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P Popik

Publications and source records attributed to P Popik.

At least 19 recordsLinked to original sources
PubMed2006

Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests.

Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.156-10 mg/kg) and mGluR5 antagonist (MTEP, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 1.25-10 mg/kg) in two behavioral screening assays commonly used to assess antidepressant-like activity. In the modified forced swim test in rats, imipramine (used as a positive control) decreased immobility (MED 40 mg/kg) and increased the duration of escape-oriented (climbing and diving; MED 20 mg/kg) behaviors. Both EMQMCM and MTEP decreased the floating duration (MED 1.25 and 2.5 mg/kg) and increased the duration of mobile behaviors (paddling and swimming; MED 2.5 and 5 mg/kg). EMQMCM but not MTEP increased the duration of escape behaviors (climbing and diving; MED 1.25 mg/kg). In the mouse tail suspension test, EMQMCM (5 but not 2.5, 10 and 25 mg/kg), 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 10 but not 1 mg/kg) and MTEP (MED 25 mg/kg) decreased immobility scores. For EMQMCM, the dose-effect relationship was biphasic. With the exception of EMQMCM (10 mg/kg), locomotor activity in mice was not affected by treatments. The present study therefore suggests that acute blockade of mGluR5 and also of mGluR1 exerts antidepressant-like effects in behavioral despair tests in rats and mice.

Animals↗
PubMed2005

Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice.

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT(3) receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT(3) receptor blockade. Ketamine (3-40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed non-matching-to-sample tasks in rats. The 5HT(3) receptor antagonist MDL 72222 (0.3-3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50-66 and 3 mg/kg, respectively) and together (12.5-25 and 1 mg/kg). The present data suggest that 5-HT(3) receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action.

Animals↗
PubMed2005

A comparison of the predictive therapeutic and undesired side-effects of the NMDA receptor antagonist, memantine, in mice.

Memantine (1-amino-3,5-dimethyl-adamantane) is the only clinically used NMDA (N-methyl-D-aspartate) glutamate receptor antagonist. The present experiments were carried out to compare the dose-response for memantine's predictive therapeutic and side-effects in a variety of tests in C57BL/6J/Han mice, and to elucidate if tolerance may develop to them. Memantine produced a dose-dependent (2.5-15 mg/kg) antidepressant-like effect in the tail-suspension test (TST); this anti-immobility effect of 15 mg/kg of memantine appeared to persist with its sub-chronic administration (3 days, twice daily). Treatment with the same doses of memantine produced no effects on locomotor activity, and sub-chronic treatment with 15 mg/kg did not affect locomotor activity. Exploratory activity was assessed in the open field. Given acutely 5 min before the test, memantine reduced rearing (1.875-30 mg/kg), ambulation (7.5 and 30 mg/kg) and grooming (30 mg/kg). These effects were more pronounced 35 min after its administration. As measured in three different tests, ataxia and stereotypy appeared only at the single dose of 30 mg/kg, 5 and 35 min after administration. In mice treated sub-chronically with 30 mg/kg, the dose of 30 mg/kg increased ambulation, and continued to decrease rearing and grooming, but no signs of ataxia and stereotypy were detected. The present data indicate that different doses of memantine are required for the purportedly therapeutic and side-effects, and that tolerance may develop to the ataxic, but not anti-immobility actions.

Animals↗
PubMed2003

Effects of memantine, an NMDA receptor antagonist, on place preference conditioned with drug and nondrug reinforcers in mice.

Antagonists of the N-methyl-D-aspartate (NMDA) receptor complex have been shown to inhibit the expression of place preferences conditioned with several drugs that are abused by humans, which suggests that this class of compounds may be beneficial in the treatment of substance dependence. Therefore it is important to assess the specificity of this effect, of whether inhibitory effects of NMDA receptor antagonists on conditioned drug stimuli generalize to behaviors produced by nondrug reinforcers. The present study was designed to compare the effects of the NMDA receptor channel blocker, memantine, on the expression of place preferences conditioned with: (1) consumption of regular laboratory food; (2) sexual encounters with females; and (3) injection of morphine (10 mg/kg) in adult male Swiss mice. For all three experiments reported here, unconditioned stimuli (food, receptive female or morphine) were presented before the exposures to the "to-be-conditioned" environments. Significant place preferences developed as a result of explicit pairings of the environmental context and food consumption, sexual encounter and morphine administration. Memantine (7.5 mg/kg, given prior to the post-conditioning test) inhibited the expression of place preferences conditioned with morphine and sexual encounter, but had no effects in food-conditioned mice. These findings suggest that the effects of NMDA receptor blockade may not be limited to drug-reinforced behaviors.

Animals↗
PubMed2002

The effects of NMDA receptor antagonists on acute morphine antinociception in mice.

Antagonists of the N-methyl- d-aspartate (NMDA) receptor complex inhibit the development of tolerance to antinociceptive effects of morphine and upon acute administration, influence morphine antinociceptive activity. The analysis of numerous studies investigating acute interaction between NMDA receptor antagonists and morphine in mice indicate a variety of procedural differences and reveal that these compounds may potentiate, attenuate and produce no effect on morphine antinociception. The conditions responsible for such conflicting experimental outcome of acute interaction remain unclear. It appears that the effects of NMDA receptor antagonists on morphine tolerance are not causally related to their acute effects on morphine antinociception.

Analgesics, Opioid↗
PubMed2002

Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist.

In the present study we examined the effect of MPEP [2-methyl-6-(phenylethynyl)-pyridine] a potent, selective and systemically active metabotropic glutamate receptor (mGluR) type I (subtype mGluR5) antagonist on conditioned morphine reward in mice. In an unbiased version of conditioned place preference (CPP) paradigm, single conditioning with 10 mg/kg of morphine produced reliable place preference. MPEP at 30, but not 10 mg/kg significantly inhibited the acquisition as well as expression of morphine-induced CPP, but it neither produced place preference or aversion, nor affected locomotor activity of mice. Effects of MPEP on learning and memory were studied in the elevated plus maze model of spatial learning. In contrast to 0.1 mg/kg of MK-801, which inhibited the acquisition of this task, 30 mg/kg of MPEP affected neither learning nor memory retrieval. These data suggest that mGluR5 may be involved in conditioned morphine reward.

Animals↗
PubMed2001

Uncompetitive NMDA receptor antagonists potentiate morphine antinociception recorded from the tail but not from the hind paw in rats.

We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA receptor antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mg/kg, respectively. These doses were used in further experiments. Thirty minutes before morphine, rats were administered the NMDA receptor antagonists dextromethorphan (2.5--30 mg/kg), memantine (2.5--15 mg/kg) and MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) (1.25--10 mg/kg). All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA receptor antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA receptor antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws.

Analgesics↗
PubMed2001

Cognitive effects of Colostral-Val nonapeptide in aged rats.

Colostrinin, a complex of polypeptides derived from sheep colostrum retards the progress of Alzheimer's disease and facilitates acquisition and retrieval of spatial memory in aged rats. Here we investigated the cognitive effects of colostrinin-derived nonapeptide (Colostral-Val nonapeptide, CVNP) in aged rats that demonstrated learning deficits. Administered for 14 days, CVNP did not affect the acquisition of spatial learning or memory retrieval in the Morris water maze. As a result of reversal learning, placebo treated rats shifted searching behavior and swam less in the area of original platform position and more in the area of recent platform position, suggesting formation of the new spatial map. CVNP treated rats did not change the searching pattern and still investigated the area that contained "original" escape platform, suggesting that CVNP treatment delays the extinction of spatial memory. In another experiment, CVNP administered for 8 days did not influence the acquisition of the active avoidance task, but significantly delayed its extinction. The present findings indicate that colostrinin-derived nonapeptide may delay the extinction of long-term memories.

Aging↗
PubMed2001

The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans.

RATIONALE: Preclinical observations suggest that NMDA receptor-mediated glutamatergic neurotransmission is involved in the expression and maintenance of opioid dependence. OBJECTIVE: The present study evaluated whether memantine, the clinically available non-competitive NMDA receptor antagonist, decreases naloxone-precipitated withdrawal in morphine-dependent humans. METHODS: Eight heroin-dependent, non-treatment seeking, inpatient participants were stabilized on a fixed dose of morphine (30 mg PO qid). Subsequently, they received a series of challenges with naloxone (0.4 mg, IM) and the severity of opioid withdrawal was monitored. Either placebo or memantine (60 mg PO) was given 6 h before each naloxone challenge. A modified multiple baseline, across-participants design was used to evaluate the effects of memantine on the severity of naloxone-precipitated opioid withdrawal. RESULTS: Naloxone increased ratings and produced physical changes consistent with opioid withdrawal. Memantine attenuated the severity of opioid withdrawal as assessed with the Clinical Institute for Narcotic Withdrawal Scale scale. Withdrawal was significantly reduced when naloxone was administered at 6 and 52 h after memantine, but not when administered 126 h (5 days) after memantine. Medication effects, assessed 5 h after memantine administration and before naloxone administration, included significant increases in ratings of "strong" and "good" drug effect, and "I feel sedated", "mellow", and "high". CONCLUSIONS: Memantine attenuated the expression of opioid physical dependence in humans, indicating that glutamatergic neurotransmission at the NMDA receptor site contributes to the maintenance of opioid dependence. This finding suggests that memantine may be a useful adjunct in the treatment of opioid dependence.

Adult↗
PubMed2000

In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists.

The most challenging aspect of treating alcohol and drug addiction is the relapsing course of these disorders. Although substitution therapies for nicotine and opioid dependence have proven to be relatively effective, there is a need for new pharmacotherapies designed to decrease the frequency and severity of relapse. The aim of this paper is to provide an overview of the potential utility of N-methyl-D-aspartate (NMDA) receptor antagonists as treatments for substance abuse as shown in preclinical models and preliminary clinical trials. It is hypothesized that NMDA receptors mediate the common adaptive processes that are involved the development, maintenance, and expression of drug and alcohol addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists offers a novel treatment approach. It is proposed that NMDA antagonists may have multiple functions in treating addictions, including an attenuation of withdrawal effects, normalization of the affective changes following initiation of abstinence which arise from neurochemical changes resulting from chronic addiction, and an attenuation of conditioned responses arising from drug-related stimuli.

Alcoholism↗
PubMed2000

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice.

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

Analgesics, Opioid↗
PubMed2000

Chronic treatment with antidepressants affects glycine/NMDA receptor function: behavioral evidence.

Like the clinically effective benzodiazepine anxiolytic, chlordiazepoxide, the glycine/NMDA receptor antagonist L-701,324 (3, 7.5 and 10 mg/kg), produces dose-related increases in the percentage of time spent in the open arms and the percentage of entries into the open arms of an elevated plus maze in mice. Consistent with its proposed mechanism of action, these anxiolytic effects of L-701,324 (7.5 mg/kg) are reversed by pretreatment with glycine (500 and 800 mg/kg). Chronic treatment with citalopram (20 mg/kg for 21 days), imipramine (15 mg/kg for 21 days) and electroconvulsive shock (ECS, for 8 days), produced a reduction in the anxiolytic-like actions of L-701,324 (7.5 mg/kg) such that they could not be reversed by glycine. In contrast, the anxiolytic effects of L-701,324 and reversal of these effects by glycine were unaffected by acute treatment with imipramine, chronic administration with placebo or the neuroleptic chlorpromazine, or sham ECS. Further, imipramine administered for 21 days did not affect the anxiolytic effect of 5 mg/kg of chlordiazepoxide. The apparent reduction in the anxiolytic-like actions of a specific glycine/NMDA receptor antagonist following chronic treatment with a variety of antidepressants is consistent with previous neurochemical and molecular studies indicating that chronic antidepressant treatment can affect NMDA receptor function.

Animals↗
PubMed2000

Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice.

1. Antagonists of glutamate N-methyl-D-aspartate (NMDA) subtype receptor inhibit the development of tolerance to the antinociceptive effects of opioids. Another way to inhibit the function of glutamate receptors is the stimulation of presynaptic metabotropic group II (mGluRII) receptors. Because LY354740 ((+)-2-aminobicyclo [3,1,0] hexane-2,6-dicarboxylic acid) is the first systemically active agonist of group II mGlu receptors, we investigated if this compound might inhibit the development of tolerance to antinociceptive effects of morphine and fentanyl. 2. As assessed by cumulative dose-response approach in the tail-flick test, administration of 10 mg kg(-1) morphine bid s.c. to male Albino Swiss mice for 6 days, right-shifted morphine dose-response curve by approximately 4 fold. In a separate group of mice, 12 injections of 0.04 mg kg(-1) of fentanyl over 3 days, right-shifted fentanyl dose-response curve by approximately 3.3 fold. 3. In experiment 1, LY354740 (1 and 10, but not 0.1 mg kg(-1)) as well as the reference compound, an uncompetitive NMDA receptor antagonist memantine (7.5 mg kg(-1)) inhibited the development of morphine tolerance. Neither LY354740 (10 mg kg(-1)) nor memantine (7.5 mg kg(-1)) affected the development of tolerance to fentanyl. In experiment 2, neither LY354740 (1 and 10 mg kg(-1)) nor memantine (7.5 mg kg(-1)) affected the tail-flick antinociceptive response, or the acute antinociceptive effect of morphine. 4. The present results are the first to suggest that the development of antinociceptive morphine tolerance may be inhibited by metabotropic group II glutamate agonist.

Analgesics, Opioid↗
PubMed2000

Therapeutic potential of NMDA receptor antagonists in the treatment of alcohol and substance use disorders.

Despite the fact that the use of alcohol, nicotine and other drugs is the major external factor contributing to mortality in industrialised countries, there are few medications available to treat alcohol and substance use disorders. In recent years, major advances have been made in the understanding of the neurobiological basis for these disorders and these advances should lead to the development of new pharmacotherapeutics. A substantial amount of the research suggests that N-methyl-D-aspartate (NMDA) receptor neurotransmission contributes to mediating the behavioural effects of alcohol and other drugs of abuse. This research supports the therapeutic potential of NMDA receptor antagonists in alcohol and substance use disorders. In this paper the authors present their opinion on the goals and stages of pharmacological treatment of these complex psychiatric disorders. Available preclinical research using designs that model aspects of alcohol and substance use disorders is summarised, with an emphasis on research published in the last two years. In animal models, NMDA antagonists inhibit physical dependence and the reinforcing effects of a variety of abused substances. The ability of NMDA antagonists to inhibit tolerance to drug effects and contribute possible antidepressant and anxiolytic effects are also important from the perspective of drug development. This review summarises the relevant clinical laboratory and treatment data. Finally, it presents the status of the current development of NMDA receptor antagonists and discusses candidates with the greatest potential for clinical development.

Alcoholism↗
PubMed2000

[Contemporary methods in pharmacotherapy in the opiate dependent treatment].

In this review, we present methods of pharmacotherapy in opiate dependence currently used in Poland and worldwide. As problems associated with drug abuse increase in severity, it is particularly important to bring these methods to the attention of medical professionals, governmental agencies and the general public. Here we describe pharmacotherapeutic approaches used in detoxification as well as relapse prevention. The presented methods of detoxification include classical treatments with clonidine and methadone as well as newer methods of rapid and ultrarapid detoxification. Agonists, partial agonists, and antagonists can be used in preventing relapse in detoxified patients. Experimental therapeutic approaches in the treatment of drug dependence are also presented. Psychotherapy and psychiatric care, central to the successful treatment of opiate dependence, are reviewed as well.

Adrenergic alpha-Agonists↗
PubMed1999

Mesolimbic NMDA receptors are implicated in the expression of conditioned morphine reward.

Systemic administration of a variety of N-methyl-D-aspartate (NMDA) receptor antagonists inhibits morphine's rewarding properties in the conditioned place preference test. In this study, we investigated the anatomical loci implicated in the inhibition of expression of morphine's reward by bilateral microinjections of a selective NMDA antagonist into the mesolimbic areas, including ventral tegmental area and nucleus accumbens. During conditioning, injections of 1 mg/kg morphine were associated with placing rats in one chamber of the place preference box; the exposures to the other chamber were associated with placebo administration. On the test day, drug-free control subjects demonstrated a marked preference for the morphine-associated chamber. Systemic administration of 5 mg/kg and 10 mg/kg of the competitive NMDA antagonist, NPC 17742 (2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), significantly reduced the expression of morphine-induced conditioned place preference; the dose of 10 mg/kg produced also an inhibition of locomotor activity. Similar attenuation of the expression of morphine-induced conditioned place preference was observed in rats receiving 15.6 and 62.5 ng/0.5 ml side of NPC 17742 injected bilaterally into the nucleus accumbens and ventral tegmental area. While the higher intra-accumbal dose of NPC 17742 produced behavioral stimulation, intra-tegmental injection did not affect locomotor activity. These findings suggest that activation of NMDA receptors in the nucleus accumbens and ventral tegmental area is necessary for the elicitation of approach by environments previously associated with morphine's rewarding action.

Amino Acids↗
PubMed1999

Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models.

Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.

Animals↗