Antiamnesic effect of the two novel κ‐opioid agonists,VA‐100 and VA‐101, in the mouse passive avoidance test

The effects of the administration of the two novel κ‐opioid agonists (VA‐100, VA‐101) on memory processes were evaluated with the mouse passive avoidance test. The administration of VA‐100 (50–100 mg kg^–1 p.o.) and VA‐101 (100 mg kg^–1 p.o.) administered 20 min before the training session prevented nor‐binaltorphimine (4.9 μg per mouse i.c.v.), scopolamine (1.5 mg kg^–1 i.p.), mecamylamine (20 mg kg^–1 i.p.), diphenhydramine (20 mg kg^–1 i.p.), and baclofen (2 mg kg^–1 i.p.) amnesia. At the highest effective doses, none of the drugs impaired motor coordination, as revealed by the rota‐rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. The antiamnesic effect induced by VA‐100 and VA‐101 was comparable to that exerted by the κ‐opioid agonist U‐50,488H, as well as that induced by the nootropic drug piracetam and the cholinesterase inhibitor physostigmine. These results suggest that the activation of κ‐opioid receptors plays an important role in the prevention of memory impairment. On these bases, κ‐opioid receptor agonists could represent a useful symptomatic treatment for cognitive deficits. Drug Dev. Res. 54:12–18, 2001. © 2001 Wiley‐Liss, Inc.     

DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer

DM235 (sunifiram), a new compound structurally related to piracetam, prevented the amnesia induced by scopolamine (1.5 mg kg(-1) i.p.), after intraperitoneal (0.001-0.1 mg kg(-1)) or oral (0.01-0.1 mg kg(-1)) administration, as shown by a passive avoidance test in mice. The antiamnesic effect of DM235 was comparable to that of well-known nootropic drugs such as piracetam (30-100 mg kg(-1) i.p.), aniracetam (100 mg kg(-1) p.o.) or rolipram (30 mg kg(-1) p.o.). DM235 also prevented mecamylamine (20 mg kg(-1) i.p.)-, baclofen (2 mg kg(-1) i.p.)- and clonidine (0.125 mg kg(-1) i.p.)-induced amnesia in the same test. In the Morris water maze test with rats, scopolamine (0.8 mg kg(-1) i.p.) inhibited the reduction of escape latency in both acquisition and retention/retraining tests. DM235 (0.1 mg kg(-1) i.p.), 20 min before each daily acquisition training, prevented the scopolamine-induced memory impairment. DM235 (1 mg kg(-1) i.p.) also reduced the duration of pentobarbitone-induced hypnosis in mice without modifying the induction time of hypnosis. At the highest effective doses, the investigated compound neither impaired motor coordination (rota-rod test), nor modified spontaneous motility and inspection activity (Animex and hole board tests).These results indicate that DM235, a compound structurally related to piracetam, is a novel nootropic endowed with the capability to prevent cognitive deficits at very low doses. Indeed, its potency is about 1,000 times higher than that of the most active piracetam-like compounds.     

AG‐4: a nicotinic agonist endowed with antiamnesic properties

The effect of the nicotinic agonist AG‐4 on memory processes was evaluated in the mouse passive avoidance test. AG‐4 (100 μg per mouse icv) prevented amnesia induced by scopolamine (1.5 mg kg^–1 ip), mecamylamine (20 mg kg^–1 ip), and dihydro‐β‐erythroidine (10 μg per mouse icv). In the same experimental conditions, AG‐4 (100 μg per mouse icv) also prevented baclofen (2 mg kg^–1 ip), clonidine (0.125 mg kg^–1 ip), and diphenhydramine (20 mg kg^–1 ip) amnesia in mice. AG‐4 exerted an antiamnesic effect comparable to that produced by nicotine (2 mg kg^–1 ip), physostigmine (0.2 mg kg^–1 ip), and the nootropic drug piracetam (30 mg kg^–1 ip). At the active dose, AG‐4 did not impair mice motor coordination and spontaneous motility as revealed, respectively, by Rota‐rod test and Animex apparatus. Present results evidence the antiamnesic activity of the nicotinic agonist AG‐4 suggesting a potential employment of this compound in the symptomatic treatment of cognitive impairments. Drug Dev. Res. 51:191–196, 2000. © 2001 Wiley‐Liss, Inc.     

Improvement of cognitive functions by the acetylcholine releaser SM 21

The effect of administration of SM 21 on memory processes was evaluated in the mouse passive avoidance and in the rat social learning tests. SM 21 (10–20 mg kg⁻¹ i.p.) prevented amnesia induced by scopolamine and dicyclomine as tested by the mouse passive avoidance test and prevented memory disruption by AF‐64A and benehexol ascertained by the rat passive avoidance test. Both SM 21 enantiomers were able to abolish dicyclomine‐induced amnesia in mice. SM 21, starting from the dose of 10 mg kg⁻¹ i.p., antagonized the memory impairment produced by mecamylamine, baclofen, and diphenhydramine in mice, as well as amnesia induced by diazepam in rats. SM 21, at doses ranging between 10 and 30 mg kg⁻¹ i.p., prevented memory reduction in mice by hypoxia in the passive avoidance test. In the social learning test, SM 21 (10 mg kg⁻¹ i.p.) injected in adult rats reduced the duration of active exploration of a familiar partner in the second session of the test. SM 21 prevented amnesia in both mice and rats comparable to that of the cholinesterase inhibitor physostigmine (0.2 mg kg⁻¹ i.p.), the M1 selective agonist AF‐102B (10 mg kg⁻¹ i.p.), and the nootropic drug piracetam (30 mg kg⁻¹ i.p.). These results demonstrated the ability of SM 21 to modulate memory functions and suggests that SM 21 could be useful in the treatment of cognitive deficits. Drug Dev. Res. 47:118–126, 1999. © 1999 Wiley‐Liss, Inc.     

AMPA-receptor activation is involved in the antiamnesic effect of DM 232 (unifiram) and DM 235 (sunifiram)

DM 232 and DM 235 are novel antiamnesic compounds structurally related to ampakines. The involvement of AMPA receptors in the mechanism of action of DM 232 and DM 235 was, therefore, investigated in vivo and in vitro. Both compounds (0.1 mg/kg^–1 i.p.) were able to reverse the amnesia induced by the AMPA receptor antagonist NBQX (30 mg/kg^–1 i.p.) in the mouse passive avoidance test. At the effective doses, the investigated compounds did not impair motor coordination, as revealed by the rota rod test, nor modify spontaneous motility and inspection activity, as revealed by the hole board test. DM 232 and DM 235 reversed the antagonism induced by kynurenic acid of the NMDA-mediated release of [³H]NA in the kynurenate test performed in rat hippocampal slices. This effect was abolished by NBQX. DM 232 increases, in a concentration dependent manner, excitatory synaptic transmission in the rat hippocampus in vitro. These results suggest that DM 232 and DM 235 act as cognition enhancers through the activation of the AMPA-mediated neurotransmission system.     

Antiamnesic activity of the nicotinic agonist DBO-83 in mice

The effect of administration of DBO-83 on memory processes was evaluated in the mouse passive avoidance test. DBO-83 (1–5 mgkg^–1 ip) prevented amnesia induced by scopolamine (1.5 mgkg^–1 ip), mecamylamine (20 mgkg^–1 ip) and dihydro-β-erythroidine (10 μg per mouse i.c.v.). In the same experimental conditions, DBO-83 (10 mgkg^–1 ip) also prevented baclofen (2 mgkg^–1 ip), clonidine (0.125 mgkg^–1 ip) and diphenhydramine (20 mgkg^–1 ip) amnesia in mice. The antiamnesic effect of DBO-83 was comparable to that exerted by nicotine (2 mgkg^–1 ip), physostigmine (0.2 mgkg^–1 ip), and the nootropic drug, piracetam (30 mgkg^–1 ip). In the antiamnesic dose-range, DBO-83 did not impair mouse motor coordination and spontaneous motility, as revealed, respectively, by the Animex apparatus and rotarod test. These results demonstrated the ability of DBO-83 to modulate memory functions and suggest that DBO-83 could be useful in the treatment of cognitive deficits. Drug Dev. Res. 45:45–51, 1998. © 1998 Wiley-Liss, Inc.     

Effect of glabridin from Glycyrrhiza glabra on learning and memory in mice

Glabridin was isolated from the roots of Glycyrrhiza glabra and its effects on cognitive functions and cholinesterase activity were investigated in mice. Glabridin (1, 2 and 4 mg kg (-1), P. O.) and piracetam (400 mg kg (-1), i. p.), a clinically used nootropic agent, were administered daily for 3 successive days to different groups of mice. The higher doses (2 and 4 mg kg (-1), P. O.) of glabridin and piracetam significantly antagonized the amnesia induced by scopolamine (0.5 mg kg (-1), I. P.) in both the elevated plus maze test and passive avoidance test. Furthermore, glabridin (2 and 4 mg kg (-1), P. O.) and metrifonate (50 mg kg (-1), I. P.), used as a standard drug, both remarkably reduced the brain cholinesterase activity in mice compared to the control group. Therefore, glabridin appears to be a promising candidate for memory improvement and it will be worthwhile to explore the potential of glabridin in the management of Alzheimer patients.     

Antinociceptive profile of the natural cholinesterase inhibitor huperzine A

The antinociceptive effect of huperzine A, a novel cholinesterase inhibitor, was investigated in the mouse hot‐plate and abdominal constriction tests. Huperzine A induced a dose‐dependent antinociception (70–110 μg kg^–1 i.p.) which was prevented by scopolamine (0.1 mg kg^–1 i.p.) and S‐(–)‐ET 126 (0.01 μg per mouse i.c.v.), but not by naloxone (1 mg kg^–1 i.p.), mecamylamine (2 mg kg^–1 i.p.), α‐methyl‐p‐tyrosine (100 mg kg^–1 i.p.), or CGP 35348 (100 mg kg^–1 i.p.). A dose‐dependent inhibition of the antinociception induced by huperzine A (110 μg kg^–1 i.p.) was observed after inactivation of the M₁ gene by an antisense oligodeoxyribonucleotide (aODN). This effect was detected 24 h after the last intracerebroventricular injection of aODN. Time‐course experiments revealed that, after the end of the aODN treatment, sensitivity to analgesic drugs progressively appeared, reaching the normal range at 96 h. Huperzine A, at the maximal effective doses, did not produce any alteration of mice motor coordination, as revealed by rota‐rod experiments. These results indicate that huperzine A is endowed by muscarinic antinociceptive properties mediated by the activation of central M₁ muscarinic receptor subtype. Drug Dev. Res. 54:19–26, 2001. © 2001 Wiley‐Liss, Inc.     

DAU 6215, a novel 5-HT3-receptor antagonist,selectively antagonizes scopolamine-induced deficit in a passive-avoidance task,but not scopolamine-induced hypermotility in rats

Abstract— This study examined the effects of DAU 6215, a selective 5-HT₃-receptor antagonist, on either impairment of a passive-avoidance task or hypermotility, both caused by scopolamine in rats. In the first experiment, scopolamine (0·75 mg kg^?1, i.p.) disrupted acquisition of a one-trial ‘step through’ passive-avoidance response. Pretreatment with DAU 6215 (1, 10, 30 and 100 μg kg^?1, i.p.) antagonized this deficit induced by scopolamine, with a bell-shaped dose-response curve. Scopolamine (0·75 mg kg^?1, i.p.) produced a significant increase in locomotor activity which was unaffected by pretreatment with DAU 6215 (10 and 30 μg kg^?1, i.p.). The present results further support the suggestion that 5-HT₃-receptor antagonists may prevent the memory disturbance caused by a reduction in central cholinergic function in the rat. The inefficacy shown by DAU 6215 on hyperactivity induced by scopolamine appears to rule out the possibility of a pharmacokinetic interference between DAU 6215 and scopolamine.     

Differential effects of adrenaline and noradrenaline on the hepatic expression of immediate early genes in mice

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Effects of vinpocetine in scopolamine-induced learning and memory impairments

Scopolamine-induced memory dysfunctions are related to reduced cholinergic transmission. In our experiments scopolamine (3.0 mg/kg i.p.) inhibited acquisition and induced retrograde amnesia in a one-trial step- through passive avoidance task in mice. We have studied the effect of vinpocetine (Cavinton^R), in the amnesic states mentioned above compared to that of vincamine, nicergoline (Sermion^R), and papaverine, to assess its activity on learning and memory processes impaired by scopolamine. Vinpocetine decreased the disrupting effect of scopolamine on acquisition and prevented and restituted the memory loss with 21.0 and 7.0 mg/kg i.p. peak effect dose, respectively. It facilitated the recall of memory traces damaged by scopolamine. Vincamine (3.5–63.7 mg/kg i.p.) showed a favorable effect in two of the four tests (reversal of amnesia and recall). Nicergoline (5–40 mg/kg i.p.) exerted moderate activity, and papaverine (10–40 mg/kg i.p.) was ineffective in the situations tested. Our findings indicate that vinpocetine directly or indirectly influences the cholinergic system, which may explain its previously reported beneficial effect in electroconvulsive shock- and hypoxia-induced experimental amnesic states, and its therapeutic activity in human mental and cognitive disorders.     

Mechanisms Involved in the Antinociceptive Effect in Mice of the Hydroalcoholic Extract of Siphocampylus verticillatus

The antinociception caused by the hydroalcoholic extract of Siphocampylus verticillatus (Campanulaceae) has been investigated in chemical and thermal models of nociception in mice. We have also assessed some of the mechanisms underlying the antinociceptive effect of the extract. The hydroalcoholic extract of S. verticillatus (60–1000 mg kg^?1, i.p. or p.o.) produced dose-related, significant and long-lasting (6 to 8 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 204 and ～1000 mg kg^?1, respectively. In the formalin test, the extract (100–1000 mg kg^?1), given either intraperitoneally or orally, resulted in graded inhibition of both phases of formalin-induced pain, being about 2- to 4-fold more potent in attenuating the second phase of the pain. The calculated mean ID50 (mg kg^?1) values for the earlier and the later phases were: 491 and 186 and 640 and 441, respectively. In addition, the extract (60–1000 mg kg^?1, i.p. or p.o.) caused marked and dose-related inhibition of capsaicin-induced neurogenic pain with mean ID50 values of 420 and 485 mg kg^?1, respectively. The hydroalcoholic extract, at the same doses, did not significantly affect the performance of animals in the rota-rod test, nor did it have any analgesic effect in the tail-flick or hot-plate tests. The treatment of animals with naloxone (5 mg kg^?1, s.c.) significantly reversed the analgesic effect of both morphine (5 mg kg^?1, s.c.) and the extract (300 mg kg^?1, i.p.) when assessed against acetic acid-induced abdominal constrictions. The treatment of animals with l-arginine (600 mg kg^?1, i.p.) significantly attenuated the antinociceptive effects of N^G-nitro-l-arginine (l-NOARG) (75 mg kg^?1, i.p.), of the hydroalcoholic extract (600 mg kg^?1, i.p.) or of morphine (5 mgkg^?1, s.c.), when analysed against the formalin test. In addition, adrenalectomy of animals 7 days before the tests significantly reversed the antinociception caused by the hydroalcoholic extract (300 mg kg^?1, i.p.) in the formalin-induced pain. These data show that the hydroalcoholic extract of S. verticillatus has significant and long-lasting oral antinociception when assessed against both neurogenic and inflammatory models of nociception in mice. The precise mechanism responsible for the analgesic effect of the extract still remains unclear, but a great part of this effect seems to be partly related to an opioid-like action and involvement of the l-arginine-nitric oxide pathway. Finally, the antinociception caused by the hydroalcoholic extract of S. verticillatus is modulated by adrenal hormones.     

The mechanism of the hypothermic effect of amantadine in rats and mice

Amantadine (25–100 mg kg^?1, i.p.) given to rats at an ambient temperature of 4°, or mice at 21°, caused a marked fall in rectal temperature. Prior administration of pimozide (1–2 mg kg^?1, s.c.) did not block hypothermia due to amantadine in rats or mice; in contrast, hypothermia due to apomorphine (2 mg kg^?1, i.p.) and piribedil (10–40 mg kg^?1, i.p.) in rats was blocked by pimozide pretreatment. Amphetamine (5 mg kg^?1, i.p.) given 2 h after reserpine (2 mg kg^?1, i.p.) caused a reversal of the hypothermic effect of reserpine in mice, but a reversal was not obtained with amantadine (50 mg kg^?1, i.p.). Direct injection of amantadine (4–8 mg kg^?1) into the cerebral ventricles (i.c.v.) of mice caused marked hypothermia which was not blocked by pimozide, but intravenous injection of the same dose of amantadine did not cause hypothermia. Rimantadine, a congener of amantadine but without anti-parkinsonian activity, also caused pimozide insensitive hypothermia in mice at doses of 50 mg kg^?1, intraperitoneally or 2–4 mg kg^?1, intracerebroventricularly. The main conclusion drawn from these results is that in causing hypothermia amantadine acts in the cns but not on dopamine receptors.     

An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate

Abstract— Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg^?1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg^?1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg^?1, i.p.), but was potentiated by prazosin (0·75 mg kg^?1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg^?1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg^?1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α₁-adrenoceptors.     

Buprenorphine-cocaine Interactions in Mice: Effect on Locomotor Activity and Hole-dipping Behaviour

Abstract— The effect of cocaine and the mixed μ-opioid partial agonist/κ-antagonist buprenorphine on locomotor activity and hole-dipping behaviour was investigated in mice. The drugs were given alone and in combination. Cocaine (7·5, 15, 30 mg kg^?1, i.p.) significantly increased locomotion in a dose-related manner in the hour following injection. The two highest doses also increased hole-dipping although this response was not consistently seen. Buprenorphine (0·5, 5 mg kg^?1, i.p.) produced an increase in locomotion which occurred 30–60 min after injection but did not alter hole-dipping behaviour. A lower dose (0·05 mg kg^?1) had no effect on either parameter. The locomotion induced by cocaine (15 mg kg^?1, i.p.) was not modified by buprenorphine (0·05, 0·5, 1, 5 mg kg^?1, i.p.; 5 min pretreatment). However, hole-dipping was almost completely abolished in animals given combinations of cocaine and buprenorphine (0·05–5 mg kg^?1, i.p.), although neither drug decreased hole-dipping when given alone. This observation, which was not simply due to the emergence of stereotyped behaviour, suggests an interaction between buprenorphine and cocaine.     

Effect of butaclamol,a new neuroleptic,on serotoninergic mechanisms

Butaclamol (1·0–0·1 mg kg^?1, i.p.) and spiroperidol (1·0–0·5 mg kg^?1, i.p.), but not (—)-butaclamol (15 mg kg^?1, i.p.), blocked the hyperactivity induced in rats by tranylcypromine-l-tryptophan pretreatment. Neither butaclamol nor spiroperidol altered the accumulation of brain 5-HT following pargyline or the decline of brain 5-HT following inhibition with the tryptophan hydroxylase inhibitor α-propyldopacetamide thus indicating that butaclamol and spiroperidol do not affect either the synthesis or the turnover of brain 5-HT. It is concluded that the antagonism of the tranylcypromine-l-tryptophan-induced hyperactivity by butaclamol and spiroperidol is due to their blockade of dopaminergic receptors rather than an action on neuronal serotoninergic mechanisms.     

Effects of bifemelane hydrochloride (MCI-2016) on experimental amnesia (passive avoidance failure) in rodents

To further predict the possible activity on memory disorders, the effect of MCI-2016 (bifemelane hydrochloride) was examined using the passive avoidance (PAR) failure technique as an experimental model of amnesia. The amnesia was produced either by post training treatments of electroconvulsive shock (ECS), scopolamine (mice) and cycloheximide or by pre-test injection of scopolamine (rats). In ECS-PAR failure model, the retention test was carried out 3 hr (3 hr experiment) or 24 hr (24 hr experiment) after ECS. MCI-2016 showed a significant improvement when administered just after ECS (3 hr experiment, 30 mg/kg, i.p.) or 0.5 hr before the retention test (24 hr experiment, 10-30 mg/kg, i.p.). Cahopantenate was only active in the 3 hr experiment (500 mg/kg, i.p.), and piracetam was rather active in the 24 hr experiment (60 mg/kg, i.p.). MCI-2016 (30 mg/kg, i.p.) prevented the scopolamine-induced PAR-failure. In this model, physostigmine (0.3 mg/kg, i.p.) exhibited a tendency to improve the failure. In another scopolamine-induced PAR failure model in mice, all of the test drugs showed a significant improvement at different dose levels. The effect of MCI-2016 (25-100 mg/kg, p.o.) was superior to those of piracetam, aniracetam and choline chloride. Higher doses of MCI-2016 were required to improve the cycloheximide-induced PAR failure. Considering the experimental conditions and results, it may be suggested that MCI-2016 ameliorates the amnesia possibly through its influence on memory consolidation and retrieval processes.     

Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure,in Mice

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg^?1. Only at intraperitoneal doses of 100mg kg^?1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg^?1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg^?1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg^?1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg^?1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg^?1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg^?1, s.c). At 200 mg kg^?1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg^?1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg^?1, i.p.) in mice pretreated with pargyline (100mg kg^?1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg^?1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg^?1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg^?1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg^?1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg^?1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg^?1 for PC4 and 5mg kg^?1 for PC13) potentiated morphine (7–5 mg kg^?1, s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT₂ receptor level.     

Comparative study of the antagonism of bemegride and picrotoxin on behavioural depressant effects of diazepam in rats and mice

Experiments carried out on rats and mice showed that bemegride and diazepam acted as antagonists. Bemegride (at doses ranging from 4 to 16 mg.kg^?1 i.p.) counteracted diazepam (8 mg.kg^?1 i.p.)-induced hypokinesia and amnesic-like activity, diazepam (4 mg.kg^?1 i.p.)-induced motor inco-ordination and diazepam (2 mg.kg^?1 i.p.)-induced reduced grip strength. A GABA receptor blocking agent, picrotoxin (2–4 mg.kg^?1 i.p.) also markedly antagonized all (except for hypokinesia) these diazepam effects. Diazepam (1. 2, 4, 8 mg.kg^?1 i.p.) exerted similar dose-related antagonisms on bemegride (24 mg.kg^?1 i.p.) and on picrotoxin (8 mg.kg^?1 i.p.)-induced seizures. Both antagonisms were observed at lower doses than were required for strychnine (6 mg.kg^?1 i.p.)-induced seizures inhibition. Picrotoxin/ diazepam antagonism seems to further support the possibility of a gabaminergic mechanism of action of benzodiazepines depressant effects. Bemegride/diazepam antagonism is discussed in terms of a possible inhibitory role of bemegride on gabaminergic transmission.     

Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers

DM232 (unifiram) and DM235 (sunifiram) are potent cognition-enhancers, which are four order of magnitude more potent than piracetam. These compounds, although not showing affinity in binding studies for the most important central receptors or channels, are able to prevent amnesia induced by modulation of several neurotransmission systems. These compounds are able to increase the release of acetylcholine from rat cerebral cortex, and, as far as unifiram is concerned, to increase the amplitude of fEPSP in rat hippocampal slices. In vitro experiments, performed on hippocampal slices, also supported the hypothesis of a role of the AMPA receptors for the cognition-enhancing properties of unifiram and sunifiram.