Morphine-induced Place Preference In Mice Research Articles

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.

Saffron (Crocus sativus) Ethanolic Extract and its Constituent, Safranal, Inhibits Morphine-induced Place Preference in Mice

The effects of saffron ethanolic extract and its constituent, safranal, on the acquisition and expression of morphine-induced place preference (CPP) in male Swiss Webster mice (20-25 g) were investigated in the present study. An unbiased place conditioning method was applied for assessment of morphine reward properties. The saffron extract and safranal were administered intraperitoneally (i.p.) during (acquisition) or after induction (expression) of morphine CPP. In a pilot study, the extract and safranal were alone administered to the animals to assess if they have any reward properties. Subcutaneous (s.c.) of morphine (4 and 8 mg kg(-1)) and extract (50 mg kg(-1); i.p.) induced CPP. Extract (10, 50 and 100 mg kg(-1); i.p.) reduced the acquisition and expression of morphine CPP. The same results were obtained when safranal (1, 5 and 10 mg kg(-1), i.p.) was used. It may be concluded that both ethanolic saffron extract and safranal can inhibit the acquisition and expression of morphine-induced CPP in the mice.

Up-regulation of Cav1.2 subunit via facilitating trafficking induced by Vps34 on morphine-induced place preference in mice

In the present study, we investigated the role of Vps34, a kinase classified into PI 3-kinase class III, in the brain of mouse after repeated in vivo treatment with morphine. The intracerebroventricular (i.c.v.) administration of nifedipine caused a dose-dependent inhibition of morphine-induced place preference. The protein levels of Vps34 in the frontal cortex including the cingulate cortex and the limbic forebrain including the nucleus accumbens significantly increased in morphine-induced place preference. I.c.v. administration of PI 3-kinase inhibitors such as wortmannin and LY294002 inhibited morphine-induced place preference in a dose-dependent manner. Cav1.2 protein level of L-type voltage-dependent calcium channels significantly increased in the frontal cortex and the limbic forebrain of the morphine psychologically dependent mice, which was significantly inhibited by PI 3-kinase inhibitors. Similar changes in the expression of Cav1.2 and Vps34 proteins are found in the primary culture of cerebral cortical neurons during short-term exposure to morphine. Under such conditions, facilitated translocation of Cav1.2 to the plasma membrane remarkably increased by the treatment of the cultured neurons with morphine when measuring protein level of Cav1.2, and such changes in Cav1.2 were also suppressed by PI 3-kinase inhibitors. These findings indicate a critical role of Vps34 in the up-regulation of Cav1.2 in the neuronal plasma membrane and the development of morphine-induced place preference.

The Effects of Lamotrigine on the Acquisition and Expression of Morphine-Induced Place Preference in Mice

The purpose of the present study is to determine the effects of the anticonvulsant drug, lamotrigine, on the acquisition and expression of morphine-induced place preference in mice. Lamotrigine prevents the release of glutamate from presynaptic neurons and inhibits action potential in postsynaptic area by inhibiting presynaptic sodium and calcium channels. Because of such properties, lamotrigine is used for reducing craving for and use of cocaine, alcohol and abused inhalant. So, to determine the effects of lamotrigine on opiates; specifically morphine, 180 male Swiss-Webster mice (20-35 g) were used in this study. Conditioned place preference, was assessed using a biased place conditioning paradigm. In a pilot study the effects of various doses of morphine (2.5, 5 and 10 mg kg(-1)), alone, or in combination with lamotrigine (1, 5 and 25 mg kg(-1)) on the place conditioning paradigm were examined. Animals were injected with the aforementioned doses of lamotrigine 60 min either prior to each morphine injections (acquisition) or prior to the start of the expression on the test day (expression). Administration of different doses of morphine (2.5, 5 and 10 mg kg(-1)) induced conditioned place preference whereas the administration of different doses of lamotrigine (1, 5 and 25 mg kg(-1)) failed to induce place preference. Acquisition and expression of morphine-induced CPP were reduced by lamotrigine at doses of 1, 5 and 25 mg kg(-1) and 5 and 25 mg kg(-1), respectively. Physiological mechanisms of action of lamotrigine and its potential therapeutic use in the treatment of drug-dependence are discussed.

Social stress is as effective as physical stress in reinstating morphine-induced place preference in mice

Relapse to drug-seeking in abstinent heroin addicts and reinstatement in experimental animals are observed when exposed to drug-associated stimuli or cues, the drug itself, and stressful events. It has been shown that footshock-induced stress increases the rewarding effects of opiates, delays extinction, and induces the reinstatement of drug-seeking. However, the effects of social stress on the reinstatement of opiate-seeking after extinction has not been studied. The role of physical (restraint and tail pinch) and social (social defeat) stressors on the reinstatement of morphine-induced conditioned place preference (CPP) was evaluated. Adult male OF1 mice were conditioned with 10, 20, or 40 mg/kg of morphine or saline. Only morphine-conditioned animals acquired CPP. All mice underwent extinction sessions until the CPP was extinguished. Then, the effects of physical or social stress on the reinstatement of CPP were evaluated. Morphine- and saline-conditioned animals were exposed to the respective stressor or control stress condition immediately or 15 min before reinstatement tests. In experiment 1, animals underwent restraint for 15 min. In experiment 2, animals were exposed to tail pinch or placed in a cage without any manipulation for 15 min. In experiment 3, animals performed an agonistic encounter with an isolated or anosmic mouse or were placed in a cage without any social contact or manipulation. Restraint, tail pinch, and social defeat in an agonistic encounter with an isolated mouse produce the reinstatement of CPP in morphine-conditioned animals. These data demonstrate that social stress is as effective as physical stress in reinstating morphine-seeking.

Cross-reinstatement by cocaine and amphetamine of morphine-induced place preference in mice

The cross-reinstatement by psychostimulants of a conditioned place preference (CPP) induced by morphine was evaluated in mice. In Experiment 1, we examined the effects of a single dose of cocaine and amphetamine on a previously extinguished morphine CPP. After acquisition of CPP induced by morphine (40 mg/kg), animals underwent daily extinction sessions of 15 min duration until the CPP was extinguished. Subsequently, animals received a non-contingent injection of cocaine (25 mg/kg) or amphetamine (4 mg/kg), which produced the reinstatement of the extinguished morphine-induced CPP. In Experiment 2, we evaluated the reinstating effects of several priming doses of cocaine (Experiment 2A) or amphetamine (Experiment 2B). As in the first experiment, after conditioning with morphine (40 mg/kg), mice underwent daily 15 min extinction sessions. When the preference was no longer evident, we tested the effects of cocaine (0, 6.25, 12.5, 25 and 50 mg/kg) and amphetamine (0, 0.5, 1, 2 and 4 mg/kg) on the reinstatement of CPP. Doses from 12.5 mg/kg of cocaine upward and doses from 1 mg/kg of amphetamine upward effectively reinstated CPP. Our results demonstrate cross-reinstatement with psychostimulants and opiates, suggesting that in abstinent individuals, drug exposure can produce craving for the previously abused drug and relapse.

Effects of the non-competitive NMDA receptor antagonist ketamine on morphine-induced place preference in mice

The effects of ketamine, a noncompetitive N-methyl- d-aspartate (NMDA) receptor antagonist, on morphine-induced place preference were examined in mice. Morphine (1–5 mg/kg, s.c.) produced a dose-related place preference in mice. Ketamine alone (3, 10 mg/kg, i.p.), like dizocilpine alone (0.2 mg/kg, i.p.), also produced a preference for the drug-associated place. Pretreatment with ketamine (10 mg/kg, i.p.) or dizocilpine (0.1 and 0.2 mg/kg, i.p) suppressed the place preference produced by morphine in a dose-dependent manner. These findings provide the first demonstration that ketamine alone produces a place preference using the conditioned place preference (CPP) paradigm, but that mice treated with ketamine combined with morphine show neither a morphine- nor a ketamine-induced place preference.

Effects of the non-competitive NMDA receptor antagonist ifenprodil on the morphine-induced place preference in mice

The effects of ifenprodil, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on the morphine-induced place preference were examined in mice. Morphine (1–5 mg/kg, s.c.) produced a dose-related place preference in mice. In contrast, ifenprodil alone (5–20 mg/kg, i.p.) did not produce either preference or aversion for the drug-associated place. Pretreatment with ifenprodil (5–20 mg/kg, i.p.) suppressed the place preference produced by morphine in a dose-dependent manner. These results indicate that ifenprodil suppresses the rewarding effect produced by morphine.

Modification of morphine-induced place preference by diabetes

The effects of diabetes on morphine-induced place preference in mice were examined. Morphine caused dose-related place preference in both diabetic and non-diabetic mice. This morphine-induced place preference in diabetic mice was greater than that in non-diabetic mice. The morphine (5 mg/kg)-induced place preference in both diabetic and non-diabetic mice was significantly antagonized by pretreatment with β-funaltrexamine, a selective μ-opioid receptor antagonist, but not with naloxonazine, a selective μ 1-opioid receptor antagonist. The morphine (5 mg/kg)-induced place preference in non-diabetic mice was attenuated by pretreatment with either naltriben, a selective δ 2-opioid receptor antagonist, or 7-benzylidenenaltrexone, a selective δ 1-opioid receptor antagonist. Moreover, the morphine (10 mg/kg)-induced place preference in non-diabetic mice was antagonized by pretreatment with 7-benzylidenenaltrexone (0.7 mg/kg). Although 7-benzylidenenaltrexone had no effect on the place preference induced by 5 mg/kg morphine in diabetic mice, it reduced the place preference induced by 3 mg/kg morphine. Furthermore, the morphine (5 mg/kg)-induced place preference in diabetic mice was significantly antagonized by co-pretreatment with β-funaltrexamine (10 mg/kg) and 7-benzylidenenaltrexone (0.7 mg/kg). 2-Methyl-4a α-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a α-octahydroquinolino[2,3,3-g]isoquinoline (TAN-67), a non-peptide δ-opioid receptor agonist, produced place preference in diabetic, but not in non-diabetic mice. These results support the hypothesis that the morphine-induced place preference is mainly mediated through the activation of the μ 2-opioid receptor. Furthermore, the enhancement of the morphine-induced place preference in diabetic mice may be due to the up-regulation of δ-opioid receptor-mediated functions.

Effects of the histaminergic system on the morphine-induced conditioned place preference in mice

The effects of an H 2 receptor antagonist, a histidine decarboxylase inhibitor and a histamine precursor on the morphine-induced place preference in mice were examined. Morphine (1–7 mg/kg) produced a place preference in a dose-dependent manner. This morphine-induced place preference was significantly antagonized by the dopamine (DA) D 1 receptor antagonist SCH 23390. The histamine precursor, L-histidine, attenuated the morphine (7 mg/kg)-induced place preference. On the other hand, the histidine decarboxylase inhibitor, α-fluoromethylhistidine (α-FMH), significantly potentiated the morphine (1 mg/kg)-induced place preference. This potentiation was antagonized by SCH 23390. The H 2 receptor antagonist zolantidine (0.3 mg/kg) significantly potentiated the morphine-induced place preference. Surprisingly, zolantidine (1 mg/kg) alone also produced a significant place preference. The zolantidine-induced place preference was antagonized by SCH 23390. In addition, zolantidine (1, 3 and 10 mg/kg) significantly increased DA turnover (DA ratio) in the limbic forebrain (nucleus accumbens and olfactory tubercle), implying that zolantidine may activate the mesolimbic DA system. Moreover, co-administration of zolantidine dose-dependently increased morphine (10 mg/kg)-induced DA turnover in the limbic forebrain. These results suggest that the activation of histaminergic neurons may attenuate the rewarding effect of morphine, while the inhibition of histaminergic neurons may potentiate the rewarding effect of morphine. Furthermore, potentiation of the morphine-induced rewarding effect by inhibition of histaminergic neurons may be mediated by D 1 receptors. We also demonstrated that the H 2 receptor antagonist zolantidine may activate the mesolimbic DA system, and as a result, zolantidine itself produces a rewarding effect and potentiates the morphine-induced rewarding effect.

Blockade of delta-opioid receptors prevents morphine-induced place preference in mice.

Effects of highly selective delta-opioid receptor antagonists on the morphine-induced place preference in ddY and mu 1-opioid receptor deficient CXBK mice were investigated. Pretreatment with naltrindole (NTI: a non-selective delta-opioid receptor antagonist), 7-benzylidenenaltrexone (BNTX: a selective delta 1-opioid receptor antagonist) or naltriben (NTB: a selective delta 2-opioid receptor antagonist) abolished the morphine-induced place preference in ddY mice in a dose-dependent manner. These findings suggest that the morphine-induced place preference may be mediated by both delta 1- and delta 2-opioid receptors. On the other hand, in mu 1-opioid receptor deficient CXBK mice, pretreatment with these selective delta-opioid receptor antagonists did not affect the morphine-induced place preference, although pretreatment with beta-funaltrexamine (beta-FNA: a selective mu-opioid receptor antagonist) significantly inhibited the morphine-induced place preference. [D-Pen2,D-Pen5]enkephalin (DPDPE: a delta 1-opioid receptor agonist) and [D-Ala2,Glu4]deltorphin (deltorphin II: a delta 2-opioid receptor agonist) induced a significant place preference in ddY mice, but not in CXBK mice. These results suggest that delta 1- and delta 2-opioid receptors in the nucleus accumbens that are related to the DPDPE- and deltorphin II-induced place preference may be dysfunctional and/or poor in CXBK mice. These findings also indicate that delta 1- and delta 2-opioid receptors may be involved in the modulation of the reinforcing effect of morphine.

Blockade of morphine reward through the activation of κ-opioid receptors in mice

The effects of systemic (s.c.) treatment with the κ-agonists U-50,488H and E-2078 (a stable dynorphin analog) on the morphine-induced place preference were examined in mice. Morphine (s.c.) caused a dose-related preference for the drug-associated place; the effects at doses of 3 and 5 mg/kg were significant. On the other hand, U-50,488H or E-2078 produced a dose-related conditioned place aversion. Both U-50,488H (1 mg/kg, s.c.) and E-2078 (0.1 mg/kg, s.c.) induced a slight, nonsignificant place aversion. Pretreatment with U-50,488H (1 mg/kg) abolished the morphine (3 mg/kg)-induced place preference. The morphine-induced place preference was also significantly decreased by pretreatment with E-2078 (0.1 mg/kg). The inhibitory effects of the κ-agonists were antagonized by the κ-antagonist nor-binaltorphimine (nor-BNI; 3 mg/kg, s.c.). In contrast, pretreatment with U-50,488H did not affect the place preference induced by the dopamine (DA) receptor agonist apomorphine (1 mg/kg, s.c.). In addition, morphine (3 mg/kg, s.c.) significantly increased the levels of the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the limbic forebrain (nucleus accumbens and olfactory tubercle) but not in the striatum, implying that activation of the mesolimbic DA system may play an important role in the morphine-induced place preference in mice. Pretreatment with U-50,488H significantly reduced the morphine-induced elevation of DA metabolites in the limbic forebrain. These results suggest that κ-agonists suppress the morphine-induced place preference, and that activation of κ-opioid receptors could suppress the reinforcing effects of morphine which may be induced by enhanced DA transmission in the mesolimbic DA system.