GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA(B) receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA(B) receptor agonist baclofen in FAST mice. We hypothesized that GABA(B) receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA(B) receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA(B) receptor activation may instead enhance some of the behavioral effects of morphine.     

GABAB receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol

Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA_B receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA_B receptor agonist baclofen in FAST mice. We hypothesized that GABA_B receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA_B receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA_B receptor activation may instead enhance some of the behavioral effects of morphine.     

Motivational properties of ethanol in mice selectively bred for ethanol-induced locomotor differences

Ethanol-induced locomotor stimulation has been proposed to be positively correlated with the rewarding effects of ethanol (Wise and Bozarth 1987). The present experiments provided a test of this hypothesis using a genetic model. Three behavioral indices of the motivational effects of ethanol (drinking, taste conditioning, place conditioning) were examined in mice from two independent FAST lines, selectively bred for sensitivity to ethanol-induced locomotor stimulation, and mice from two independent SLOW lines, selectively bred for insensitivity to ethanol-induced locomotor stimulation. In a single-bottle procedure, mice were allowed access to drinking tubes containing ethanol in a concentration (1–12% v/v) that increased over 24 consecutive days. FAST mice consumed greater amounts of ethanol solution. In a two-bottle procedure, mice were allowed access to tubes containing water or various concentrations of ethanol (2–8% v/v) over 6 days. FAST mice generally showed greater preference for ethanol solutions than SLOW mice. In a conditioned taste aversion procedure, mice received access to saccharin solution followed by injection of 2.5 g/kg ethanol (IP). SLOW mice developed aversion to the saccharin flavor more readily than FAST mice. In a series of place conditioning experiments, tactile stimuli were paired with various doses of ethanol (0.8–2.0 g/kg). During conditioning, FAST mice showed locomotor stimulation after 1.0, 1.2 and 2.0 g/kg ethanol while SLOW mice did not. During testing, mice conditioned with 1.2 g/kg and 2.0 g/kg ethanol showed conditioned place preference, but there were no line differences in magnitude of preference. These results indicate that genetic selection for sensitivity to ethanol-stimulated activity has resulted in genetic differences in ethanol drinking and ethanol-induced conditioned taste aversion but not ethanol-induced conditioned place preference. Overall, these data provide mixed support for the psychomotor stimulant theory of addiction.     

Effect of selective antagonism of mu(1)-, mu(1/2)-, mu(3)-, and delta-opioid receptors on the locomotor-stimulating actions of ethanol

Previous studies have demonstrated that administration of nonspecific opioid antagonists such as naltrexone or naloxone reduces ethanol-induced locomotor activity in mice. However, because of their broad pharmacological profile, it remains unclear through which opioid receptor this antagonism is achieved. Therefore, the present study was aimed at further investigating the role of the different opioid receptors in ethanol-induced (2.5 g/kg) locomotion in mice. First, we compared the effect of naltrexone (0-2 mg/kg) on ethanol-induced locomotion with that of the selective delta-opioid receptor antagonist, naltrindole (0-10 mg/kg). Results of this first set of data revealed that naltrexone completely blocked this effect of ethanol at doses suggested to occupy only mu-opioid receptors, and naltrindole did not modify ethanol-induced locomotion. In a second set of experiments, we further investigated the involvement of mu-opioid receptors in ethanol-stimulated motor activity by assessing the implication of mu(1)-, mu(1/2)-, and mu(3)-opioid receptor subtypes. Results revealed that mu(1/2)-, and to a lesser extent mu(3)-, but not mu(1)-opioid receptor subtypes are involved in the psychomotor actions of ethanol. Data are discussed together with previous results which have emphasized the critical dependence of ethanol-induced motor behaviors on opioid receptors, as well as, of the integrity of beta-endorphin synthesizing neurons from the hypothalamic Arcuate Nucleus.     

Mice genetically selected for differences in open-field activity after ethanol

Starting from a population of genetically heterogeneous mice, selective breeding is being used to develop lines differing in sensitivity to ethanol-induced open-field activity. Mice are tested twice for 4 min in an open field. The first test is between min 2-6 after injection of saline. Twenty-four hr later, a similar test is performed after injection of ethanol (1.5 g/kg). Two independent FAST lines are being selected for ethanol-induced increases in activity, and two independent SLOW lines are being selected for ethanol-induced decreases. After four generations of selection, the lines have diverged significantly. These lines should be useful for exploring the neuropharmacological basis for the activating and rewarding properties of ethanol.     

Accentuating effects of nicotine on ethanol response in mice with high genetic predisposition to ethanol-induced locomotor stimulation

BackgroundCo-morbid use of nicotine-containing tobacco products and alcohol is prevalent in alcohol dependent individuals. Common genetic factors could influence initial sensitivity to the independent or interactive effects of these drugs and play a role in their co-abuse.MethodsLocomotor sensitivity to nicotine and ethanol, alone and in combination, was assessed in mice bred for high (FAST) and low (SLOW) sensitivity to the locomotor stimulant effects of ethanol and in an inbred strain of mouse (DBA/2J) that has been shown to have extreme sensitivity to ethanol-induced stimulation in comparison to other strains.ResultsThe effects of nicotine and ethanol, alone and in combination, were dependent on genotype. In FAST and DBA/2J mice that show high sensitivity to ethanol-induced stimulation, nicotine accentuated the locomotor stimulant response to ethanol. This effect was not found in SLOW mice that are not stimulated by ethanol alone.ConclusionsThese data indicate that genes underlying differential sensitivity to the stimulant effects of ethanol alone also influence sensitivity to nicotine in combination with ethanol. Sensitivity to the stimulant effects of nicotine alone does not appear to predict the response to the drug combination, as FAST mice are sensitive to nicotine-induced stimulation, whereas SLOW and DBA/2J mice are not. The combination of nicotine and ethanol may have genotype-dependent effects that could impact co-abuse liability.     

Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice

The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D₁) and raclopride (D₂), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D₁ and D₂ receptor systems contribute to the full expression of the ethanol stimulant response.This work was supported by the Department of Veterans Affairs, by NIAAA grants AA06498 and AA08621 (J.C.C. and T.J.P.), and by an N. L. Tartar Research Fellowship from the Medical Research Foundation of Oregon (E.H.S.). A portion of this work was completed in partial fulfillment of the requirements for Master of Science degree, Department of Medical Psychology, Oregon Health Sciences University (E.H.S.).     

Sensitivity to ethanol-induced motor incoordination in FAST and SLOW selectively bred mice

Earlier studies using the grid test have indicated a negative genetic correlation between sensitivity to ethanol-induced locomotor stimulation and ethanol-induced motor incoordination in FAST and SLOW mice, lines selectively bred for differential sensitivity to ethanol's stimulant effects. Because different tests of motor coordination may not measure the same behavioral competencies or physiological substrates, the present experiments tested adult ethanol- or saline-exposed FAST and SLOW mice of two replicates (FAST-1, FAST-2, SLOW-1, and SLOW-2) using three additional tests of coordination: a stationary dowel, fixed-speed rotarod, and accelerating rotarod. After ethanol treatment, FAST-1 mice fell from the stationary dowel at shorter latencies than SLOW-1 mice, suggesting that they had relatively greater sensitivity to ethanol. However, brain ethanol concentrations (BrECs) were similar at time of fall, and no differences were found between replicate-2 lines. SLOW-1 mice fell from the fixed-speed rotarod at lower BrECs than FAST-1 mice, suggesting possibly greater sensitivity of the SLOW-1 line. Again, no replicate-2 line differences were found. No significant differences were detected for the accelerating rotarod. These results provide little support for a negative genetic relationship between sensitivity to the stimulant and ataxic effects of ethanol using these measures of motor coordination.     

Shared genes influence sensitivity to the effects of ethanol on locomotor and anxiety-like behaviors, and the stress axis

RATIONALE: In rodents, a common response to many drugs of abuse, including ethanol (EtOH), is locomotor stimulation. It has been proposed, although debated, that EtOH-induced locomotor stimulation may represent an animal model of EtOH's euphoric effects. Another possibility is that this behavioral phenotype may represent an altered state of anxiety, and/or stress axis activation. OBJECTIVES: Mouse lines selectively bred for sensitivity (FAST) or resistance (SLOW) to EtOH's low dose locomotor stimulant effects were tested for differential sensitivity to EtOH's anxiolytic and/or stress axis activating effects, with the goal of detecting genetic correlations. METHODS: Saline- and EtOH-treated FAST and SLOW mice were tested on the elevated plus maze and the light-dark box, two widely used measures of anxiety-related behavior in rodents. In addition, serum corticosterone (CORT) levels were measured at various time points following injection of saline or ethanol. RESULTS: Behavioral data from both anxiety tests showed that FAST mice were less sensitive to EtOH's anxiolytic effects than were SLOW mice. Moreover, late recovery of elevated serum CORT levels following mild saline injection stress, as well as reduced CORT release in response to EtOH, suggested that FAST mice may possess a less responsive stress axis. CONCLUSIONS: These results provide evidence that sensitivity to the effects of EtOH on locomotor behavior, anxiety-like behavior, and the stress axis share some genetic influence.     

RO 15-4513 and FG 7142 reverse the reduction in social behavior caused by ethanol in mice

Ethanol (2 g/kg) reduces the time spent in social interaction and increases locomotor activity of pairs of NIH Swiss mice. This study examined whether two benzodiazepine receptor inverse agonists, RO 15-4513 (3 mg/kg) and FG 7142 (30 mg/kg) are able to reverse these effects. Neither drug alone altered social behavior, but both significantly attenuated the effect of ethanol on social interaction. They did not affect the ethanol-induced increase in motor activity. Benzodiazepine receptor inverse agonists thus appear capable of antagonizing some, but not all of the behavioral effects of ethanol in this paradigm.     

Ketamine-induced potentiation of morphine analgesia in rat tail-flick test: role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels

Ketamine is known to improve opioid efficacy, reduce postoperative opioid requirement and oppose opioid associated pain hypersensitivity and tolerance. However, the mechanisms underlying these beneficial effects are not clear. This study investigated the effects of ketamine at a non-analgesic dose (30 mg/kg, i.p.) on analgesia induced by morphine (2.5, 5.0, 7.5 mg/kg, s.c.), using rat tail-flick test as an animal model of acute pain. Further, the role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels was examined on the potentiating effect of ketamine. Male rats received morphine alone at 5.0 and 7.5 but not at 2.5 mg/kg showed a dose-related increase in tail-flick latencies. The combination of morphine and ketamine resulted in dose-related increase in morphine analgesia, both on the intensity as well as on duration. The ketamine-induced potentiation of morphine (7.5 mg/kg) analgesia was unaffected by glibenclamide (3 mg/kg, s.c.) and only partially blocked by yohimbine (2 mg/kg, i.p.), but more completely abolished by naloxone (2 mg/kg, i.p.). Both morphine (5.0 mg/kg) and ketamine (30 mg/kg) alone did not evoke catalepsy in rats but on combination produced a synergistic effect, which was however, abolished by naloxone pretreatment. In the open-field test, while morphine (5.0 mg/kg) caused a depressant effect, ketamine (30 mg/kg) enhanced the locomotor activity. Nevertheless, in combination potentiated the morphine's depressant effect on locomotion, which was also antagonized by naloxone. These results indicate that ketamine at a non-analgesic dose can potentiate morphine analgesia, induce catalepsy and cause locomotor depression, possibly involving an opioid mechanism. This potentiation, although favorable in acute pain management, may have some adverse clinical implications.     

Daily injections of cyanamide enhance both ethanol-induced locomotion and brain catalase activity

A role for brain catalase in the mediation of some psychopharmacological effects of ethanol has been proposed. In the present study, we investigated the effects of repeated cyanamide injections on the activity of brain catalase, as well as on the ethanol-induced locomotion of mice. Male Swiss mice were pre-treated with cyanamide (10 mg/kg; three times per day, 5 days) or saline. At different times (2, 3, 6 or 9 days) following this treatment, animals were injected with ethanol. Immediately following this ethanol challenge, animals were placed in the open field chambers and locomotor activity was assessed for 10 min. Results indicated an increase in ethanol-induced locomotion of mice pre-treated with cyanamide 2, 3 or 6 days before the ethanol challenge. Brain catalase activity showed an enhancement at the same time period and the two variables showed a significant correlation. No differences between pre-treatment groups on ethanol blood levels were observed at time of testing. In a second study, the effects of these cyanamide treatment conditions on d-amphetamine-induced locomotor activity were assessed. Results indicated no differences between pre-treatment groups in d-amphetamine-induced locomotion. Thus, these data suggest that repeated daily injections of cyanamide can simultaneously induce both brain catalase and locomotor activity, and that these effects may be strongly related. Furthermore, the present study provides further support for the notion that brain catalase activity may be a factor mediating some of the psychopharmacological effects of ethanol.     

Influence of morphine and dopamine receptor sensitization on locomotor activity in mice

In the present study, the influence of morphine- and dopamine receptor antagonists-induced sensitization on morphine-induced locomotion in mice was investigated. Morphine (30, 40 and 50 mg/kg) increased, while lower doses of the opioid (10 and 20 mg/kg) decreased locomotor activity of mice. Subchronic repeated pretreatment of animals with morphine showed an increase in locomotion induced by the opioid. Clozapine reduced locomotor activity induced by morphine in both the na?ve and subchronic morphine-treated animals. Subchronic pretreatment of clozapine also caused an increase in the locomotion induced by morphine. Sulpiride also decreased locomotion induced by morphine and its subchronic administration of the drug caused an increase in morphine- or apomorphine-induced locomotion. Co-administration of clozapine with sulpiride did not elicit potentiation in inhibiting the morphine effect. The D2 receptor mRNA expression was also increased by repeated morphine administration. It may be concluded that morphine-induced sensitization may be due to increase in D2 receptor mRNA expression. Sulpiride and clozapine may induce sensitization and also inhibit morphine-induced locomotion through their dopamine receptor blocking properties.     

Lead acetate potentiates brain catalase activity and enhances ethanol-induced locomotion in mice

Several reports have demonstrated that acute lead acetate administration enhances brain catalase activity in animals. Other reports have shown a role of brain catalase in ethanol-induced behaviors. In the present study we investigated the effect of acute lead acetate on brain catalase activity and on ethanol-induced locomotion, as well as whether mice treated with different doses of lead acetate, and therefore, with enhanced brain catalase activity, exhibit an increased ethanol-induced locomotor activity. Lead acetate or saline was injected IP in Swiss mice at doses of 50, 100, 150, or 200 mg/kg. At 7 days following this treatment, ethanol (0.0, 1.5, 2.0, 2.5, or 3.0 g/kg) was injected IP, and the animals were placed in the open-field chambers. Results indicated that the locomotor activity induced by ethanol was significantly increased in the groups treated with lead acetate. Maximum ethanol-induced locomotor activity increase was found in animals treated with 100 mg/kg of lead acetate and 2.5 g/kg of ethanol. Total brain catalase activity in lead-pretreated animals also showed a significant induction, which was maximum at 100 mg/kg of lead acetate treatment. No differences in blood ethanol levels were observed among treatment groups. The fact that brain catalase and ethanol-induced locomotor activity followed a similar pattern could suggest a relationship between both lead acetate effects and also a role for brain catalase in ethanol-induced behaviors.     

Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization

Selectively bred FAST mice are highly susceptible, while SLOW mice are less susceptible, to the locomotor stimulant effects of ethanol. Heritability estimates indicate that approximately 15% of the variance in the FAST lines is of additive genetic origin, while low susceptibility is ostensibly nonheritable. Inbreeding has increased at the rate of 2% per generation, but fertility has been unaffected. Measurement reliability for sensitivity to this ethanol effect was high when measured in both circular (r=0.6) and square (r=0.7) open-fields. In addition, our results indicate that we have selected for differences in sensitivity to ethanol rather than for differences in habituation to the test environment. The difference in response to ethanol between FAST and SLOW mice extended to tests varying in duration, and to a range of ethanol doses. We conclude that the divergence between FAST and SLOW mice generalizes to related test parameters, and speculate that the genetic architecture underlying the locomotor stimulant response may be simpler than previously proposed.Supported by a grant from the Department of Veterans Affairs, and by PHS-NIAAA Research Grants AA05828, AA06243, and AA06498, and PHS-NIDA Contract No. 217-87-8120     

Acute administration of 3-nitropropionic acid, a reactive oxygen species generator, boosts ethanol-induced locomotor stimulation. New support for the role of brain catalase in the behavioural effects of ethanol

The antioxidant enzyme catalase by reacting with H₂O₂, forms the compound known as compound I (catalase-H₂O₂). This compound is able to oxidise ethanol to acetaldehyde in the CNS. It has been demonstrated that 3-nitropropionic acid (3-NPA) induces the activity of the brain catalase-H₂O₂ system. In this study, we tested the effect of 3-NPA on both the brain catalase-H₂O₂ system and on the acute locomotor effect of ethanol. To find the optimal interval for the 3-NPA–ethanol interaction mice were treated with 3-NPA 0, 45, 90 and 135 min before an ethanol injection (2.4 mg/kg). In a second study, 3-NPA (0, 15, 30 or 45 mg/kg) was administered SC to animals 90 min before saline or several doses of ethanol (1.6 or 2.4 g/kg), and the open-field behaviour was registered. The specificity of the effect of 3-NPA (45 mg/kg) was evaluated on caffeine (10 mg/kg IP) and cocaine (4 mg/kg)-induced locomotion. The prevention of 3-NPA effects on both ethanol-induced locomotion and brain catalase activity by l-carnitine, a potent antioxidant, was also studied. Nitropropionic acid boosted ethanol-induced locomotion and brain catalase activity after 90 min. The effect of 3-NPA was prevented by l-carnitine administration. These results indicate that 3-NPA enhanced ethanol-induced locomotion by increasing the activity of the brain catalase system.     

Behavioral consequences of the hypotaurine-ethanol interaction.

In order to evaluate the effect of hypotaurine on ethanol-induced locomotion, different groups of mice received an injection of saline or 5.62, 8.45, 11.25, 16.87 or 33.75 mg/kg of hypotaurine 30 min prior to administering ethanol (2.4 g/kg). The duration of the effect of hypotaurine was explored by treating animals with ethanol 0, 30, 60 and 90 min after hypotaurine pretreatment. The effect of hypotaurine on acute stimulating ethanol locomotion was evaluated by pretreating animals with saline or 11.25 mg/kg of hypotaurine 30 or 60 min before ethanol (1.6, 2.4, 3.2 g/kg) or saline injections. Hypotaurine (11.25 mg/kg) required 30 min to boost, specifically ethanol-stimulated locomotion (2.4 g/kg). These results suggest a central locus for the interaction, firstly, because blood ethanol levels were not different between hypotaurine and saline pretreated mice, and, secondly, because a cotreatment with beta-alanine (22 mg/kg), a beta-amino acid that counteracts the transfer of hypotaurine across the blood-brain barrier (BBB), prevented the enhancement in ethanol-induced locomotion produced by hypotaurine.     

Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c,C57BL/6, and DBA/2 mice

The effects of naltrexone on the increase in locomotor activity induced by a low dose (1.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity.     

Agmatine blocks ethanol-induced locomotor hyperactivity in male mice

Ethanol-induced locomotor activity is associated to rewarding effects of ethanol and ethanol dependence. Agmatine is a novel endogenous ligand at α₂-adrenoceptors, imidazoline and N-methyl-d-aspartate (NMDA) receptors, as well as a nitric oxide synthase (NOS) inhibitor. There is no evidence presented for the relationship between the acute locomotor stimulating effect of ethanol and agmatine. Thus, the present study investigated the effects of agmatine on acute ethanol-induced locomotor hyperactivity in mice. Adult male Swiss–Webster mice (26–36 g) were used as subjects. Locomotor activity of the mice was recorded for 30 min immediately following intraperitoneal administration of ethanol (0.5, 1 and 2 g/kg) or saline (n = 8 for each group). Agmatine (5, 10 and 20 mg/kg) or saline was administered intraperitoneally to another four individual groups (n = 8 for each group) of the mice 20 min before the ethanol injection. In these groups, locomotor activity was also recorded immediately following ethanol (0.5 g/kg) injection for 30 min. Ethanol (0.5 g/kg) produced some significant increases in locomotor activity of the mice. Agmatine (5–20 mg/kg) significantly blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity. These doses of agmatine did not affect the locomotor activity in naive mice when they were administered alone. Our results suggest that agmatine has an important role in ethanol-induced locomotor hyperactivity in mice. There may be a relationship between the addictive psychostimulant effects of the ethanol and central agmatinergic system.     

Differential Effects of Morphine-6-glucuronide,an Active Metabolite of Morphine,and Morphine on Locomotor Activity in Mice: Involvement of the Opioid Receptor

Abstract: Subcutaneous administration of morphine (2.5 to 20 mg/kg) or an active metabolite of morphine, morphine-6-glucuronide (2.5 to 20 mg/kg), increased the locomotor activity of mice in a dose-dependent manner. Fifteen mg/kg of morphine and 20 mg/kg of morphine-6-glucuronide were almost equipotent. Subcutaneous administration of the universal opioid antagonist, naloxone, but not the δ-selective antagonist, naltrindole, significantly suppressed the hyperlocomotion induced by morphine (15 mg/kg). On the other hand the subcutaneous administration of relatively higher doses of naloxone or naltrindole significantly reduced the hyperlocomotion induced by morphine-6-glucuronide (20 mg/kg). These findings suggest that agonistic actions at the opioid receptors, especially at the δ- and μ-receptors, contribute to the morphine-6-glucuronide-induced hyperlocomotion.