l-701324 and Substance-Withdrawal-Syndrome

The endocannabinoid system is a neuromodulatory system which controls the release of multiple neurotransmitters, including glutamate and both, the endocannabinoid and glutamatergic systems, have been implicated in alcohol relapse. Cannabinoid agonists induce an increase in relapse-like drinking whereas glutamate receptor antagonists could prevent it. Here we hypothesize that cannabinoid-induced increases in relapse-like alcohol drinking could be mediated by glutamatergic N-methyl-d-aspartate (NMDA) receptors. To test this hypothesis, Wistar rats with a background of alcohol operant self-administration were treated with the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl), pyrrolo [1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55.212-2, WIN) (2.0 mg/kg) during periods of alcohol deprivation. For five consecutive days, 30 min before the reintroduction of alcohol, rats were injected with the NMDA/glycine receptor antagonist 7-chloro-4-hydroxy-3-(3-phenoxy)phenylquinolin-2-[1H]-one (L-701) (1.25-5.0 mg/kg) and alcohol reinforcement was evaluated. Our results clearly show that L-701 prevented the cannabinoid-induced increase in relapse-like drinking in a dose-dependent manner, whereas L-701 alone, in the absence of WIN treatment, did not significantly alter alcohol intake. The potentiation of relapse-like drinking induced by WIN is not caused by nonspecific anxiogenic effects, since no effect was observed in the elevated-plus maze test. These alcohol-related behaviors are linked to differential changes in CNR1 and NR1 subunit mRNA transcripts. In WIN-treated rats, an increase in CNR1 transcript levels was observed in the hypothalamus and striatum, whereas in the amygdala and anterior cingulate cortex, brain regions involved in emotional processing, a decrease was observed. Interestingly, such changes were blocked after L-701 treatment. Finally, WIN treatment also caused a reduction in NR1 mRNA levels in the amygdala. In conclusion, pharmacological inactivation of the glycine-binding site of NMDA receptors may control cannabinoid-induced relapse-like drinking, which is associated with altered expression of CNR1 and NR1 gene expression as observed after WIN treatment.

Topics: Alcohol Drinking; Alcoholism; Animals; Benzoxazines; Binding Sites; Cannabinoids; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Excitatory Amino Acid Antagonists; Glycine; Male; Maze Learning; Morpholines; Naphthalenes; Quinolones; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, N-Methyl-D-Aspartate; Self Administration; Substance Withdrawal Syndrome

Numerous data indicate that noncompetitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists inhibit the development of physical dependence on opioids when these substances are administered together, and NMDA receptor antagonists are used at lower range of doses. Higher doses of these antagonists can enhance some opioid-induced effects. The present study extends these findings to the effects of NMDA/glycine (glycine(B)) site antagonists. Wistar rats were rendered dependent on morphine by implantation of morphine pellets. Both of the glycine(B) site antagonists used, 7-chloro-4-hydroxy-3-(3-phenoxy)-phenyl-2(H)-quinolone (L-701,324; 2.5 and 5.0 mg/kg) and 5,7-dichlorokynurenic acid (5,7-DCKA; 25, 50, and 100 mg/kg), suppressed the expression of morphine withdrawal syndrome estimated as wet dog shakes. Furthermore, L-701,324 (2.5 and 5 mg/kg), given twice a day during the development of morphine dependence, attenuated the development of morphine dependence, and the results were comparable to those obtained after administration of noncompetitive NMDA receptor antagonist - MK801 (0.1 mg/kg). Our data suggest that glycine(B) site antagonists may attenuate wet dog shakes (withdrawal) and the development of dependence, both being induced by chronic morphine administration in rats.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Implants; Excitatory Amino Acid Antagonists; Glycine Agents; Kynurenic Acid; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Quinolones; Rats; Rats, Wistar; Receptors, Glycine; Substance Withdrawal Syndrome

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.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Binding, Competitive; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Quinolones; Rats; Rats, Wistar; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Reinforcement, Psychology; Substance Withdrawal Syndrome

Cessation of chronic administration of orally administered large amounts of ethanol for 7 days resulted in a markedly increased frequency of audiogenic seizures in Sprague-Dawley rats. Oral administration of the novel glycine receptor antagonist, L-701,324, produced a dose-dependent (2.5 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal signs when measured about 12 h after withdrawal of the ethanol treatment. Similarly, using the same experimental paradigm, oral administration of the specific polyamine receptor antagonist, eliprodil, caused a dose-related (2.0 and 5.0 mg/kg; -30 min) inhibition of ethanol withdrawal-induced audiogenic seizure activity. The inhibition of ethanol withdrawal seizures produced by L-701,324 and eliprodil, respectively, was obtained at doses which by themselves did not change the locomotor activity in naive Sprague-Dawley rats. The findings that L-701,324 and eliprodil are potent inhibitors of seizure activity induced by cessation of chronic ethanol administration and the fact that they, in contrast to currently available NMDA receptor antagonists, do not produce psychotomimetic and/or sedative effects, suggest that these drugs may represent a new class of therapeutically useful pharmacological agents for the treatment of ethanol withdrawal seizures. Furthermore, since there is evidence that eliprodil produces its pharmacological actions through a specific inhibition of NMDAR1 and/or NMDAR2B subunits, these data may indicate that certain NMDA receptor subunits may be of particular importance for the mediation of seizure activity following the discontinuation of chronic ethanol exposure.

Topics: Acoustic Stimulation; Administration, Oral; Animals; Anticonvulsants; Central Nervous System Depressants; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Male; Motor Activity; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Seizures; Substance Withdrawal Syndrome