Naloxone does not attenuate the locomotor effects of ethanol in FAST,SLOW, or two heterogeneous stocks of mice

Rationale Previous studies suggest that some behavioral effects of ethanol and morphine are genetically correlated. For example, mice bred for sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effects of ethanol differ in their locomotor response to morphine. Objective To evaluate a possible common mechanism for these traits, we examined the effect of naloxone, an opioid receptor antagonist, on ethanol- and morphine-induced locomotion in FAST and SLOW mice, as well as on ethanol-induced locomotion in two heterogeneous stocks of mice. Method In experiments 1 and 2, naloxone was given to FAST and SLOW mice 30 min prior to 2 g/kg ethanol or 32 mg/kg morphine, and locomotor activity was measured for 15 min (ethanol) or 30 min (morphine). In experiments 3 and 4, naloxone was administered 30 min prior to 1.25 g/kg ethanol, and locomotor activity was assessed in FAST mice and in a heterogeneous line of mice [Withdrawal Seizure Control (WSC)]. Experiment 5 assessed the effect of naloxone on ethanol-induced stimulation in outbred National Institutes of Health (NIH) Swiss mice. Results There was no effect of naloxone on the locomotor response to ethanol in FAST, SLOW, WSC, or NIH Swiss mice. However, naloxone did significantly attenuate the locomotor effects of morphine in FAST and SLOW mice. Conclusions These results suggest that a common opioidergic mechanism is not responsible for the correlated locomotor responses to ethanol and morphine in FAST and SLOW mice, and that activation of the endogenous opioid system is not critical for the induction of ethanol-induced alterations in activity.     

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.     

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.     

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.     

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     

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

Objective and rationale Alcohol and nicotine are commonly co-abused; one possible explanation for co-abuse is that each drug ameliorates the aversive effects of the other. Both drugs have dose-dependent effects on learning and memory. Thus, this study examined the interactive effects of acute ethanol and acute, chronic, or withdrawal from chronic nicotine on fear conditioning in C57BL/6J mice. Materials and methods Conditioning consisted of auditory conditioned stimulus-foot-shock unconditioned stimulus pairings. For acute studies, saline or ethanol, then saline or nicotine was administered before training, and saline or nicotine was also administered before testing. For chronic and withdrawal studies, saline or nicotine was administered chronically, and ethanol or saline was administered before training. Results Acute nicotine (0.09 mg/kg) reversed ethanol-induced deficits (1.0 and 1.5 g/kg) in contextual and cued fear conditioning, whereas a low dose of ethanol (0.25 g/kg) reversed nicotine (6.3 mg kg⁻¹ day⁻¹) withdrawal-induced deficits in contextual conditioning. Tolerance developed for the effects of nicotine on ethanol-induced deficits in conditioning and cross-tolerance between chronic nicotine and acute ethanol was seen for the enhancing effects of ethanol on conditioning. Conclusions The complex and sometimes polar actions of ethanol and nicotine on behavior may contribute to co-abuse of these drugs. Specifically, smoking may initially reduce the aversive effects of ethanol, but tolerance develops for this effect. In addition, low doses of alcohol may lessen nicotine withdrawal symptoms.     

Determining the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection

Rationale

Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the degree to which genes influence this complex behavioral phenomenon.

Objectives

The primary goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection.

Methods

Genetically heterogeneous C57BL/6J (B6) × DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. Selective breeding was conducted in two independently generated replicate sets to increase the confidence of our heritability estimates and for future correlated trait analyses.

Results

Large and significant differences in locomotor sensitization between HLS and LLS lines were evident by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h ²?=?.22). Interestingly, locomotor activity in the absence of ethanol was genetically correlated with ethanol sensitization; high activity was associated with high sensitization.

Conclusions

That changes in ethanol sensitivity following repeated exposures are genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. As alcohol use and abuse disorders develop following many repeated alcohol exposures, these data emphasize the need for future studies determining the genetic basis by which changes in response to alcohol occur.     

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.     

Verticalization of behavior elicited by dopaminergic mobilization is qualitatively different between C57BL/6J and DBA/2J mice

Behavioral effects of dopaminergic stimulation were evaluated in C57BL/6J mice and compared to the effects occurring in DBA/2J mice, an inbred strain with reduced densities of striatal dopamine receptors. Effects of apomorphine (0.5–64 mg/kg) alone and in combination with cocaine (30 mg/kg) were assessed using a time-sampling technique that classified climbing and leaning in separate categories. Locomotion was also assessed in a separate experiment. Climbing occurred in DBA/2J mice only at doses of apomorphine that were 16 times higher than the smallest effective dose in C57BL/6J mice; nevertheless, relative to baseline values, effects were fairly comparable. By contrast, whereas DBA/2J mice showed dose-dependent leaning under apomorphine, C57BL/6J mice exhibited little leaning even at doses not producing climbing, and only after the highest apomorphine dose was leaning significantly increased. Apomorphine was equipotent in inducing gnawing across strains, although somewhat less efficacious in DBA/2J mice. When given alone, cocaine produced significant climbing, but not leaning or gnawing, in either strain. Whereas cocaine potentiated apomorphine-induced climbing and gnawing in both strains, apomorphine-induced leaning was not consistently changed by cocaine in either strain. These effects were not indirectly due to hyperkinesia, since neither apomorphine alone nor apomorphine and cocaine in combination was stimulant; apomorphine alone reduced locomotor activity and attenuated cocaine-induced hyperkinesia. The present data do not support a unitary, purely quantitative, account of insensitivity to dopaminergic stimulation based upon low densities of striatal dopamine receptors in DBA/2J mice. Rather, this constellation of results is suggestive of qualitative interstrain dissimilarities in dopaminergic responsiveness that could reflect organizational differences in receptor populations.The facilities in which the mice were maintained are fully accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC), and the studies described here were conducted in accordance with the Guide for Care and Use of Laboratory Animals provided by the NIH and adopted by NIDA.     

Differential effects of GABAA and GABAB agonists on sensitization to the locomotor stimulant effects of ethanol in DBA/2 J mice

 Contemporary theories of drug abuse suggest that behavioral sensitization plays an important role in addiction. However, few studies have examined the mechanisms underlying behavioral sensitization to ethanol. The present study examined the ability of THIP (2, 4, or 8 mg/kg) and baclofen (5.0, 6.25, or 7.5 mg/kg), GABA_A and GABA_B agonists, respectively, to prevent development of sensitization to the locomotor stimulant effects of ethanol (2 g/kg) in DBA/2 J mice. Ethanol was administered immediately before four 5-min activity trials conducted at 48-h intervals. Administration of ethanol on each of the four trials resulted in behavioral sensitization in control groups. While having few effects on activity when given alone, both GABA agonists completely blocked the acute stimulant response to ethanol on the first trial. Administration of THIP prior to ethanol on each trial failed to prevent development of sensitization. In contrast, all doses of baclofen blocked sensitization. Assessment of blood ethanol levels 15, 50 and 100 min after administration of ethanol indicated that baclofen did not change the pharmacokinetics of ethanol. These results indicate an important role for GABA_B receptors, but not GABA_A receptors, in development of sensitization to the locomotor stimulant effects of ethanol. Received: 11 April 1998 / Final version: 24 June 1998     

Role of test activity in ethanol-induced disruption of place preference expression in mice

Rationale Reduced expression of a drug-induced conditioned place preference (CPP) may reflect a decrease in the drug’s conditioned rewarding effects. However, CPP is also open to disruption by processes unrelated to the underlying motivation. In unpublished studies, we previously observed that ethanol pretreatment before testing disrupted expression of ethanol-induced CPP in DBA/2J mice. We hypothesized that this interference effect was due to large ethanol-induced increases in activity. Objective The present studies were designed to examine the relationship between test activity and expression of ethanol-induced CPP both in the presence and absence of ethanol. To assess the generality of this relationship, we examined these effects both in DBA/2J (which are highly activated by ethanol) and in NZB/B1NJ mice (which show similar CPP, but less ethanol-induced activation). Materials and methods In separate experiments, inbred mice from each strain underwent ethanol (2 g/kg) place conditioning. Saline or ethanol was then administered immediately before the test. Results Ethanol, given immediately before the test, blocked the expression of ethanol CPP in DBA/2J, but not in NZB/B1NJ mice. Moreover, ethanol significantly increased test activity levels in DBA/2J and to a much lesser degree in NZB/B1NJ mice. Correlation analyses showed an inverse phenotypic relationship between preference and test activity, reflecting stronger preferences in less active mice. Conclusions Disruption of ethanol-CPP observed in DBA/2J mice may be a consequence of high ethanol-induced activity levels. More generally, these studies suggest that competing behaviors can affect expression of a drug-induced CPP independent of affecting the conditioned rewarding effects of the drug.     

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.     

Studies on the interaction between ethanol and amfonelic acid

Amfonelic acid (AFA), a non-amphetamine central stimulant dose-dependently reduced the hypnotic effect of ethanol in C57B1/6 mice. It did not enhance the elimination of ethanol. Amfonelic acid failed to modify the duration of pentobarbitone-induced hypnosis or the ethanol-induced hypothermia in these animals. Combined treatment with amfonelic acid and a lipophilic alpha 1-adrenoceptor agonist was not more effective than amfonelic acid alone in blocking ethanol hypnosis. The stimulation of locomotor activity by amfonelic acid in C57B1/6 mice was more sensitive to the blocking effect of ethanol than stimulation induced by d-amphetamine. The blocking effect of amfonelic acid, but not that of d-amphetamine, on the effects of ethanol developed tolerance. In pimozide-pretreated mice, amfonelic acid failed to reduce the ethanol-induced hypnosis. Hence it appears that dopamine (DA) released by amfonelic acid is responsible for its antagonism of ethanol. However, though amfonelic acid acted as a strong releaser of DA in Swiss-Webster, CD-1, DBA-2 and BALB/c mice, in these strains it failed to reduce the effect of ethanol. Moreover, methylphenidate, a dopaminergic stimulant, which acts by a mechanism similar to that of amfonelic acid was not effective in reducing the hypnotic effect of ethanol in C57B1/6 mice. For these reasons, additional mechanisms may have to be considered to explain this strain-dependent effect of amfonelic acid.     

Discrimination of ethanol–nicotine drug mixtures in mice: dual interactive mechanisms of overshadowing and potentiation

Rationale

One possible basis for the proclivity of ethanol and nicotine co-abuse is an interaction between the discriminative stimulus (S^D) effects of each drug.

Objectives

The current work sought to assess the discriminative control of ethanol and nicotine cues in mice trained with drug mixtures and to determine whether interactive mechanisms of overshadowing and potentiation occur.

Methods

Male C57BL/6J mice were trained to discriminate ethanol (1.5?g/kg) alone or ethanol plus nicotine (0.4, 0.8, or 1.2?mg/kg base) in experiment 1 and nicotine (0.8?mg/kg) alone or nicotine plus ethanol (0.5, 1.0, or 2.0?g/kg) in experiment 2. Stimulus generalizations of the training mixtures to ethanol, nicotine, and the drug combination were assessed.

Results

Ethanol (1.5?g/kg) retained discriminative control despite the inclusion of a progressively larger nicotine dose within the training mixtures in experiment 1. Although the nicotine S^D was overshadowed by ethanol training doses > 0.5?g/kg in experiment 2, nicotine did potentiate the effects of low-dose ethanol.

Conclusions

These findings are suggestive of dual mechanisms whereby ethanol (>0.5?g/kg) overshadows the S^D effects of nicotine, and at lower doses (<1?g/kg) the salience of ethanol??s S^D effects is potentiated by nicotine. These mechanisms may contribute to the escalation of concurrent drinking and smoking in a binge-like fashion.     

Baclofen alters ethanol-stimulated activity but not conditioned place preference or taste aversion in mice.

The present experiments examined the effects of the GABA(B) receptor agonist, baclofen, on the acquisition of ethanol-induced conditioned place preference (CPP) and conditioned taste aversion (CTA) in male DBA/2J mice. Mice in the CPP experiment received four pairings of ethanol (2g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). On intervening days (CS- sessions), mice received saline injections paired with a different floor type. On CS+ days, mice also received one of four doses of baclofen (0.0. 2.5, 5.0, or 7.5 mg/kg) 15 min before an injection of ethanol. For the preference test, all mice received saline injections, and were placed on a half-grid and half-hole floor for a 60-min session. Baclofen dose dependently reduced ethanol-stimulated activity, but did not alter the magnitude of ethanol-induced CPP at any dose. For the CTA experiment, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of saline or baclofen (2.0 and 6.0 mg/kg) 15 min before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Baclofen did not alter the magnitude of ethanol-induced CTA at any dose. In addition, baclofen alone did not produce a CTA. Overall, these studies show that activation of GABA(B) receptors with baclofen reduces ethanol-induced locomotor activation, but does not alter ethanol's rewarding or aversive effects in the CPP and CTA paradigms in DBA/2J mice.     

Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine,and the dopamine reuptake inhibitor GBR12909 in mice

Rationale Recent evidence suggests that, in addition to ascending monoaminergic systems, glutamate systems also play a role in psychostimulant-induced locomotor activity. The present study was conducted to examine the effects of the selective type-5 metabotropic glutamate receptor (mGluR5) antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant effects of cocaine, d-amphetamine, and the dopamine reuptake inhibitor GBR12909.Methods Male DBA/2J mice were treated with saline or MPEP (1, 5, 20 or 30 mg/kg i.p.) 10 min prior to the administration of cocaine (15 mg/kg or 30 mg/kg i.p.), d-amphetamine (3 mg/kg or 5 mg/kg i.p.) or GBR12909 (10 mg/kg or 20 mg/kg i.p.). Locomotor activity was then monitored in an open-field environment for 30 min. The effects of MPEP alone (1, 5, 20 and 30 mg/kg i.p.) on locomotor activity were also examined.Results MPEP dose dependently inhibited the acute locomotor stimulant effects of cocaine, d-amphetamine, and the 10-mg/kg dose of GBR12909. However, MPEP had no effect on the locomotor stimulant effects of the higher (20 mg/kg) dose of GBR12909. When tested alone, MPEP increased locomotor activity at doses of 5 mg/kg and 20 mg/kg.Conclusions Our data suggest that mGluR5 receptors not only mediate spontaneous locomotor activity in DBA/2J mice but also the acute locomotor stimulant effects of cocaine, d-amphetamine and lower doses of GBR12909. However, the fact that MPEP did not attenuate the locomotor stimulant effects of the high (20 mg/kg) dose of GBR12909 suggests complex interactions between metabotropic glutamate receptors, dopamine transporters and possibly other monoamines in the regulation of psychostimulant-induced locomotor activity.     

Calcium channel antagonists attenuate cross-sensitization to the locomotor effects of nicotine and ethanol in mice

The present study was focused on evaluation of locomotor cross-sensitization between nicotine and ethanol in mice. First, we demonstrated that, after 5 daily injections, nicotine (0.5 mg/kg, ip) produced sensitization to its own locomotor stimulant effect. Moreover, nicotine-experienced mice manifested an enhanced response to ethanol challenge (2 g/kg, ip) indicating the development of cross-sensitization between nicotine and ethanol in mice. Additionally, the L-type voltage-dependent calcium channel antagonists: verapamil and diltiazem, but not nimodipine, at the dose of 20 mg/kg, injected before the ethanol challenge, blocked the expression of this cross-sensitization. These findings support the hypothesis that similar neural calcium-dependent mechanisms are involved in the sensitization to locomotor stimulant effects of nicotine and ethanol and point to certain differences in acute behavioral effects of various classes of calcium channel inhibitors.