Modulation of morphine sensitization in the rat by contextual stimuli

Rationale: The repeated administration of addictive drugs, such as amphetamine, cocaine, and morphine, produces a progressive enhancement (sensitization) of their psychomotor activating effects. We have previously shown that administration of amphetamine or cocaine in a distinct test environment promotes more robust psychomotor sensitization than if they are given at home. No information is available, however, on whether this environmental manipulation has a similar effect on sensitization to morphine, a drug that enhances dopamine (DA) release in the striatum indirectly by disinhibiting midbrain DA neurons. Objectives: The main goal of present study was to determine whether exposure to a distinct environmental context facilitates morphine sensitization. Methods: As an index of psychomotor activation, we used rotational behavior in rats with a uni- lateral 6-hydroxydopamine lesion of the mesostriatal DA system. There are inconsistencies in the literature regarding the ability of morphine to elicit rotational behavior. Therefore, in experiment 1 we determined the effect of 2.0, 3.0, 4.0, 6.0, and 8.0 mg/kg, IP, of morphine on rotational behavior. In experiment 2, we studied the effect of five consecutive IV infusions of saline or morphine (2.0 mg/kg) in rats treated either in their home cage or in a distinct and relatively novel test environment. After 5 days of withdrawal, all rats received an IV infusion of 2.0 mg/kg morphine (Morphine challenge). The following day all rats received an IV infusion of saline (Saline challenge). Results: Morphine produced a dose-dependent increase in rotational behavior. Environmental novelty enhanced both the acute psychomotor response to morphine and its ability to induce psychomotor sensitization. Furthermore, a conditioned rotational response was seen only in animals treated in the novel environment. Conclusions: Environmental novelty can facilitate the development of sensitization to the psychomotor activating effects of major addictive drugs, such as amphetamine, cocaine, and morphine. Received: 29 November 1999 / Accepted: 14 March 2000     

Inhibitory effects of glycine on morphine-induced hyperactivity,reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice

The effects of glycine on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity in mice was examined. A single administration of morphine (10 mg/kg, s.c.) induced hyperactivity as measured in mice. The morphine-induced hyperactivity was inhibited by pretreatment with glycine (100, 200 and 400 mg/kg, i.p.). In addition, it was found repeated administration of morphine (10 mg/kg, s.c.) to mice daily for 6 days caused an increase in motor activity which could be induced by a subsequent morphine dose, an effect known as reverse tolerance or sensitization. Glycine (100, 200 and 400 mg/kg, i.p.) also inhibited morphine-induced reverse tolerance. Mice that had received 7 daily repeated administrations of morphine also developed postsynaptic dopamine receptor supersensitivity, as shown by enhanced ambulatory activity after administration of apomorphine (2 mg/kg, s.c.). Glycine inhibited the development of postsynaptic dopamine receptor supersensitivity induced by repeated administration of morphine. It is suggested that the inhibitory effects of glycine might be mediated by dopaminergic (DAergic) transmission. Accordingly, the inhibition by glycine of the morphine-induced hyperactivity, reverse tolerance and dopamine receptor supersensitivity suggests that glycine might be useful for the treatment of morphine addiction.     

Effect of selective monoamine oxidase inhibitors on the morphine-induced hypothermia in restrained rats

Morphine (30 mg/kg i.p.) produced a hypothermic effect in restrained rats which was antagonized by naloxone pretreatment (10 mg/kg s.c.). This hypothermia was inhibited by deprenyl pretreatment (5 mg/kg i.p.) and by beta-phenylethylamine treatment (25 mg/kg i.p.). However, the effect of morphine was partially potentiated when a higher dose of deprenyl (10 mg/kg i.p.) was administered. Pretreatment with clorgyline (1 mg/kg i.p.) potentiated the morphine-induced hypothermia. In contrast, the effect of morphine was antagonized when a higher dose of clorgyline was used (5 mg/kg i.p.). Based on these results, a possible role of brain serotonin and dopamine in the thermoregulatory effects of morphine is proposed in this paper.     

Role of nitric oxide in the acquisition and expression of apomorphine- or morphine-induced locomotor sensitization

In the present study, the effects of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on apomorphine- or morphine-induced locomotor sensitization in male albino mice were investigated. Our data showed that subcutaneous (s.c.) injection of apomorphine (2-10 mg/kg) or morphine sulphate (5-50 mg/kg) significantly increased locomotor behaviour in a dose-dependent manner. Intraperitoneal (i.p.) administration of L-arginine (100 mg/kg) increased locomotor activity, whereas L-NAME (20 mg/kg) decreased it. L-Arginine and L-NAME increased and decreased apomorphine- or morphine-induced locomotions, respectively. The locomotor behavioural response was enhanced in mice pretreated with apomorphine (2 mg/kg, daily x3 days) or morphine (10 mg/kg, daily x3 days) alone, indicating that sensitization had developed. Administration of L-arginine 30 min before each of three daily doses of apomorphine or morphine increased the development of sensitization, while administration of L-NAME 30 min before each of three daily doses of apomorphine or morphine decreased the acquisition of sensitization induced by apomorphine or morphine. Administration of L-arginine significantly increased and L-NAME significantly and dose-dependently decreased the expression of both apomorphine- and morphine-induced sensitization. The results indicate that NO may be involved in the acquisition and expression of apomorphine- or morphine-induced sensitization.     

Inhibitory effects of MPEP,an mGluR5 antagonist,and memantine,an <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate receptor antagonist,on morphine antinociceptive tolerance in mice

Abstract Rationale. Inhibition of N-methyl-D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known. Objective. In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice. Methods. Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose–response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test. Results. MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception. Conclusions. The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance. Electronic Publication     

Femoxetine blocks the morphine-induced increase in 5-HT metabolism, as measured by in vivo voltammetry in the nucleus raphe magnus of freely-moving rats.

Tricyclic antidepressants, when administered acutely, are known to potentiate morphine-induced antinociception. Systemic administration of morphine has been shown to increase the metabolism of serotonin (5-HT) at the level of the nucleus raphe magnus, as measured by in vivo electrochemistry, in freely-moving rats. Using a similar electrochemical detection of 5-hydroxyindole (peak "3") in the nucleus raphe magnus, the present study investigated the effect of the specific 5-HT uptake inhibitor, femoxetine, on peak 3 and on changes in the metabolism of 5-HT, induced by morphine. Acutely administered femoxetine (40 mg/kg i.p.) induced a significant decrease in peak 3 and completely abolished the effect of morphine (10 mg/kg i.p.) on the metabolism of 5-HT. These data do not support the contention that potentiation of morphine-induced analgesia, by tricyclic depressants results from an interaction between the tricyclic antidepressants and the morphine-induced increase in metabolism of 5-HT, at the level of the nucleus raphe magnus.     

Dexamethasone reduces morphine-induced Straub reaction in mice

This study examined the effect of dexamethasone on morphine-induced straub reaction in mice. When morphine was administered in doses of 7.5, 15 and 30 mg kg(-1) intraperitoneally, a dose-dependent straub reaction was produced. Dexamethasone per-se (0.1-10 mg kg(-1) i.p.) did not modify the tail of control mice. Pre-treatment with dexamethasone 120 min before morphine injection caused a dose-dependent reduction of straub reaction. Cycloheximide (15 mg kg(-1) i.p.) administered 2 h before morphine did not change morphine-induced straub reaction, but was able to prevent the effects of dexamethasone on morphine-induced straub reaction. The glucocorticoid receptor antagonist RU-38486 (15 mg kg(-1) i.p.) did not affect morphine-induced straub reaction, whereas it was able to block the effects of dexamethasone on morphine-induced straub reaction. Results of this study indicate that dexamethasone reduced morphine-mediated straub reaction in mice, indicating a further important functional interaction between dexamethasone and the opioid system. The ability of cycloheximide and RU-38486 to block dexamethasone's effects indicates that the steroid's interference with morphine-mediated straub reaction involves a protein-synthesis-dependent mechanism via glucocorticoid receptors.     

Effects of repeated exposure to morphine in adolescent and adult male C57BL/6J mice: age-dependent differences in locomotor stimulation,sensitization, and body weight loss

Rationale

Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults).

Objectives

This study compared the motor stimulating and ataxic effects of repeatedly administered morphine in adolescent, late adolescent, and adult mice.

Methods

Mice were treated with saline or morphine (10–100 mg/kg, i.p.) once per day for 4 days, and morphine (3.2–56 mg/kg)-induced locomotion was assessed 3 days or 5 weeks later. Different mice were treated repeatedly with morphine and ataxia was measured.

Results

Acute administration of morphine increased locomotion more in adolescents than in adults. Repeated morphine enhanced morphine-induced locomotion, assessed 3 days later, to a similar extent in each age group (minimum effective dose 17.8 mg/kg). This sensitization was still evident 5 weeks later when the adolescents had become adult, but was smaller and occurred at a higher dose (56 mg/kg). In animals treated repeatedly with morphine as adults, sensitization was no longer apparent 5 weeks later. Intermittent morphine was at least 10-fold less potent to produce body weight loss in adolescents than in adults. Repeated morphine did not alter morphine-induced ataxia at any age.

Conclusions

Compared with adults, adolescents were more sensitive to the acute locomotor stimulating effects of morphine and to its long-lasting locomotor sensitizing effects, consistent with overactivity of dopamine systems during adolescence. In contrast, adolescents were less sensitive than adults to body weight loss induced by intermittent morphine, an effect indicative of morphine withdrawal in adult rodents.     

The effect of the CS-UCS interval and extinction on place conditioning and analgesic tolerance with morphine

In experiment 1, a CS-UCS interval study of place conditioning and analgesic tolerance with morphine was conducted. Morphine (10 mg/kg i.p.) was administered to separate groups of rats either 2 h prior to, 1 h prior to, immediately prior to, immediately after or 2 h after 30-min confinement in one end compartment of a place conditioning apparatus. A total of three choice tests was given, one after every six morphine injections. A preference for the end compartment contingent upon morphine injection was shown in groups that received morphine prior to end compartment placement. Groups that received morphine after end compartment placement were not different in their preference behavior from groups that received only saline during place conditioning training. A hot-plate test for tolerance to the analgesic effect of morphine was given at the end of all choice testing. All groups that had received morphine during place conditioning training were equally tolerant. These results indicate a dissociation between the analgesic effect of morphine and the effect that produces place preference, since the former was not affected by temporal parameters that did affect the latter. In the second experiment, the effect of extinction on a morphine-induced place preference was studied using extinction procedures that, in contrast to previous studies, equated exposure to both end compartments. Whereas the morphine-induced place preference was undiminished by a 10-day retention period in which animals received saline injections in the home cage, extinction trials during the same period eliminated the place preference. These results provide evidence that morphine-induced place preferences involve associative processes.     

Alpha 2-adrenoceptor modulates the release of acetylcholine from the rostral ventrolateral medulla in response to morphine

The present study examined the role of the noradrenergic system in the modulation of acetylcholine (ACh) release in the rostral ventrolateral medulla (RVLM) using in vivo microdialysis of morphine. The basal level of ACh was 325.0 +/- 21.1 fmol/20 microl/15 min in the presence of neostigmine (10 microM). Intraperitoneal (i.p.) administration of 5 and 10 mg/kg morphine significantly increased ACh release by the RVLM. This enhancement was reversed by naloxone (1 mg/kg, i.p.). In addition, pretreatment with yohimbine (0.5 mg/kg, i.p.) or prazosin (0.2 mg/kg, i.p.) attenuated the systemic morphine-induced release of ACh in the RVLM. However, propranolol (0.2 mg/kg, i.p.) did not affect the morphine-induced ACh release. The addition of morphine (10(-4) M) to the perfusion medium increased the ACh release by 72.4% of the predrug values. The increased ACh release induced by local application of morphine was attenuated by pretreatment with yohimbine, but not prazosin. These findings suggest that morphine exerts an indirect stimulatory effect on the release of ACh by the RVLM and that the morphine-induced increase in ACh release is modulated by alpha2-adrenoceptors in freely moving rats.     

Effects of adrenoceptor agonists and antagonists on morphine-induced Straub tail in mice

Straub-tail behavior was induced by subcutaneous injection of different doses (10-60 mg/kg) of morphine to mice. The maximum response was obtained with 20-40 mg/kg of the drug. The response induced by morphine (40 mg/kg) was decreased by intraperitoneal administration of different doses of clonidine (0.05-0.1 mg/kg). Pretreatment of animals with yohimbine (1-4 mg/kg i.p.) reversed the inhibitory action of clonidine. Yohimbine did not elicit any response by itself. Administration of prazosin (0.25, 0.5, and 1 mg/kg) reduced the morphine response. The combination of prazosin with yohimbine (1 mg/kg), but not with clonidine (0.05 mg/kg), caused a potentiated inhibition of the morphine effect. Phenylephrine (2-6 mg/kg i.p.) did not elicit any effect by itself and also did not alter the response induced by morphine or morphine plus clonidine. Dobutamine (2.5-10 mg/kg i.p.), atenolol (2.5-10 mg/kg i.p.), salbutamol (2.5-10 mg/kg i.p.), and propranolol (2.5-10 mg/kg i.p.) did not alter morphine-induced Straub-tail behavior in mice. In conclusion, activation of alpha2-adrenergic pathways contributes to morphine-induced Straub tail, while alpha1- and beta2-adrenergic may not be involved in this phenomenon.     

Blockade of morphine-induced behavioral sensitization by a combination of amisulpride and RB101, comparison with classical opioid maintenance treatments

BACKGROUND AND PURPOSE: Maintenance treatments with methadone or buprenorphine are more or less efficient procedures for helping heroin addicts to stop or reduce drug abuse. Another approach to treat opiate dependence could be to target the endogenous opioid system by enhancing the effects of enkephalins by protecting them from enzymic degradation by the dual peptidase inhibitor RB101. EXPERIMENTAL APPROACH: As chronic treatment with the dopamine D2 antagonist amisulpride facilitates RB101-induced behavioral effects, we chose in this study to treat mice previously sensitized to the hyperlocomotor effects induced by morphine with a combination of amisulpride and RB101. KEY RESULTS: Expression of morphine-induced locomotor sensitization was abolished after combined treatment with amisulpride (20 mg x kg(-1), i.p.) and RB101 (80 mg x kg(-1), i.p.), whereas these drugs were not effective when used alone. We then compared these results with the effects of amisulpride combined with buprenorphine (0.1 mg x kg(-1), i.p.) or methadone (2.5 mg x kg(-1), i.p.) upon morphine-induced behavioral sensitization. Whereas the combination of amisulpride and buprenorphine partially blocked the expression of morphine sensitization, amisulpride+methadone was not effective in this paradigm. CONCLUSIONS AND IMPLICATIONS: The combination of amisulpride+RB101 appears to be very efficient in blocking the expression of morphine-induced behavioral sensitization. This could reflect a reinstatement of a balance between the function of the dopamine and opioid systems and could represent a new approach in maintenance treatments for opiate addiction.     

Morphine-induced sensitization in mice: changes in locomotor activity by prior scheduled exposure to GABAA receptor agents

This study investigated the effects of a gamma-amino-butyric acid type A (GABAA) receptor agonist and antagonist on morphine-induced locomotor sensitization in male albino mice. Subcutaneous administration to mice of a high dose of morphine (30 mg/kg), but not lower doses (5, 10 and 20 mg/kg) increased locomotion. The maximum locomotor activity was achieved during a 20-min measurement period. The locomotor response to a low dose of morphine (5 mg/kg, subcutaneously) given on day 9 was enhanced in mice pretreated with morphine (7.5, 15 and 30 mg/kg/day x 3 days), indicating that sensitization had developed. Three-day intracerebroventricular (i.c.v.) administration of the GABAA receptor agonist, muscimol (0.025, 0.05, 0.1 and 0.2 microg/mouse/day) significantly decreased both morphine-induced motor stimulation and locomotor sensitization. On the other hand, a 3-day pretreatment with the GABAA-receptor antagonist, bicuculline (0.25, 0.5 and 1 microg/mouse/day) reduced morphine (15 mg/kg)-induced locomotor sensitization. Repeated i.c.v. injections of a lower dose of bicuculline (0.25 microg/mouse/day x 3 days) by itself also decreased morphine-induced locomotion. Furthermore, repeated i.c.v. administration of bicuculline (0.25, 0.5 and 1 microg/mouse/day x 3 days) decreased the effect of i.c.v. injection of muscimol (0.1 microg/mouse/day x 3 days) on locomotor activity induced by morphine (5 mg/kg) in both control and sensitized mice. The magnitude of this response was, however, variable. The results indicate that GABAA receptors might be involved in the acquisition of morphine-induced sensitization.     

The effect of L-stepholidine, a novel extract of Chinese herb, on the acquisition, expression, maintenance, and re-acquisition of morphine conditioned place preference in rats

The effect of L-stepholidine (SPD), a novel alkaloid extract of the Chinese herb Stephania with partial dopamine D1 receptor agonistic and D2 receptor antagonistic dual actions, on morphine conditioned place preference (CPP) was studied. Daily injection of morphine (10 mg/kg, i.p.) for 6 days induced CPP in rats, and daily treatment with SPD at 10 or 20 mg/kg before morphine injection dose-dependently attenuated morphine-induced CPP. On the day following acquisition of morphine CPP, a single administration of SPD at 10 or 20 mg/kg failed to block the expression of CPP. However, daily administration of SPD at 20 mg/kg for 7 days attenuated the maintenance of CPP. Morphine-induced CPP extinguished after a 21-day saline training and then a single injection of morphine (3 mg/kg, i.p.) induced re-acquisition of morphine CPP; however, pretreatment with SPD at 10 or 20 mg/kg 30 min before morphine injection dose-dependently blocked morphine (3 mg/kg, i.p.)-induced re-acquisition of morphine CPP. Furthermore, our data indicate that SPD had no effect on food-induced CPP or state-dependent learning, suggesting that the observed effect of SPD does not result from an inhibition of general learning ability. These results demonstrate that SPD can inhibit acquisition, maintenance, and re-acquisition of morphine conditioned place preference and suggest its potential for treatment of opioid addiction.     

Agmatine inhibits morphine-induced memory impairment in the mouse step-down inhibitory avoidance task

The effect of agmatine on memory formation in morphine-treated mice on the step-down inhibitory avoidance test was examined. Pre-training and pre-test administration of agmatine (5, 10 and 20 mg/kg, s.c.) facilitated memory formation and retrieval while post-training administration of agmatine (5, 10 and 20 mg/kg, s.c.) had no effect on memory consolidation. Idazoxan (5 mg/kg, i.p.) inhibited the effect of agmatine on memory formation and retrieval. Pre-training administration of morphine (1.25, 2.5 and 5 mg/kg, s.c.) impaired memory formation while post-training and pre-test administration of morphine (1.25, 2.5 and 5 mg/kg, s.c.) had no effect on memory consolidation and retrieval. Pre-training agmatine treatment reversed the impairment of morphine on memory formation. Moreover, pre-test administration of agmatine inhibited morphine-induced amnesia. Pre-training and pre-test idazoxan (5 mg/kg, i.p.) treatment inhibited the effect of agmatine on morphine induced memory impairment. In conclusion, agmatine inhibited morphine-induced memory impairment on the mice step-down inhibitory avoidance test. The mechanism was exerted, at least in part, through activation of imidazoline receptors.     

Effect of kappa-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats

The effect of i.p. administration of kappa-opioid receptor agonists, bremazocine, tifluadom and U-50,488H on morphine (8 mg/kg i.p.)-induced analgesia in morphine-naive and morphine tolerant male Sprague-Dawley rats was determined using the tail-flick test. The tolerance to morphine in the rats was induced by s.c., implantation of six morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of tolerance as evidenced by the decrease in the analgesic response to morphine when compared to placebo pellets implanted rats. Bremazocine (0.3, 1.0 and 3.0 mg/kg) and U-50,488H (16 mg/kg) antagonized morphine-induced analgesia in morphine-naive rats while tifluadom (8 and 16 mg/kg) potentiated the effect. In morphine-tolerant rats, bremazocine (3 mg/kg) and U-50,488H (16 mg/kg) potentiated morphine-induced analgesia. Tifluadom at any of the doses had no effect on morphine-induced analgesia in morphine-tolerant rats. These results provide evidence that different kappa-opioid agonists modify morphine-induced analgesia differentially in morphine-naive and morphine-tolerant rats.     

5-HT3 receptor antagonists inhibit the response of κ oploid receptors in the morphine-reduced straub tail

We used the morphine-induced Straub tail to examine the actions of a 5-HT₃ receptor antagonist and κ opioid receptor agonist. The κ opioid receptor agonist, U-50,488H (4–16 mg/kg i.p.), produced a dose-related inhibition of the tail elevation induced by morphine (10 mg/kg s.c.) in ICR male mice. ICS-205-930 (3 and 10 mg/kg i.p.) and zacopride (0.3 and 1 mg/kg i.p.), 5-HT₃ receptor antagonists, attenuated the inhibitory effect of U-50,488H in a dose-dependent manner. ICS-205-930 and zacopride did not inhibit the morphine-induced Straub tail. These observations suggest that the actions of κ opioid receptors may be modulated by 5-HT³ receptors in the morphine-induced Straub tail.     

Anxiolytic effects of acute morphine can be modulated by nitric oxide systems

This study was performed to investigate whether nitric oxide (NO) precursor (L-arginine), NO donor (S-nitroso-N-acetylpenicillamine, SNAP) and NO synthase inhibitors [N(G)-nitro-L-arginine-methylester (L-NAME) and N(G)-nitro-L-arginine (L-NOARG)] modulate morphine-induced anxiolytic effects in the plus-maze. L-Arginine (100, 200 and 300 mg kg(-1), i.p.) and SNAP (4, 8 and 10 mg kg(-1), i.p.) reduced the anxiolytic effect of morphine (20 mg kg(-1), s.c.). L-NAME (10, 20 and 40 mg/kg, i.p.) and L-NOARG (10, 15 and 20 mg kg(-1), i.p.) enhanced the anxiolytic effects of morphine (20 mg kg(-1), s.c.). On the other hand, L-arginine and SNAP increased the morphine-induced locomotor activity. L-NAME decreased the morphine-induced locomotor activity, but L-NOARG did not modify the morphine-induced locomotor activity. Therefore, these results suggest that the anxiolytic effects of morphine can be modulated by NO systems.     

Aripiprazole blocks reinstatement but not expression of morphine conditioned place preference in rats

Aripiprazole is an atypical antipsychotic drug primarily characterized by partial agonist activity at dopamine (DA) D₂ receptors and serotonin-1A (5-hydroxytryptamine, 5-HT_1A) receptors and minimal side effects. Based on its pharmacological profile, including stabilization of mesocorticolimbic DA activity (a pathway implicated in drug addiction), we investigated the effects of aripiprazole on relapse to morphine seeking in rats. In experiment 1, rats underwent morphine-induced conditioned place preference (CPP) training with alternate injections of morphine (5 mg/kg, s.c.) and saline (1 ml/kg, s.c.) for 8 consecutive days. To examine the effect of aripiprazole on the expression of morphine-induced CPP, rats received aripiprazole (0, 0.03, 0.1, and 0.3 mg/kg, i.p.) 30 min before testing for the expression of CPP. In experiment 2, rats underwent the same CPP training as in experiment 1 and subsequent extinction training. To examine the effect of aripiprazole on reinstatement of morphine-induced CPP, rats received aripiprazole 30 min before testing for reinstatement of CPP. In experiment 3, to assess the effects of aripiprazole on locomotor activity, aripiprazole was administered 30 min before testing for locomotor activity. Aripiprazole significantly decreased the reinstatement of CPP induced by a priming injection of morphine but had no effect on the expression of morphine-induced CPP or locomotor activity. The D₂ and 5-HT_1A partial agonist and 5-HT_2A antagonist properties of aripiprazole likely account for the blockade of relapse to drug seeking. These findings suggest that aripiprazole may have therapeutic value for reducing craving and preventing relapse to drug seeking.     

Is the nociceptin (NOP) receptor involved in attenuation of the expression of sensitization to morphine-induced hyperlocomotion in mice?

In the present study we investigated whether synthetic agonists of the nociceptin (NOP) receptors, Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one] and Ro 65-6570 (8-acenaphthen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one), influence the expression of sensitization to the locomotor stimulant effect of morphine in mice. Sensitization was produced by five repeated administrations of morphine (10 mg/kg, s.c.) at 3-day intervals. Seven days after the last morphine injection, Ro 64-6198 (1 and 3 mg/kg, i.p.) and Ro 65-6570 (3 and 6 mg/kg, i.p.) were given immediately before the challenge dose of morphine (10 mg/kg, s.c.). Both substances inhibited the expression of sensitization to the locomotor stimulant action of morphine. However, the selective NOP receptor antagonist, [Nphe1]NC(1-13)NH2 (30 nmol, i.c.v.) did not reverse the inhibitory effect of the Ro-compounds. Therefore, our results suggest that the NOP receptor may not be critical for the influence of Ro-compounds on the morphine-induced sensitization, or the observed effect may be attributed to one functional subset of this receptor, stimulation of which is not blocked by [Nphe1]NC(1-13)NH2.