Bromocriptine and quinpirole,but not 7-OH-DPAT or SKF 38393, potentiate the inhibitory effect of L-NAME on ethanol-induced locomotor activity in mice

The effects of N(G)-nitro- l-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, SKF 38393, bromocriptine (BRM), quinpirole (QPR) and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), dopamine receptor agonists, and combinations of the dopamine agonists and L-NAME on ethanol-induced locomotor activity in adult male Swiss-Webster mice were investigated. The mice were given ethanol (0.5-2 g/kg), L-NAME (15-60 mg/kg), SKF 38393 (5-20 mg/kg), BRM (2.5 and 5 mg/kg), QPR (0.25 and 0.5 mg/kg), 7-OH-DPAT (0.5 and 1.0 mg/kg), a combination of l-arginine (1 g/kg) and L-NAME (60 mg/kg), combinations of SKF 38393, BRM, QPR or 7-OH-DPAT with L-NAME (60 mg/kg) or ethanol (0.5 g/kg) and saline or vehicle by i.p. injection. Triple combinations (dopaminergic agonist, 60 mg/kg L-NAME and 0.5 g/kg ethanol) were also given. Locomotor activity was measured for 30 min immediately following ethanol injections. Ethanol (0.5 g/kg) significantly increased locomotor activity. L-NAME, BRM, QPR and 7-OH-DPAT blocked the ethanol (0.5 g/kg)-induced locomotor hyperactivity dose dependently and at doses that did not affect locomotor activity in naive mice when administered alone. The inhibitory effects of L-NAME (60 mg/kg) were not prevented by pretreatment with l-arginine. BRM and QPR, but not 7-OH-DPAT, significantly and dose-dependently potentiated the inhibitory effect of L-NAME. Our results suggest that L-NAME inhibits ethanol-induced locomotor hyperactivity in mice by a mechanism not involving NO. The inhibitory effect of L-NAME may be related to the activation of presynaptic dopamine D(2) receptors rather than dopamine D(3) receptors.     

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.     

Investigation of a possible sensitization development to a challenge dose of ethanol after 2 weeks following the single injection in mice

In the present study, a possible sensitization development to a single injection of ethanol in mice was investigated. Subjects were adult male Swiss-Webster mice. Ethanol (0.5-4 g/kg) or saline (control) was intraperitoneally injected to mice. Horizontal, vertical and ambulatory locomotor activities were recorded for 30 min immediately following the ethanol or saline injections. After 2 weeks, each group of mice was randomly assigned to two groups. A single challenge dose of ethanol (1 g/kg) was administered to the first group, and saline was injected to the second group. Then, the locomotor activities were recorded for 30 min. In the first experiment, ethanol significantly increased the horizontal and ambulatory activities of the mice at the doses of 0.5 and 1 g/kg, but not at 2 g/kg, while they were decreased at the dose of 4 g/kg. Ethanol (0.5 g/kg) also significantly increased the vertical activity. After 2 weeks, the challenge injection of ethanol (1 g/kg) produced some significant increases in the horizontal and ambulatory activities of the group pretreated with ethanol (2 g/kg). It did not cause any significant change on the locomotor activities of the other three groups treated with lower (stimulant) or higher (depressant) doses of ethanol. In addition, there was no significant difference between locomotor activities of the groups challenged with saline. However, a two-way ANOVA of the data on the challenge injections did not indicate any sensitization development to the effects of ethanol on locomotor activities of the mice. Our results suggest that a locomotor sensitization did not develop to a single injection of ethanol after 2 weeks following the first injection in mice.     

A psychopharmacological study of the relationship between brain catalase activity and ethanol-induced locomotor activity in mice

OBJECTIVE: The present experiments analyze the effects of the brain catalase inhibitor 3-amino-1,2,4-triazole (AT) on the locomotor activity induced by ethanol. METHOD: In the first experiment, mice received injections of either AT (0.5 g/kg) or saline (S) 5 hours prior to an ethanol injection (0, 0.8, 1.6, 2.4, 3.2 or 4 g/kg). In the second experiment, five different groups of mice received injections of AT (0, 0.010, 0.030, 0.060, 0.125, 0.250 or 0.500 g/kg) 5 hours prior to being injected with 1.6 g/kg of ethanol. In the third experiment, six groups of mice were treated with AT (0.5 g/kg), simultaneously, 2.5, 5, 10 or 20 hours before the administration of 1.6 g/kg of ethanol. Immediately after ethanol injection, mice were placed individually in the open-field apparatus for 20 minutes. In another set of experiments, the effects of AT on brain catalase activity were studied. Animals were injected with AT at 0, 0.010, 0.030, 0.060, 0.125, 0.250 or 0.500 g/kg, and 5, 10 or 20 hours following AT treatment mice were perfused and the brain was removed. RESULTS: Pretreating mice with AT reduces ethanol-induced locomotor activity (1.6, 2.4 and 3.2 g/kg) without altering spontaneous locomotion. Pretreatment with AT (from 0.125 g/kg to 0.5 g/kg) produced a clear dose-dependent decrease of ethanol locomotion and brain catalase activity. The effect of AT was observed 5 and 10 hours after the injection of this drug, and it disappeared 20 hours following AT treatment. CONCLUSIONS: Current data showed a parallel property of AT in producing a remarkable dose- and time-dependent decrease in catalase activity and ethanol locomotion.     

Apomorphine effects on behavioral response to ethanol in mice selectively bred for differential sensitivity to ethanol

Two lines of mice selectively bred for differences in response to a hypnotic dose of ethanol were administered apomorphine alone or in combination with ethanol. When administered by itself, apomorphine produced similar dose-dependent depression of locomotor activity and increases in stereotypy in the two lines. Doses of apomorphine (0.5 microM/kg and 2 microM/kg) thought to bind only presynaptic dopamine receptors blocked the slight locomotor activation to 1.5 g/kg ethanol in the ethanol-sensitive Long-Sleep (LS) mice; in the ethanol-insensitive Short-Sleep (SS) mice which show marked activation to all subhypnotic doses of ethanol, these doses of apomorphine only attenuated the activation. A higher apomorphine dose (8 microM/kg) antagonized the locomotor depressant effects of 2.0 and 2.5 g/kg of ethanol in LS mice but did not alter the shape of the SS ethanol dose response curve for locomotor activity. Apomorphine (2 and 8 microM/kg) potentiated ethanol-induced loss of the righting reflex in LS mice in a dose dependent fashion, but did not alter this soporific effect of ethanol in SS mice. These findings extend the data base suggesting a role for dopamine both in the mechanism(s) differentiating the LS and SS mice and the stimulant and intoxicating properties of ethanol.     

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.     

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.     

Comparison of ethanol locomotor sensitization in adolescent and adult DBA/2J mice

Rationale The mammalian adolescent period is characterized by enhanced vulnerability to drug-induced neuroadaptations. Epidemiological evidence indicates that individuals who start drinking alcohol during adolescence are four times more likely to develop alcohol dependence in adulthood, but little is known about the adaptive mechanism(s) that may underlie this observation. Behavioral sensitization in rodents is a model of neurobehavioral plasticity that occurs following repeated drug exposure and may underlie components of addiction. Objectives The goal of this study was to determine if adolescent mice are differentially sensitive to ethanol-induced locomotor sensitization as compared to adults. Materials and methods Adolescent and adult DBA/2J mice were treated with saline or ethanol (1.0, 1.5, 2.0, 2.5 g/kg) for 7, 11, or 15 days and tested for acute and sensitized locomotor activity. Blood ethanol clearance (BEC) was also assessed 10, 60, and 180 min following treatment with ethanol 2 g/kg. Results Adolescent mice were more sensitive than adult mice to the acute locomotor activating effects of ethanol. However, adolescent mice were less sensitive than adult mice to locomotor sensitization, as only the highest dose of ethanol (2.5 g/kg) induced sensitization in the adolescent mice, while lower doses of ethanol elicited sensitization in the adult mice. The differential response to ethanol sensitization was not related to duration of treatment or differential BEC. Conclusions These results indicate that adolescent mice are less sensitive to ethanol sensitization, and this blunted behavioral response in adolescents might reflect differential ethanol-induced neurobehavioral adaptations.     

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.     

Learning and memory in agmatine-treated rats

Agmatine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, was examined for its role in water maze place learning, contextual and auditory-cued (discrete) fear learning and conditioned taste aversion learning, when administered systemically. Male Wistar rats were given saline or 1, 5, 10 or 50 mg/kg agmatine ip 20 min prior to or 30 min following daily training sessions in a hidden-platform (place learning) water maze task. Agmatine did not affect latencies to find the hidden platform or preference for the training quadrant during probe trials. When administered 20 min prior to contextual or auditory-cued fear-conditioning sessions, these doses of agmatine evoked a linear dose-dependent impairment in the magnitude of learned fear to the contextual stimuli when assessed during extinction trials 24 h later, but had no effect on the magnitude of learned fear to the auditory stimulus. Inferences of baseline motor activity and ability to respond to the presentation of footshock stimuli were not affected by the treatment. Injections of 50 mg/kg agmatine concurrently with a malaise-evoking agent following presentations to a novel sucrose solution abolished learned taste aversions; this agent did not evoke conditioned taste aversions alone. These studies indicate that systemically administered agmatine selectively impairs behavioral inferences of specific types of learning and memory.     

Influence of captopril and enalapril on some central effects of ethanol

The influence of captopril and enalapril on acute toxicity of ethanol, ethanol-induced hypothermia, ethanol sleeping time has been investigated in mice. Moreover, the combined effect of captopril and enalapril on spontaneous locomotor activity in mice has been examined. The captopril (5 and 20 mg/kg) and enalapril (5 and 20 mg/kg) were injected intraperitoneally i.p. The drugs were given as single or repeated doses for 10 days. It has been shown that the captopril and enalapril administered in single doses decreases, but chronic administration increases acute toxicity of ethanol. Captopril and enalapril in single doses enhanced, but chronic administration inhibits hypothermic effect of ethanol. Captopril and enalapril reduces ethanol sleeping time. Captopril and enalapril administered for 10 days and enalapril in a single dose 20 mg/kg decreases ethanol induced hyperactivity.     

Influence of felbamate on selected central effects of ethanol in experimental animals

Both felbamate and ethanol demonstrate complex action on central nervous system (CNS). There are several data indicating that ethanol influences pharmacokinetics of new generation of antiepileptic drugs. Investigation of CNS interaction of felbamate and ethanol may bring up some suggestions as for adverse reactions of concomitance of these substances and consequences of such reactions are concerned. The influence of felbamate on the action of ethanol in a rota-rod test (1.5 g/kg), the duration of ethanol sleeping time (4 g/kg) as well as on spontaneous locomotor activity (2 g/kg) and ethanol-induced hypothermia (2.5 g/kg) was investigated. Felbamate was administered at a single dose (200 mg/kg i.p.) or as daily injections dose (50 mg/kg for 10 days). At a single dose, felbamate prolonged ethanol-sleeping time, increased ethanol-induced disturbances of motor coordination and ethanol-induced hypothermia as well as prevented increased locomotor activity observed after ethanol intake. Felbamate administered for 10 days reduced ethanol sleeping time, did not effect ethanol on locomotor activity of mice, but augmented ethanol-induced changes in motor coordination and ethanol hypothermia. These interactions may be of pharmacodynamic character, but pharmacokinetic nature cannot be excluded, felbamate and ethanol are substrates for the cytochrome CYP2E1.     

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.     

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.     

Analysis of the biphasic locomotor response to ethanol in high and low responders to novelty: a study in nijmegen wistar rats

The aim of the study was to investigate the biphasic locomotor response to ethanol in rats. Based on the recent finding that high responders to novelty (HR) and low responders to novelty (LR), selected from an outbred Nijmegen Wistar rat population, show differences in ethanol intake and preference, it was initially investigated to what extent HR and LR differ in their locomotor response to ethanol. A dose-response curve (0.2–2.0 g/kg, IP) was established using standardized activity boxes. HR showed a significant increase at 0.5 g/kg, followed by a significant decrease at doses 1.0–2.0 g/kg; LR showed only a decrease at doses 1.0–2.0 g/kg. Secondly, it was investigated to what extent stress altered the ethanol-induced increase and decrease, respectively. For that purpose, the ethanol-induced locomotor effects (0.5 and 1.0 g/kg) were analyzed in habituated and non-habituated (stressed) HR and LR; habituation consisted of a 15-min adaptation period to the activity cages. Stress significantly enhanced the excitatory effects in HR, but had no effect on the sedative effects in HR and LR. Finally, the locomotor effects of sub-chronic treatment (7 days) with an excitatory (0.5 g/kg) or sedative (1.0 g/kg) dose were analyzed in HR and LR. The excitatory effect of 0.5 g/kg disappeared throughout the treatment in HR, whereas the sedative effects of 1.0 g/kg remained the same in HR and LR. It is concluded that the mechanism underlying the ethanol-induced motor excitation differs completely from that underlying the ethanol-induced sedation. Given the known differences in the make-up of the brain and endocrine system between HR and LR, these animals are suggested to be good models for studying the mechanisms underlying the biphasic locomotor response to ethanol in rats.     

Inhibitory influence of mecamylamine on the development and the expression of ethanol-induced locomotor sensitization in mice

Several evidences have indicated the involvement of neuronal nicotinic acetylcholine receptors (nAChR) in behavioral effects of drugs of abuse, including ethanol. nAChRs are implicated in ethanol-induced behaviors as well as neurochemical responses to ethanol. Recently, it is demonstrated that mecamylamine, a nAChR antagonist blocks cocaine-, d-amphetamine-, ephedrine-, nicotine-, and methylphenidate-induced psychomotor sensitization. However, no reports are available on its role in ethanol-induced psychomotor sensitization. Therefore, an attempt was made to evaluate its effect on ethanol-induced locomotor sensitization using a model previously described by us. The results revealed that acute administration of mecamylamine (1 and 2 mg/kg, i.p.) blocked the acute stimulant effect of ethanol (2.0 g/kg, i.p.). In addition, treatment with mecamylamine (0.5-2.0 mg/kg, i.p.), 30 min prior to the challenge dose of ethanol (2.0 g/kg, i.p.) dose dependently attenuated expression of sensitization to locomotor stimulant effect of ethanol. Moreover, administration of mecamylamine (1 and 2 mg/kg, i.p.) during development (prior to each ethanol injection on days 1, 4, 7, and 10) blocked acquisition as well as expression (day 15) of sensitization to locomotor stimulant effect of ethanol. Mecamylamine per se did not affect locomotor activity. Further, it also did not influence blood ethanol levels and rotarod performance in mice. These results support the hypothesis that neuroadaptive changes in nAChRs may participate in the development and the expression of ethanol-induced locomotor sensitization.     

Effect of taurine on ethanol-induced changes in open-field locomotor activity

In the present investigation we questioned whether taurine antagonized the effects of ethanol on motor activity measured in the open field. Ten minutes following simultaneous administration (IP) of ethanol (1.0, 1.5, 2.0 and 2.5 g/kg) or saline and taurine (30, 45 and 60 mg/kg) or saline, mice were placed in open field chambers and locomotor activity was measured during a 10 min testing period. A significant interaction was found between taurine and ethanol. Taurine-treated mice displayed lower motor excitation with the 1.0 g/kg dose of ethanol than the saline group treated with the same dose of ethanol. However at the 2.0 g/kg ethanol dose, taurine-treated mice demonstrated higher motor activity than the saline treated mice, once again, treated with the same dose of ethanol. No differences in blood ethanol levels were observed between the two groups. In a second study, taurine administration (30, 45 and 60 mg/kg) did not show any effect ond-amphetamine-induced enhancement of locomotor activity (1, 2, and 3 mg/kg). Data from this study demonstrated an interaction between taurine and ethanol in their effect on locomotor activity in the open field.     

Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents

The effect of agmatine in preclinical behavioral tests of schizophrenia has been examined in rodents. Agmatine at the doses of 40 and 80 mg/kg blocked conditioned avoidance responding, attenuated apomorphine induced climbing, diminished amphetamine and ketamine hyperlocomotor activity and augmented plasma prolactin levels. Pretreatment of animals with 20 mg/kg of agmatine potentiated the inhibitory effect of haloperidol (0.1 mg/kg, ip) and olanzepine (0.5 mg/kg, ip) in conditioned avoidance response test and apomorphine induced climbing. Agmatine alone at the doses tested here did not induce any cataleptic behavior in mice. However significant catalepsy was exhibited when agmatine (80 mg/kg, ip) was injected to mice pretreated with 5-HT1A receptor antagonist, WAY100, 635. These results indicate that agmatine via regulation of brain dopaminergic signaling modulates dopamine mediated behaviors. The alteration in the levels of endogenous agmatine may contribute to the genesis of psychosis and development of drugs that enhance endogenous agmatine content may be better therapeutic approach to treat schizophrenia with low incidences of extra pyramidal side effects.     

Evidence for the role of nitric oxide in caffeine-induced locomotor activity in mice

Rationale Nitric oxide (NO) is implicated in the acute locomotor activating effects of some addictive drugs such as amphetamine and cocaine, but has not been investigated in the case of caffeine.Objectives We investigated the effects of a nitric oxide synthase (NOS) inhibitor N-Nitro-l-arginine methyl ester (l-NAME) and a combination of l-arginine, a NO precursor, and l-NAME on caffeine induced locomotor activity in Swiss Webster mice.Methods Locomotor activity was recorded for 30 min immediately following caffeine (0.25–128 mg/kg) or saline administration. In a further study, l-NAME (15 and 30 mg/kg) was administered to another group of mice 30 min before caffeine (1 and 16 mg/kg) injections. Finally, l-arginine (1000 mg/kg), a nitric oxide precursor, was administered 20 min before the l-NAME (15 and 30 mg/kg) treatments and locomotor activities were again recorded immediately after caffeine (1 and 16 mg/kg) injections.Results Caffeine (0.5–16 mg/kg) significantly increased locomotor activity, while l-NAME (30 mg/kg) blocked caffeine (1 and 16 mg/kg)-induced locomotor activity. The low dose of l-NAME blocked only caffeine (1 mg/kg)-induced locomotor activity. l-Arginine reversed the inhibitory effects of l-NAME on caffeine-induced locomotor activity. l-NAME and l-arginine had no effect on the locomotor activity of the mice when given by themselves.Conclusions The results suggest that caffeine-induced locomotor activity might be modulated by NO in mice.     

Cyanamide reduces brain catalase and ethanol-induced locomotor activity: is there a functional link?

The present study was designed in an attempt to assess a previously suggested role of brain catalase activity in ethanol-induced behaviour by examining ethanol-induced locomotor activity in cyanamide-treated mice. Mice were pretreated with IP injections of the catalase inhibitor cyanamide (3.75, 7.5, 15, 30 or 45 mg/kg) or saline. Following this treatment, animals in each group received IP injections of ethanol (0.0, 1.6, 2.4 or 3.2 g/kg) and locomotion was recorded. Several time intervals (0, 5, 10, 15, 20 or 25 h) between the two treatments were also evaluated. Results indicated that cyanamide administration produced a dose-dependent decrease in ethanol-induced locomotor activity that depends on the time between treatments. However, cyanamide did not change spontaneous or d-amphetamine-induced locomotor activity. Moreover, an additive effect of cyanamide and another brain catalase inhibitor, 3-amino-1,2,4-triazole (AT), on the reduction of ethanol-induced locomotor activity was observed. Perfused brain homogenates of mice treated with cyanamide, AT or cyanamide+AT showed a significant reduction of brain catalase activity. The dose and time patterns of both effects were closely related and a significant correlation between them was obtained. These results suggest that cyanamide could reduce locomotor activity through its inhibition of brain catalase, giving further support to the notion that brain catalase may be an important regulator of some ethanol-induced behavioural effects. Received: 16 November 1998/Final version: 22 December 1998