hyperforin and hyperforin-free Hypericum extract on the extracellular transmitter concentrations point to the presence of an additional biologically active compound in Hypericum perforatum. Inescapable shock increases the release of monoamines and several amino acids, as well as motility, blood pressure and heart rate. Conditioned fear, similar to hyperforin-free Hypericum extract, decreases the release of serotonin in the locus coeruleus. Conditioned fear also leads to tachycardia. The latter finding shows that telemetric heart rate recording is a good index for conditioned fear. In vivo findings confirm the idea that the anti-depressive properties of Hypericum extract and hyperforin result from increases in extracellular neurotransmitter concentrations. Since hyperforin-free extract, like conditioned fear, reduces the extracellular concentration of serotonin, hyperforin may be more beneficial than Hypericum extract in the treatment of depressive disorders.     

Effects of cholinergic drugs on learning impairment in ventral globus pallidus-lesioned rats

The excitotoxin kainic acid (10 nmol/microliter) was used to produce bilateral lesions in the nucleus basalis magnocellularis (NBM) of rats which provides extensive cholinergic innervation to the cerebral cortex. The behavioral effects of physostigmine, THA (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and NIK-247 (9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline monohydrate hydrochloride) were investigated by observing locomotor activity, shock sensitivity and passive avoidance response in the NBM-lesioned rats. Evaluation of locomotor activity and shock sensitivity in the experimental animals did not reveal any sensorimotor disturbances caused by the lesions. Oral administration of 1 and 2 mg/kg physostigmine reduced the locomotor activity in the NBM-lesioned rats, while physostigmine (0.5 mg/kg), THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) had no effect on locomotor activity. Compared with the sham-operated controls, the NBM-lesioned rats exhibited a significantly lesser deficit in the retention of the passive avoidance response. THA (1 or 3 mg/kg) and NIK-247 (1 or 3 mg/kg) elicited good retention of the passive avoidance response. Rats with NBM lesions showed impaired acquisition of a passive avoidance response when trained repeatedly at 24-h intervals. Also, when post-training NBM lesions were induced, there was rapid extinction of the acquired passive avoidance response. THA or NIK-247 administered at doses of 3 mg/kg significantly increased response latencies of post-trained NBM-lesioned rats. THA or NIK-247 administered once a day in doses of 1 or 3 mg/kg p.o. produced a very significant increase of acetylcholine in the cerebral cortex of NBM-lesioned rats after the 21st administration. These finding suggest that THA and NIK-247 exert an ameliorating effect on memory disturbance induced by NBM lesions in rats.     

Acute and chronic actions of a dry methanolic extract of Hypericum perforatum and a hyperforin-rich extract on dopaminergic and serotonergic neurones in rat nucleus accumbens

Dry hydroalcoholic extract of Hypericum perforatum L. is effective in the treatment of mild-to-moderate depression. Neither the mechanism of action nor the component or components of the extract responsible are known to date. In several in vitro and ex vivo models, the extract and hyperforin, one of its active components, cause changes similar to those of tricyclic antidepressants. Little is known about effects on a complex neuronal system relevant to antidepressant actions such as the mesolimbic system in the brain. In animal models of depression, the levels of dopamine were reduced in the nucleus accumbens, which is an important part of the mesolimbic system. These and other deficits were compensated by imipramine. We investigated the actions of the methanolic Hypericum extract LI 160 and a hyperforin-rich research extract in the shell region of the nucleus accumbens under in vivo conditions after acute administration, and after application repeated fourteen times. Both extracts induced an increase of dopamine (DA) and 5-hydroxytryptamine (5-HT) levels measured by in vivo microdialysis. The dose-response curve followed an inverse U-shape. Repeated application caused a rapid tolerance of DA but not of 5-HT neurones. Similar changes were observed after acute and repeated applications of imipramine. Several lines of evidence have suggested other active components in the Hypericum extract. The potency of hyperforin surpassed that of imipramine in the acute release of both DA and 5-HT by the nucleus accumbens. The effect of hyperforin correlated well with the inhibiting potency on high-affinity DA and 5-HT uptake. The missing effect of relatively high doses on DA and 5-HT levels as found in dose-response experiments may be explained by self-inhibition caused by the activation of autosomal receptors and by the inhibition by GABA. The inhibition of neuronal GABA transport occurs at somewhat higher concentrations of hyperforin. In conclusion, the findings demonstrate an imipramine-like effect of methanolic Hypericum extract LI 160 and of hyperforin on mesolimbic, dopaminergic and serotonergic neurones in acute and chronic experiments, which probably contributes to the antidepressant action of the medication. The methanolic Hypericum extract contains active compounds other than hyperforin.     

Alpha-2 agonist-induced memory impairment is mediated by the alpha-2A-adrenoceptor subtype

The activation of alpha2-adrenoceptors has been reported to impair memory functions in both rats and humans. The alpha2-adrenoceptor subtype responsible for this detrimental effect is still unknown. The effect of the alpha2-agonists clonidine and guanabenz on memory processes, in dependence to the time of administration, was evaluated in the mouse passive avoidance test. Clonidine (0.02-0.2 mg kg(-1) i.p.) and guanabenz (0.1-0.3 mg kg(-1) i.p.) induced amnesia in a dose-dependent manner. From time-course experiments emerged that the impairment of memory function was detectable only when clonidine and guanabenz were administered 60 min before or immediately after the training test, respectively. This detrimental effect was prevented by pretreatment with the alpha2-antagonist yohimbine (1-3 mg kg(-1) i.p.) and by the alpha2A-antagonist BRL-44408 (0.3-1 mg kg(-1) i.p.). By contrast, the alpha(2B,C) antagonists ARC-239 (10 mg kg(-1) i.p.) and prazosin (1 mg kg(-1) i.p.) did not revert the amnesia induced by both clonidine and guanabenz. At the highest effective doses, clonidine and guanabenz were devoid of behavioral side-effects as well as maintained unaltered the motor coordination, as revealed by the rota-rod test. Furthermore, none of the compounds used modified the spontaneous motility as indicated by the Animex apparatus. These results indicate that clonidine and guanabenz impaired memory processes in a mouse passive avoidance paradigm through the selective activation of the alpha2A-adrenoceptor subtype.     

Genetically dystrophic mdx/mdx mice exhibit decreased response to nicotine in passive avoidance

mdx mice are considered as a genetic homologous of human Duchenne muscular dystrophy. Recent evidence demonstrates that in mouse sympathetic ganglion dystrophin is involved in the stabilization of nicotinic acetylcholine receptor clusters. The purpose of this study was to verify possible effects of dystrophin alterations at the central level. This was assessed by evaluating the response to nicotine administration in mdx and wild-type mice. Thus the effects of post-training nicotine administrations (0.1, 0.25 and 0.5 mg/kg) were tested in mice subjected to a passive avoidance memory task, that measures the ability of mice to remember on test day a shock received 24 h before. Nicotine enhanced memory in wild-type as well as in mdx mice. However, the doses needed to increase memory in mdx were higher than in wild-type. These results are discussed in terms of possible functional changes in central nicotinic acetylcholine receptor in mdx mice.     

Learning and memory effects of neonatal methamphetamine exposure in rats: Role of reactive oxygen species and age at assessment

In utero methamphetamine (MA) exposure leads to a range of adverse effects, such as decreased attention, reduced working‐memory capability, behavioral dysregulation, and spatial memory impairments in exposed children. In the current experiment, preweaning Sprague‐Dawley rats—as a model of third trimester human exposure—were administered the spin trapping agent, N‐tert‐butyl‐α‐phenylnitrone (PBN), daily prior to MA. Rats were given 0 (SAL) or 40 mg/kg PBN prior to each MA dose (10 mg/kg, 4× per day) from postnatal day (P) 6–15. Littermates underwent Cincinnati water maze, Morris water maze, and radial water maze assessment beginning on P30 (males) or P60 (females). Males were also tested for conditioned contextual and cued freezing, while females were trained in passive avoidance. Findings show that, regardless of age/sex, neonatal MA induced deficits in all tests, except passive avoidance. PBN did not ameliorate these effects, but had a few minor effects. Taken together, MA induced learning deficits emerge early and persist, but the mechanism remains unknown.     

Effects of oral administration of the competitive N-methyl-D-aspartate antagonist, CGP 40116, on passive avoidance, spatial learning, and neuromotor abilities in mice

The effects were investigated of the potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 40116[D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] on the performance of mice in water maze and passive avoidance tasks, and in wire suspension, rotarod, and cage activity tests. The drug was administered per os (p.o.) in its anticonvulsant dose range. CGP 40116 dose-dependently impaired passive avoidance learning when given before, but not when given after training. The antagonist (5, 10, and 20 mg/kg, administered 4 h before each training session) dose-dependently affected water maze acquisition, and impaired retention test performance in both hidden- and visible-platform water maze tasks. In addition, the drug dose-dependently decreased swimming speed during water maze acquisition. Repeated administration of CGP 40116 (20 mg/kg, p.o.) persistently decreased cage activity and wire suspension test performance, whereas motor coordination and equilibrium on the rotarod apparatus remained unimpaired. In our administration protocol, no tolerance was found to the effects of the drug on passive avoidance learning and neuromotor abilities. The parallel effects of CGP 40116 on memory and motor performance are discussed, and it was concluded that the antagonist impairs neuromotor abilities and also induces memory impairments which cannot be entirely reduced to motor interference.     

A tripeptide protease inhibitor attenuates conditioned avoidance behavior

In a single 10-s training trial, hatchling chicks were conditioned to suppress their spontaneous peck response to a small spherical target by coating it with an aversive liquid. A 24-h test trial employing a dry target demonstrated a robust memory for the training manifested in passive avoidance behavior. Leupeptin, a low-molecular-weight antiprotease, injected i.c.v. 1 h or 15 min prior to training attenuated the long-term avoidance response but not the initial training-induced peck suppression. Leupeptin had no effect on memory if given posttraining. A dose response experiment revealed that a 100- or 200-micrograms dose of leupeptin reliably impaired conditioned avoidance, whereas a 25 or 50-micrograms dose was ineffective. A dipeptide leupeptin analog (L-leucyl-L-arginine) possessed one-half the potency of the tripeptide in the memory task, and a different protease inhibitor (aprotinin) failed to effect the conditioned avoidance behavior. The mechanisms by which leupeptin may exert its influence in this behavioral paradigm and others are discussed.     

Effect of Leu-enkephalin on the memory reactivation produced by blockade of the benzodiazepine/GABA-chloride ionophore receptor complex

This investigation sought to characterize the interaction between GABA/benzodiazepine and opioid systems in memory retrieval deficit induced by detaining an animal in the training apparatus after acquisition. Mice pretreated with saline or Leu-enkephalin (0.2 mg/kg) were trained in one-trial passive avoidance test with following detention. Pre-testing administration of bicuculline (1 mg/kg), picrotoxin (1 mg/kg), or flumazenil (10 mg/kg) produced the memory-enhancing effect in the saline-pretreated mice. Pretraining treatment with Leu-enkephalin blocked the reactivation of memory produced by bicuculline and picrotoxin, but not flumazenil. The present investigation suggest that both benzodiazepine/GABA and opioid systems are important modulators of memory retrieval and that a specific interaction between these systems is responsible for the observed recovery of impaired memory trace.     

DMCM, a benzodiazepine site inverse agonist, improves active avoidance and motivation in the rat

There are several modulatory sites at GABA(A) receptors, which mediate the actions of many drugs, among them benzodiazepine. Three kinds of allosteric modulators act through the benzodiazepine binding site: positive (agonist), neutral (antagonist), and negative (inverse agonist). The goal of the present study was to examine the influence of the inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) acting on α GABA(A) receptor and compare its dose-response effects on memory and depression-like behavior. We independently studied the effects of DMCM (0.05-1.0mg/kg) on retention versus acquisition of active avoidance and depression-like behavior in the forced swim test. Throughout the study, drugs were given intraperitoneally, 30min before testing. ANOVA has showed that treatment with DMCM significantly affected retrieval of avoidance response (p<0.05), exerted promnesic effects in inverted U-shape manner. Dunnett's test indicated that the DMCM avoidance-facilitatory dose was 0.1mg/kg. At the dose facilitating retrieval of avoidance memory, DMCM significantly (p<0.05, comparison of regression coefficients by Student's t-test) and progressively increased acquisition rate during 5 days training, compared to the saline group. In forced swim test, ANOVA indicated statistically significant effects of DMCM (p<0.05). Dunnett's analysis showed that DMCM significantly decreased immobility time at the dose of 0.1mg/kg, exerted acute antidepressant-like effects. Our results experimentally support the findings that under certain circumstances, nonselective benzodiazepine site inverse agonists, produce memory-enhancing and antidepressant-like effects. The molecular and neuronal substrates linking the actions of specific GABA-benzodiazepine receptor complex subunits remains to be further elucidated.