PubMed Health⌕ Search

Biomedical subjects

P Popik

Publications and source records attributed to P Popik.

At least 37 records · Page 2Linked to original sources
PubMed1999

Colostrinin, a polypeptide isolated from early milk, facilitates learning and memory in rats.

Initial observations in humans indicated that colostrinin, a complex of polypeptides derived from the colostrum of sheep, facilitates cognitive functioning in patients with Alzheimer's disease. Its effect on learning and memory in more controlled settings as well as the specificity of these effects were, however, unknown. The present experiments evaluated the effects of colostrinin on spatial learning (Morris water maze) and incidental memory (habituation test) in male Wistar rats of two age groups. Colostrinin, at a dose of 4 microg/rat IP, facilitated acquisition of spatial learning of 13- (aged) but not 3-month-old (young) rats. At the same dose, it improved incidental learning in aged rats, while the dose of 20 microg/rat attenuated it. Colostrinin did not change locomotor activity of rats. Taken together, the present findings indicate that colostrinin may have some beneficial effects on cognitive functioning, particularly in aged subjects. Given the fact that colostrum is the first nutritive agent of neonates, it might be speculated that its peptides may facilitate the early postnatal development of the cerebral neurons and their plasticity.

Aging↗
PubMed1999

A partial agonist at strychnine-insensitive glycine sites facilitates spatial learning in aged rats.

1-Aminocyclopropanecarboxylic acid (ACPC) is a high affinity ligand at strychnine-insensitive glycine sites of the N-methyl-D-aspartate (NMDA) channels and exhibits partial agonist properties in both biochemical and electrophysiological measures. While ACPC was reported active in animal models used to evaluate potential antidepressants and anxiolytics, its effects on learning and memory are unknown. In the present study we investigated the effects of ACPC on spatial learning in the Morris water maze. On a schedule of 12 learning trials, one trial per day, mature male Wistar rats (3 months of age) rapidly acquired the task. Electroconvulsive shocks applied after each of the learning trials markedly inhibited the consolidation of spatial memory. Administration of either a muscarinic agonist, arecoline (1 mg/kg) or ACPC (250 or 400 mg/kg) 20 min before each of the learning trials did not affect the acquisition of spatial learning. Aged (16 months old) male Wistar rats demonstrated difficulties in the acquisition of spatial learning task. In these subjects, ACPC administered 20 min before each of the learning trials at a dose of 400, but not 250 mg/kg, facilitated the acquisition of spatial memory as indicated on trials 3-5. ACPC did not affect the strength of spatial memory as assessed at the end of conditioning, by measuring swimming behavior of rats in the pool with platform removed. It is suggested that ACPC may alleviate learning deficits observed in the elderly.

Age Factors↗
PubMed1998

Molecular features associated with polyamine modulation of NMDA receptors.

The effect of 1,3-diamines on basal and spermine-stimulated [3H]MK-801 binding was investigated. Systematic variations in the molecular parameters revealed that, in general, lipophilic 1,3-diamines inhibited and hydrophilic 1,3-diamines enhanced [3H]MK-801 binding in the nominal absence of glutamate and glycine. Furthermore, 1,3-diamines which were highly monoprotonated at physiologic pH were more effective in modulating basal binding (at 100 microM 1,3-diamine) than analogues which were mostly diprotonated or unprotonated. Finally, the internuclear distance between the amino nitrogens and the extent of modulation of basal [3H]MK-801 binding were correlated. Similar, but more modest, effects were seen for spermine-enhanced [3H]MK-801 binding. These results are consistent with the existence of two polyamine binding sites associated with the NMDA receptor complex. One of the sites appears to preferentially recognize lipophilic substances while the other favors hydrophilic materials. Both sites appear to recognize polyamines with at least one charged (protonated) amino group and one uncharged amino group. The distance between amino groups is a determining factor as well.

Animals↗
PubMed1998

Adaptation of cortical NMDA receptors by chronic treatment with specific serotonin reuptake inhibitors.

Glycine displaces [3H]CGP-39653 ([3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid) binding to the glutamate recognition site with both high and low affinity. We reported previously that chronic treatment with antidepressants reduced the proportion of high to low affinity sites, or, even eliminated the high affinity sites in case of citalopram. Here, we compared the effects of citalopram with another serotonin specific reuptake inhibitor, fluoxetine on this measure. Chronic administration of citalopram or fluoxetine eliminated high affinity glycine-displaceable [3H]CGP-39653 binding to the mouse cortex in 78 and 56% of animals, respectively, indicating that selective serotonin reuptake inhibitors produce qualitatively similar adaptive changes at NMDA receptors, that differ from other antidepressants in this neurochemical measure.

2-Amino-5-phosphonovalerate↗
PubMed1998

GlycineB antagonists as potential therapeutic agents. Previous hopes and present reality.

It is not clear what therapeutic application is most likely for agents blocking glycine site of the NMDA receptors (glycineB). Majority of the studies to date used either glycineB antagonists with doubtful brain penetration or partial agonists. Following systemic administration to rats of our newly developed glycineB antagonists (MRZ 2/570; 2/571 and 2/576) and L-701,324 (MSD) as a reference agent the following behavioural effects were observed: weak (if any) antiparkinsonian-like effects, lack of anxiolytic activity, inhibition of physical and motivational aspects of morphine dependence and neuroprotective activity in global ischaemia. The side effects include: sedation, ataxia, and myorelaxation. We detected neither vacuolisation in the cingulate cortex nor impairment of pre-pulse inhibition indicating lack of psychotomimetic potential.

Animals↗
PubMed1998

Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists.

The glycine site (MRZ 2/570 and L-701,324), and uncompetitive (MRZ 2/579) NMDA receptor antagonists inhibited morphine-produced behaviors related to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects of glycine/NMDA antagonists were not dose-dependent. Mice which were morphine-free for 3 days still displayed a significant severity of the withdrawal syndrome when challenged again with naloxone. This extinction of a residual morphine dependence was markedly diminished by treatment with similar doses of NMDA receptor antagonists at the test following the wash-out period. The rewarding impact of morphine was investigated in rats using the place preference (CPP) paradigm. All NMDA receptor antagonists (2.5-10 mg/kg) inhibited both the acquisition and expression of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA receptor antagonists given for 3 days after the end of conditioning did not influence the extinction of morphine-induced CPP. Microdialysis studies revealed that the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA receptor antagonist. These data suggest that novel glycine site and uncompetitive NMDA receptor antagonists may have therapeutic potential in the treatment of opioid abuse.

Analgesics, Opioid↗
PubMed1998

Neurohypophyseal peptides and social recognition in rats.

An encounter between rats results in bouts of social investigation consisting mainly of sniffing, nosing, following and grooming. The assessment of social recognition is based on the tendency of rodents to investigate unfamiliar conspecifics more intensely, than familiar ones. In the laboratory an immature conspecific is normally used as the social stimulus because the use of juveniles eliminates possible sexual and/or aggressive behaviors of the rat whose memory is assessed. When a juvenile is presented for the first time, it is intensely investigated. A second presentation shortly after the first one elicits less attention. This is not due to satiation or fatigue, since the presentation of a novel juvenile triggers the full sequence of investigation. Social recognition is defined as a specific decrease in social investigation during the second encounter of the same individual. This form of memory is short lasting (< 40 min) and based on the olfactory characteristics of the stimulus animal. Social memory is prolonged by repeated exposure to the stimulus juvenile rat and is impaired by retroactively interfering stimuli. It can be facilitated by vasopressin and derivatives as well as by several other memory facilitating compounds, and, depending on the dose, attenuated or facilitated by oxytocin and derivatives. Ethologically oriented memory tests, that are based on olfactory characteristics of the information to-be-remembered, have an advantage over 'classical' ones: they estimate behavioral patterns which are important to an animal and not only to the investigator. Social memory paradigms can reveal information about memory processes in animals that is relevant for memory deficits in humans.

Animals↗
PubMed1997

Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine.

The present study focused on the effects of 1-amino-3,5-dimethyladamantane (memantine), a clinically used, low-affinity N-methyl-D-aspartate channel blocker, on the motivational impact of morphine and morphine withdrawal syndrome. Memantine (7.5 mg/kg) inhibited the acquisition as well as the expression of morphine-induced conditioned place preference. However, memantine did not affect significantly the acquisition or expression of conditioned place preference induced by food presentation. In addition, at the dose that blocked morphine-induced conditioned place preference, memantine by itself produced neither conditioned place preference nor conditioned place aversion. Memantine attenuated the negative motivational aspects of morphine withdrawal as assessed by conditioned place aversion produced by a low dose (0.1 mg/kg) of naloxone in morphine-dependent rats. Drug discrimination studies revealed that the inhibitory effects of memantine on morphine-induced conditioned place preference could not be attributed to the attenuation by memantine of the interoceptive cue produced by morphine. In addition, the inhibitory effects of memantine on the expression of morphine-induced conditioned place preference seemed not to be related to effects on memory retrieval, as revealed in the Morris water maze spatial task. These data suggest that memantine at a low, pharmacologically relevant dose of 7.5 mg/kg blocks the reinforcing effects of morphine and aversive effects of morphine withdrawal in rats, which suggests a new potential clinical indication for this agent in the treatment of opioid abuse.

Animals↗
PubMed1996

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors.

Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+)-[3-3H]5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10- imine ([3H]MK-801) binding to NMDA receptors were examined. This series of analogs included the putative ibogaine metabolite O-desmethylibogaine, its metabolism resistant analog O-t-butyl-O-desmethylibogaine, the iboga alkaloids (+/-)-ibogamine, (+/-)-coronaridine, tabernanthine, harmaline, and the indolotropanes endo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]loctane (RS 075194-190), exo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 075237-190), and endo-3-(indol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 025989-190). Among these compounds, ibogaine was the most potent inhibitor of [3H]MK-801 binding (Ki = approximately 1.2 microM), whilst the compounds with the greatest structural similarity to ibogaine, O-desmethylibogaine and O-t-butyl-O-desmethylibogaine were less potent (Ki = approximately 5.5 and 179.0 microL, respectively). In morphine-dependent mice, ibogaine, but not O-desmethylibogaine or O-t-butyl-O-desmethylibogaine, attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties.

Animals↗
PubMed1996

Facilitation and attenuation of social recognition in rats by different oxytocin-related peptides.

The memory-modulating effects of subcutaneously administered oxytocin and related peptides were investigated in the social recognition paradigm in rats. The attenuation of social recognition by 0.6 and 6 micrograms/kg of oxytocin was mimicked by the same doses of des-Gly8-oxytocin, [pGlu4, Cyt6]oxytocin-(4-9) and prolyl-leucyl-glycinamide (PLG) and by 0.6 micrograms/kg of oxytocin-(1-6) and [pGlu4,Cyt6]oxytocin-(4-8). The peptide leucyl-glycinamide (LG) was not active in this respect. The facilitation of social recognition by 0.6 and 6 ng/kg of oxytocin was mimicked by the same doses of PLG and LG but not by the other peptides and the amino acid glycine. It is concluded that the active moieties for attenuation and facilitation of social memory reside in different parts of the oxytocin molecule, e.g. the 5-7 and 8-9 region, respectively.

Animals↗
PubMed1996

The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence.

The ability of memantine (1-amino-3,5-dimethyl-adamantane) to block the expression and maintenance of morphine dependence was examined in mice. When administered to morphine-dependent mice 45 min prior to naloxone challenge, memantine (7.5-30 mg/kg IP) in a dose-dependent manner reduced jumping behavior (a manifestation of the expression of dependence). The ability of memantine to attenuate naloxone-precipitated jumping was reversed by administration of glycine, an observation consistent with electrophysiological studies indicating that memantine is a use-dependent (uncompetitive) N-methyl-D-aspartate (NMDA) antagonist. In an independent series of experiments, the effect of memantine on a preestablished morphine dependence was investigated. A residual dependence to morphine was present 3 days after cessation of morphine administration. Repeated administration of memantine (10 mg/kg, IP) or the competitive NMDA antagonist NPC 17742 [2R, 4R, 5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid)] (6 mg/kg, IP) during this 3-day period abolished subsequent naloxone-precipitated jumping. In contrast, when administered concurrently with morphine after dependence had already been well established, memantine (10 and 20 mg/kg, IP) did not affect the maintenance of morphine dependence. Based on these finding, NMDA antagonists appear to inhibit the maintenance of opioid dependence, an action distinct from their acute inhibitory effects on the expression of dependence. Nonetheless, these regimen-dependent effects of memantine indicate that the most efficacious use of NMDA antagonists would be in detoxified subjects, rather than in individuals with an established dependence who are currently abusing opioids.

Amino Acids↗
PubMed1996

Facilitation of memory retrieval by the "anti-addictive" alkaloid, ibogaine.

Anecdotal observations in humans indicate that indole alkaloid ibogaine may have anti-addictive properties. It has been suggested that the therapeutic action of ibogaine may depend upon facilitated access to the past experiences, purportedly influencing the initiation of drug addiction. To determine if ibogaine may facilitate memory retrieval, rats were trained in the Morris maze spatial navigation task. It has been found that ibogaine (0.25 or 2.5 mg/kg) or O-desmethyl-ibogaine (2.5 mg/kg) but not t-Butyl ibogaine, administered just before the test trial, facilitated spatial memory retrieval compared to rats receiving placebo treatment. It is concluded that although previously described NMDA receptor antagonistic properties of ibogaine may represent a locus for at least some of its actions, other mechanisms, involving facilitation of memory retrieval may be of importance for its anti-addictive effects.

Animals↗
PubMed1996

Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression.

NMDA antagonists mimic the effects of clinically effective antidepressants in both preclinical tests predictive of antidepressant action and procedures designed to model aspects of depressive symptomatology. These findings led to experiments demonstrating that chronic administration of NMDA antagonists to rodents results in a downregulation of cortical beta-adrenoceptors, a phenomenon also observed following chronic treatment with many antidepressants. These neurochemical and behavioral similarities between antidepressants and NMDA antagonists prompted us to examine the impact of chronic antidepressant treatment on NMDA receptors. Chronic (14 days) but not acute (1 day) administration of seventeen different antidepressants to mice produced adaptive changes in radioligand binding to NMDA receptors. Detailed studies with three antidepressants (imipramine, citalopram, and electroconvulsive shock) show that these changes develop slowly, persist for some time after cessation of treatment, and (for imipramine and citalopram) are dose dependent. Moreover, following chronic treatment with imipramine, these changes in radioligand binding to NMDA receptors appear restricted to the cerebral cortex. Based on the consistency of these effects across antidepressant treatments, we propose that adaptive changes in NMDA receptors may be the final common pathway for antidepressant action. The recent demonstration (Nowak et al., 1995) that radioligand binding to NMDA receptors is altered in frontal cortex of suicide victims (compared to age and post-mortem interval matched controls) is consistent with the hypothesis (Trullas and Skolnick, 1990) that this family of ligand gated ion channels is involved in the pathophysiology of depression.

Animals↗
PubMed1995

[3H]1-aminocyclopropanecarboxylic acid, a novel probe for strychnine- insensitive glycine receptors.

[3H]1-Aminocyclopropanecarboxylic acid (ACPC) exhibits high affinity, specific binding to strychnine-insensitive glycine receptors. In extensively washed rat forebrain membranes, the specific binding of [3H]ACPC was optimal at 25 degrees C in the presence of 10 mM MgCl2. Comparable levels of specific [3H]ACPC binding were obtained using centrifugation and filtration for separation of bound from free radioligand. [3H]ACPC labels two sites with Kdl and Bmax1 values of 129 +/- 34 nM and 2.30 +/- 0.37 pmol/mg protein and Kd2 and Bmax2 values of 7.26 +/- 1.69 microM and 20.6 +/- 2.2 pmol/mg protein for the high and low affinity sites, respectively. The Kd of [3H]ACPC (66 nM) estimated under non-equilibrium conditions (koff = 8.91 +/- 0.78 x 10(-3) s-1; kon = 1.35 x 10(-4) nM-1 s-1) was similar to the value obtained for the high affinity site obtained by equilibrium binding. The Kd1 of[3H]ACPC is in good agreement with the previously reported Ki values of ACPC to inhibit the binding of other glycinergic ligands including [3H]glycine, [3H]5,7-dichlorokynurenic acid (5,7-DCKA) and [3H]L-689,560 ((+/-)-4-(trans)-2-carboxy-5,7-dichloro-4- phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline). Moreover, the potencies of a series of glycine site ligands, including glycine. ACPC, 1-aminocyclobutanecarboxylic acid (ACBC), 5,7-DCKA, 7-chlorokynurenic acid (7-CKA), R(+)-3-amino-1-hydroxy-2- pyrrolidine (HA-966) and D-serine, to inhibit [3H]ACPC binding were highly correlated with their potencies to inhibit [3H]glycine and [3H]5,7-DCKA binding (r2 = 0.98-0.51). These results demonstrate that [3H]ACPC is a useful tool for examining the neurochemical and pharmacological properties of strychnine-insensitive glycine receptors.

Amino Acids↗
PubMed1995

Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715).

Functional N-methyl-D-aspartate (NMDA) antagonists including competitive antagonists, glycine partial agonists, and use-dependent channel blockers exhibit antidepressant-like actions in preclinical models. The present study examined the effects of eliprodil (SL-82.0715), an NMDA antagonist acting at polyamine sites, in behavioral and neurochemical tests predictive of antidepressant activity. In mice, eliprodil produced a dose-dependent reduction in immobility in the forced swim test, but was inactive in the tail suspension test. Chronic treatment with eliprodil produced both a significant downregulation of beta-adrenoceptors and a reduction in the potency of glycine to inhibit [3H]5,7-dichlorokynurenic acid binding to strychnine-insensitive glycine receptors in neocortical membranes. In toto, these data indicate that like other NMDA antagonists, eliprodil possesses antidepressant-like actions in preclinical tests predictive of clinical efficacy.

Adrenergic Uptake Inhibitors↗
PubMed1995

NMDA antagonist properties of the putative antiaddictive drug, ibogaine.

Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (Ki, 2.3 microM at -60 mV). Consistent with this observation, ibogaine competitively inhibits [3H]1-[1-(2-thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (Ki, 1.5 microM) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 microM). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED50, 64.9 mg/kg) in mice trained to discriminate the prototypic voltage-dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone-precipitated jumping in morphine-dependent mice (ED50, 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone-precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative "antiaddictive" property of this alkaloid, its ability to reduce the expression of morphine dependence.

Animals↗