Effects of the NMDA receptor antagonist, D-CPPene, on sensitization to the operant decrement produced by naloxone in morphine-treated rats.

Sensitization to the rate-decreasing effects of opioid antagonists induced by acute pretreatment with opioid agonists has been suggested to reflect initial changes in opioid systems that underlie physical dependence. Glutamate receptors are implicated in the development and expression of opioid dependence, and antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown repeatedly to attenuate the severity of opioid withdrawal. The present study evaluated the ability of a competitive NMDA receptor antagonist, D-CPPene (SDZ EAA 494; 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid), to affect morphine-induced sensitization to naloxone in rats trained to lever-press on a multiple-trial, fixed-ratio 10 schedule of food reinforcement. D-CPPene (0.3-3 mg/kg) was administered either 4 h or 30 min prior to the test session. Morphine (10 mg/kg) or its vehicle was administered 4 h before naloxone challenge (0.3-3 mg/kg). D-CPPene failed to prevent morphine-induced potentiation of the naloxone-produced decrement in operant performance. Thus, these results suggest that agonist-induced sensitization to behavioral effects of opioid antagonists may be insensitive to NMDA receptor blockade.

Effects of calcium channel blockers on behaviors induced by the N-methyl-D-aspartate receptor antagonist, dizocilpine, in rats.

The present study assessed the ability of voltage-sensitive calcium channel (VSCC) blockers to affect the behavioral effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine, in male Wistar rats. Dizocilpine produced dose-dependent increases in locomotor activity. Nimodipine, verapamil, and flunarizine suppressed dizocilpine-facilitated vertical activity, while horizontal activity was attenuated by verapamil and nimodipine but not flunarizine. Repeated dizocilpine injections resulted in the development of sensitization to its locomotor stimulating properties. Development of sensitization was not context specific, and was observed following repeated exposures to 0.1 but not 0.056 or 0.3 mg/kg of dizocilpine. Nimodipine retarded the development of sensitization to dizocilpine's stimulating effects on horizontal activity, while verapamil suppressed sensitization to the vertical stimulating effects of dizocilpine. Flunarizine had no significant effects on sensitization to dizocilpine's locomotor stimulating properties. In rats trained to discriminate between injections of 0.056 mg/kg of dizocilpine and vehicle, none of the tested VSCC blockers was able to completely antagonize the discriminative stimulus properties of dizocilpine. Nimodipine, when administered in combination with the training dose of dizocilpine, modestly decreased the dizocilpine-lever selection. Dizocilpine dose dependently decreased the self-determined stimulation threshold implanted in rats with electrodes into the ventral tegmental area. Nimodipine exhibited some tendency to block the facilitating effects of dizocilpine, while verapamil and flunarizine had no effects. In summary, in the present experiments VSCC blockers exerted only modest interactions with the behavioral effects of dizocilpine, and it is unlikely that VSCC blockers have remarkable potential as adjunct treatment aimed at correcting the negative side effects of NMDA receptor antagonists (e.g., dizocilpine).

Differential effects of nitric oxide synthase inhibitor, 7-nitroindazole, on discriminative stimulus and somatic effects of naloxone in morphine-dependent rats.

Our previous report suggested that antagonists acting at NMDA receptors attenuate discriminative stimulus effects of naloxone in morphine dependent rats. Nitric oxide (NO) is a putative second messenger which mediates NMDA receptor activation. The present study evaluated behavioral effects of NO synthase inhibitor, 7-nitroindazole in morphine-dependent rats trained to discriminate 0.1 mg/kg naloxone from saline. 7-Nitroindazole did not significantly affect naloxone's discriminative stimulus effects but decreased naloxone-induced weight loss and abolished expression of several withdrawal signs--diarrhea, scream on touch, tremor and 'wet dog'-like shaking suggesting different mechanisms for subjective and somatic components of opioid withdrawal.

[The discriminative stimulus properties of naloxone during dissociative learning in a Y maze in morphine-dependent rats]. / Diskriminativnye stimul'nye svoistva naloksona pri dissotsiirovannom obuchenii v Y-obraznom labirinte u morfinzavisimykh krys.

The study was dedicated to evaluation of discriminative stimulus properties of opiate withdrawal syndrome precipitated by naloxon. The possibility of naloxon-appropriate reaction significantly increased in a dose-dependent manner (0-1.0 mg/kg, ED50 = 0.03 mg/kg) and was observed during the period of morphine withdrawal (8-96 h, peak at 24 h). Naloxone stimulus effects were antagonized by morphine (10-100.mg/kg), thus providing the experimental evidence for competitive and saturatable nature of interaction with opiate receptors. The probability of naloxone-appropriate reaction decreased during administration of the conditioned stimulus associated with morphine injection. Ligands of peripheral opiate receptors failed to either substitute for naloxone (methylnaloxon, 0.1-3.0 mg/kg) or attenuate naloxone stimulus effects (loperamide, 1-30 mg/kg).

Behavioural effects of glutamate receptor agonists in morphine-dependent rats.

Glutamate receptors are implicated in the development and expression of drug dependence. Substantial experimental evidence suggests that antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors attenuate the severity of opioid withdrawal. However, it is less clear whether opioid withdrawal can be potentiated by agonists of glutamate receptors. The present study evaluated the behavioural effects of various agonists of glutamate receptors, as well as a nitric oxide (NO) donor, in morphine-dependent rats trained to discriminate 0.1 mg/kg of naloxone from saline. None of the following drugs produced appreciable levels of naloxone-like responding (substitution tests) or potentiated the discriminative stimulus effects of naloxone: NMDA (3-56 mg/kg), glycine (100-1000 mg/kg), glutamate (1000-3000 mg/kg), kainate (0.3-3 mg/kg), isosorbide dinitrate (30-300 mg/kg). Nevertheless, expression of some morphine withdrawal-like somatic and behavioural signs ('wet-dog'-like shaking, scream on touch, ptosis, tremor, chewing, weight loss) was facilitated by NMDA, glycine, and isosorbide dinitrate. These results suggest that, compared to somatic symptoms, subjective effects of opioid withdrawal (as reflected by discriminative stimulus effects) are not mimicked by direct activation of glutamate receptors.

Effects of N-methyl-D-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm.

The present study assessed the ability of various site-selective N-methyl-D-aspartate (NMDA) receptor antagonists to affect the discriminative stimulus properties of naloxone in morphine-dependent rats. Adult male Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxone from saline using a Y-maze shock-avoidance procedure. Naloxone-appropriate responding was exhibited as a function of naloxone dose (0.01-1.0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treatment temporarily was discontinued (8-96 hr, peak at 24 hr). Discriminative stimulus effects of naloxone (0.1-3.0 mg/kg) were antagonized by morphine (10-100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1-3.0 mg/kg) or attenuate naloxone's stimulus effects (loperamide, 1-30 mg/kg). In rats treated with the training dose of naloxone, administration of dizocilpine (0.03-0.3 mg/kg) and D-CPPene (1-10 mg/kg) decreased levels of naloxone-appropriate responding, whereas memantine (1-30 mg/kg), ACEA-1021 (10 and 50 mg/kg) and eliprodil (3-30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a decrease in the occurrence of two or more of the following opioid withdrawal signs: weight loss, forelimb tremor, ptosis, diarrhea and "wet-dog"-like shaking. Additionally, dizocilpine (0.1 mg/kg), D-CPPene (5.6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or eliprodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morphine treatment 24 hr after the last morphine injection. Thus, NMDA receptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, and this ability depends on the type of antagonist applied.