R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder1.

Substance abuse disorder continues to have devastating consequences for individuals and society and current therapies are not sufficient to provide the magnitude of medical impact required. Although some evidence suggests the use of ketamine in treating various substance use related- symptoms, its adverse event profile including dissociation, dysphoria, and abuse liability limit its potential as a therapy. Here, we outline experiments to test our hypothesis that (R)-ketamine can both alleviate withdrawal symptoms and produce effects that help sustain abstinence. In morphine-dependent rats, (R)-ketamine alleviated naloxone-precipitated withdrawal signs. (R)-ketamine also blocked morphine-induced place preference in mice without inducing place preference on its own. We also evaluated whether (R)-ketamine would induce anhedonia, a counter-indicated effect for a drug abuse treatment agent. S-(+)- but not R-(-)-ketamine produced anhedonia-like responses in rats that electrically self-stimulated the medial forebrain bundle (ICSS). However, time-course studies of ICSS are needed to fully appreciate these differences. These data begin to support the claim that (R)-ketamine will dampen withdrawal symptoms and drug liking, factors known to contribute to the cycle of drug addiction. In addition, these data suggest that (R)-ketamine would not produce negative mood or anhedonia that could interfere with treatment. It is suggested that continued investigation of (R)-ketamine as a novel therapeutic for substance abuse disorder be given consideration by the preclinical and clinical research communities. This suggestion is further encouraged by a recent report on the efficacy of (R)-ketamine in treatment-resistant depressed patients at a dose with little measurable dissociative side-effects.

Dopamine induces an optimism bias in rats-Pharmacological proof for the translational validity of the ambiguous-cue interpretation test.

Recent findings have revealed that pharmacological enhancement of dopaminergic (DA) function by the administration of a dopaminergic precursor (dihydroxy-l-phenylalanine; l-DOPA) increases an optimism bias in humans. This effect is due to l-DOPA's impairment of the ability to update beliefs in response to undesirable information about the future. To test whether an 'optimistic' bias is also mediated by dopamine in animals, first, two groups of rats received either a dopaminergic precursor, l-DOPA, or a D2 receptor antagonist, haloperidol, and were subsequently tested using the ambiguous-cue interpretation (ACI) paradigm. To test whether similar effects might be observed when manipulating another neurotransmitter implicated in learning about reward and punishment, we administered the serotonin (5-HT) reuptake inhibitor escitalopram to a third group of animals and the selective and irreversible tryptophan hydroxylase inhibitor para-chlorophenylalanine (PCPA) to a fourth group. The results of our study demonstrated that prolonged (2 weeks), but not acute, l-DOPA administration induced optimistic bias in rats. Neither acute nor chronic treatment with the other tested compounds had significant effects on the cognitive judgment bias of rats. The convergence of these results with human studies suggests the translational validity of the ambiguous-cue interpretation paradigm in testing the effects of pharmacological manipulations on cognitive judgment bias (optimism/pessimism) in rats.

Anandamide mediates cognitive judgement bias in rats.

In the present study, we investigated the effects of acute pharmacological manipulation of the endocannabinoid (EC) system on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. To accomplish this goal, after initial behavioural training, different groups of rats received single, systemic injections of the irreversible anandamide (AEA) hydrolysis inhibitor URB597, the cannabinoid receptor type 1 (CB1) inverse agonist AM251, the cannabinoid receptor type 2 (CB2) inverse agonist AM630, the combination of URB597 and AM251, and a combination of URB597 and AM630 and were subsequently tested with the ACI paradigm. We report that URB597 at a dose of 1 mg/kg significantly biased animals towards positive interpretation of the ambiguous cue and that this effect was abolished by pre-treatment with AM251 (1 mg/kg) or AM630 (1 mg/kg). The CB1 and CB2 inverse agonists administered alone (1 mg/kg) had no statistically significant effects on the interpretation of the ambiguous cue by rats. Our findings suggest involvement of the endocannabinoid system in the mediation of optimistic judgement bias.

Pro-cognitive activity in rats of 3-furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor.

BACKGROUND AND PURPOSE: α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro-cognitive activity of selective α7-nAChR ligands, including the partial agonists, DMXBA and A-582941, as well as the positive allosteric modulator, 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2). EXPERIMENTAL APPROACH: The attentional set-shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro-cognitive activity of each ligand [i.e., PAM-2 (0.5, 1.0, and 2.0 mg·kg(-1) ), DMXBA and A-582941 (0.3 and 1.0 mg·kg(-1) )], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM-2 (0.5 mg·kg(-1) ) was co-injected with inactive doses of either agonist - DMXBA: 0.1 (NORT); 0.3 mg·kg(-1) (ASST) or A-582941: 0.1 mg·kg(-1) . KEY RESULTS: PAM-2, DMXBA, and A-582941 improved cognition in a MLA-dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co-injection of inactive doses of PAM-2 and DMXBA or A-582941 also improved cognition, suggesting drug interactions. Moreover, PAM-2 reversed the scopolamine-induced NORT deficit. The electrophysiological results also support the view that PAM-2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 µM) of DMXBA with apparent EC50 = 34 ± 3 µM and Emax = 225 ± 5 %. CONCLUSIONS AND IMPLICATIONS: Our results support the view that α7 nAChRs are involved in cognition processes and that PAM-2 is a novel promising candidate for the treatment of cognitive disorders.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.