Involvement of the opioid system in the development and expression of sensitization to the locomotor-activating effect of ethanol

Previous studies have shown that pretreatment with naloxone (Nlx), an opiate antagonist, attenuates the stimulating effect of ethanol. The purpose of the present study was to determine the influence of Nlx on the development and expression of the sensitization to ethanol. Initially, effects of different doses of Nlx on the response to a low dose of ethanol (2.0 g/kg) were assessed. Nlx (1.0 and 3.0 mg/kg i.p.) decreased the stimulating effect of ethanol. Groups of mice were treated with saline or Nlx (1.0 mg/kg i.p.) plus saline or ethanol (2.0 g/kg i.p.) during 21 d. On day 25 of treatment all animals received an ethanol challenge (2.0 g/kg i.p.). It significantly increased the locomotor activity of mice that had received chronic ethanol (2.0 g/kg) once daily as compared to those that had received saline. Chronic administration of Nlx (1.0 mg/kg i.p.), during the same period of time, did not change the locomotor activity of the mice. However, the group concomitantly treated with Nlx+ethanol did not develop sensitization to the locomotor-activating effect of ethanol. Another experiment was carried out to determine the effects of Nlx on the expression of sensitization to ethanol. Acute pretreatment with Nlx did not change the response of the mice that had developed sensitization to ethanol. These data show Nlx's prevention of the development of ethanol-induced sensitization but not of its expression, suggesting an important role of the opioid neurotransmitter systems modulating the development of sensitization to the locomotor-activating effect of ethanol.     

An evaluation of the locomotor stimulating action of ethanol in rats and mice

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.0 and 4.0 g/kg, and was decreased by 5.0 g/kg. The dose (2.0 g/kg) that caused the greatest increase in locomotor activity did not impair motor coordination, measured by the height of aerial righting in mice. Tests after oral administration of ethanol showed that the increase in locomotor activity of mice was not due to peritoneal irritation. The same dose (2.0 g/kg) did not increase the locomotor activity of C57BL/6J mice. Ethanol (0.1 to 3.0 g/kg) had no effect or decreased the locomotor activity of individual male Sprague-Dawley rats. These findings suggest that biological differences in strains and species of laboratory rodents contribute to the apparent variability of locomotor stimulation caused by ethanol. The presence or absence of an ethanol-induced increase in locomotor activity was not dependent on the sex or number of mice or rats tested. Intertrial-interval crossing by rats acquiring or performing an active avoidance task in a shuttle box was increased by ethanol. This action was dependent on the presentation of electric foot shock. Apomorphine (0.25 and 2.5 mg/kg) and fenmetozole (7.5 and 15.0 mg/kg) failed to inhibit the ethanolinduced increase in intertrial-interval crossing by rats, although these drugs have been shown previously to antagonize the ethanol-induced increase in the activity of mice ethanol treatment. The ethanol-induced increases in the spontaneous locomotor activity of CD-1 mice in photocell activity monitors and in intertrial-interval crosses in rats in a shuttle box task thus do not appear to share a common mechanism.     

Sex differences in locomotor activity after acute and chronic cocaine administration.

Adult, intact and gonadectomized male and female Wistar rats (n = 9) were exposed to an automated open field to assess the behavioral effects of acute cocaine administration (saline, 1.0 and 10.0 mg/kg subcutaneous). The subjects were exposed to the open field for 10 min, removed to be injected and returned to the open field for another 30 min. Three saline and two drug sessions were run in counterbalanced order. Locomotor activity in intact and castrated male rats and ovariectomized female rats decreased following injection, irrespective of the dose of cocaine. The locomotor activity of intact female rats was higher than that of any other group of subjects. It decreased during the session after saline and 1.0 mg/kg cocaine, but increased towards the end of the 30 min session after 10.0 mg/kg. Rearing measures paralleled the observations on locomotor activity. To determine the effects of chronic, home-cage, cocaine administration, five of the subjects in each group were injected with 10.0 mg/kg cocaine for 9 consecutive days. The remaining four subjects received saline injections. On day 10, all subjects were re-exposed to the open-field for 10 min, removed, injected with 10.0 mg/kg cocaine and returned to the open field for another 30 min. Chronic home cage cocaine administration produced an increase in cocaine's effects on locomotor activity and rearing in intact female rats only. However, behavioral sensitization was also observed in intact female rats who had been treated with saline for 9 consecutive days, suggesting that behavioral sensitization to cocaine in intact female rats may develop very rapidly and independent of environmental context.     

Concurrent administration of diethyldithiocarbamate and 4-methylpyrazole enhances ethanol-induced locomotor activity: the role of brain ALDH

RATIONALE: It has been proposed that brain aldehyde dehydrogenase (ALDH) plays a role in the modulation of some psychopharmacological effects of ethanol. Diethyldithiocarbamate (DDTC), an ALDH inhibitor, elevates blood acetaldehyde levels in the presence of ethanol. Concurrent administration with 4-methylpyrazole (4-MP), an alcohol dehydrogenase inhibitor, prevents peripheral accumulation of acetaldehyde by DDTC. OBJECTIVE: To investigate the effects of concurrent DDTC and 4-MP administration on ethanol-induced locomotor activity in mice. METHODS: Mice were pretreated IP with saline (S+S) or 4-MP (10 mg/kg) (S+4-MP), then received IP injections of ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg) prior to testing in the open field. RESULTS: Pretreatment with 4-MP does not modify the spontaneous or ethanol-induced locomotor activity. In the second experiment, the DDTC (114, 228 and 456 mg/kg) and 4-MP (DDTC+4-MP) were administered 8 h prior to testing locomotor activity in the open field. Animals were then treated with ethanol (0, 0.8, 1.6, 2.4, 3.2 and 4 g/kg), and placed in open field chambers. The locomotor activity of animals pretreated with DDTC and 4-MP was significantly enhanced here compared to groups S+S and S+4-MP. These effects cannot be attributed to elevated blood acetaldehyde levels, as pretreatment with 4-MP prevented peripheral accumulation of acetaldehyde. CONCLUSIONS: These data suggest that brain ALDH may contribute to the effects of ethanol on locomotor activity. This role of the enzyme ALDH in some of the psychopharmacological effects of ethanol may be a result of its ability to regulate levels of acetaldehyde in brain.     

Taurine and ethanol interactions: behavioral effects in mice

Taurine is an abundant amino acid in the brain that shares pharmacological effects and similar potency with ethanol. Recently, taurine-containing beverages have been reported to enhance the euphoric effects of ethanol, though the extent of this effect and the role of taurine remain speculative. The present study was designed to explore interactions between taurine and ethanol on several behaviors including locomotion, ataxia, and loss of righting. Two strains of mice, C57BL/6J and DBA/2J mice, were used to examine potential strain differences. In the first experiment, effects of various doses of taurine (0.3-3.0 g/kg), ethanol (1.0-4.2 g/kg), or taurine in combination with ethanol were assessed in a within-subjects design. Although taurine did not appear to alter effects of ethanol on any measure in either strain, the development of tolerance to locomotor effects and sensitization to ataxic effects of ethanol in DBA/2J mice complicated interpretation of these results. In a second experiment, drug-na?ve mice were assigned to one of four treatment groups: saline+saline, saline+ethanol (1.78 g/kg), taurine (1.78 g/kg)+saline, or ethanol+taurine. In this experiment, taurine pretreatment significantly attenuated the locomotor-stimulating effect of ethanol in both strains (but to a greater extent in C57BL/6J mice) and appeared to reduce the ataxic effects of ethanol in C57BL/6J mice. In conclusion, the interaction between taurine and ethanol is subtle. Further, results are inconsistent with the notion that taurine plays a major role in the locomotor, ataxic, or loss of righting effects of ethanol.     

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.     

Decrease in d-methamphetamine sensitivity in mice due to ethanol: apparent inhibitory and stimulatory effects of ethanol on d-methamphetamine-induced locomotor activity

The locomotor activity of mice was recorded after administration of d-methamphetamine-HCl (1.5, 2.5, 5.0 and 7.5 mg/kg body weight) and/or ethanol (0.8 and 1.6 g/kg body weight). Mice injected with lower doses of d-methamphetamine (1.5 or 2.5 mg/kg) showed a marked increase in locomotor activity, while in those with higher doses of d-methamphetamine (5.0 or 7.5 mg/kg), locomotor activity was not further enhanced, but slightly decreased. Administration of ethanol inhibited the stimulated locomotor activity caused by low doses of d-methamphetamine (1.5 or 2.5 mg/kg), while the stimulation of motility after higher doses of d-methamphetamine (5.0 or 7.5 mg/kg) was potentiated by administering ethanol. Although apparent inhibition and stimulation of d-methamphetamine-induced locomotor activity of mice due to ethanol was observed, it is suggested that mice administered ethanol showed the decreased sensitivity to d-methamphetamine by plotting total locomotor activity of mice against doses of d-methamphetamine administered. The half maximum effective dose of d-methamphetamine for locomotor activity was increased from 1.5 mg/kg to 3.0 mg/kg by concomitant administration of 1.6 g/kg ethanol.     

Response variability of ethanol-induced locomotor activation in mice

Mice from a randomly bred strain were divided into two groups according to their locomotor responses to ethanol (0.8–3.0 g/kg): in two thirds of the tested animals ethanol increased locomotor activity (ethanol activated — EA), whereas in the remaining one third it did not (ethanol non-activated — ENA). Both groups did not differ in their locomotor activity after saline administration. Furthermore, EA and ENA mice presented a similar increase in locomotor activity after challenge with 1.0 and 2.0 mg/kgd-amphetamine. Chronic exposure to ethanol increased the ethanol-induced locomotor activation in both EA and ENA groups. The possibility that the lack of responsiveness of ENA mice to ethanol's acute activating effect could be due to a higher sensitivity to the depressant effect of ethanol is discussed.With funds from Financiadora de Estudos e Projetos (FINEP) and Associação Fundo de Incentivo a Psicofarmacologia (AFIP)     

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.     

Apomorphine-induced motor behavior in rats exposed prenatally to alcohol

We psychopharmacologically examined dopamine function in rats exposed to ethanol prenatally. Pregnant rats received liquid diets of 35% or 0% ethanol-derived calories (EDC), or ad lib lab chow (LC). Twenty-eight-day-old offspring received systemic doses of apomorphine chosen to stimulate predominantly presynaptic (0.02 or 0.1 mg/kg) or postsynaptic dopamine receptors (2.0 or 5.0 mg/kg). Behavior was scored automatically for 60 min in an "open field." For males, prenatal ethanol exposure resulted in a dose-response shift to the left for locomotor activity. Females exposed to the liquid diet, with or without ethanol, showed less of an increase in locomotor activity following the 5.0 mg/kg dose of apomorphine than did LC controls. There were no effects of prenatal treatment on repetitious motor behavior in the automated "open field" or on stereotypy scored by direct observation in separate groups of rats. The results are consistent with an hypothesis that prenatal ethanol exposure alters the sensitivity of postsynaptic (perhaps mesolimbic) dopamine systems important to locomotor activity in young male rats.     

Behavioral correlations of gradual forced administration of psychoactive drugs

The study was aimed at evaluating the behavioral correlations of the forced administration of psychoactive drugs. Wistar rats received the following drugs in elevated doses (over 4 days, i. p.): (i) physiological saline (control; 0.1-0.2-0.4-0.8 ml/rat), (ii) psychostimulant amphetamine (0.5-1.0--2.0-4.0 mg/kg); (iii) opioid analgetic fentanyl (0.00625-0.0125--0.025-0.05 mg/kg), (iv) ethanol 40% solution (0.5-1.0--2.0-4.0 g/kg), (v) barbiturate sodium ethaminal (2.5-5--10-20 mg/kg); and(vi) synthetic glucocorticoid dexamethasone (0.5-1.0--2.0-4.0 mg/kg). The forced regime of drug administration led to gradual load of the organism and prevented drug tolerance. The dynamics of self-stimulation reaction of the lateral hypothalamus was registered every day over drug administration period and revealed the following regularities: (I) dose-dependent effect of psychostimulant amphetamine and opioid analgetic fentanyl; (II) dexamethasone modulated self-stimulation, increasing (2 day, 1 mg/kg) or decreasing it (3 day, 2 mg/kg); (III) ethanol (1-2 g/kg) activated self-stimulation slightly; (IV) sodium ethaminal slightly inhibited self-stimulation and increased the thresholds of self-stimulation. In 24 h and 72 h after the last administration of drugs, the rat behavior was assessed in open field, elevated plus maze, resident-intruder paradigm, and Porsolt's test. In the open field, significant signs of post-intoxication exposure of psychoactive drugs were revealed, which were registered for 24-72 h after drug withdrawal. The withdrawal of drugs was accompanied with reduction (in 24 h) and subsequent recovery (in 72 h) of the vertical motor activity, exploration behavior, and emotionality. The anxiety indexes were increased up to the 3rd day after withdrawal. The antidepressant effect was also increased. The system of aggression-defense was restored only in rats treated with ethanol. The indexes of individual behavior and communicability in the post-intoxication period were decreased as well. It is suggested that the forced regime of drug administration in increasing doses with subsequent withdrawal of drug injections is a suitable method to evaluate the behavioral elements of drug dependence.     

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.     

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.     

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.     

Attenuation of apomorphine-induced sensitization by buspirone

Apomorphine, a dopamine D₁/D₂ agonist is effective in the treatment of parkinson's disease; but its long term use is often associated with the dependence and addiction. The development of locomotor sensitization to psychostimulants including apomorphine is considered to be an important contributor to psychostimulant drug abuse. Previous studies have shown that long term administration of drugs of abuse increases the effectiveness of somatodendritic 5-hydroxytryptamine (5-HT)-1A receptors. Repeated administration of buspirone attenuates the effectiveness of somatodendritic 5-HT_1A receptors. The present study was designed to test the hypothesis that coadministration of buspirone may attenuate apomorphine induced sensitization. Administration of apomorphine at a dose of 1.0, 2.0 & 4.0 mg/kg increased motor activity in an activity box in a dose dependent manner. Locomotor enhancing effects of a low dose of apomorphine were augmented upon repeated administration suggesting drug-induced sensitization. The sensitization effects were significant in an activity box as well as in an open field. Coadministration of buspirone at a dose of 1.0 mg/kg reversed apomorphine-induced sensitization. Repeated administration of buspirone at a dose of 2.0 mg/kg but not 1.0 mg/kg also elicited sensitization in motor behavior. It is suggested that buspirone may oppose the development of sensitization to apomorphine by decreasing the sensitivity of somatodendritic 5-HT_1A receptors. Findings may help in extending therapeutics in parkinson's disease.     

Anti-depressant action of caesium chloride and its modification of chlorpromazine toxicity in mice.

1. Adult male mice were treated with caesium chloride (1.0 mEq/kg, i.p.) once daily for 54 consecutive days before administration of a single dose or reserpine (2.0 mg/kg) or (+)-amphetamine (1.0 mg/kg). Pretreatment with caesium chloride resulted in potentiation of amphetamine-produced enhancement of motility and in antagonism of reserpine-induced behavioural depression in mice as measured by a locomotor activity test, compared to the respective controls. 2. Chronic administration of caesium chloride (1.0 mEq/kg daily) with gradual dose build-up of chlorpromazine (up to 50 mg kg-1 day-1) counteracted chlorpromazine-produced mortality in mice. 3. The results suggest an antidepressant property of Cs+ and the combined treatment of caesium chloride with chlorpromazine might have a clinical application, i.e. in the management of chlorpromazine-induced adverse reaction.     

Taurine and ethanol preference: a microdialysis study using Sardinian alcohol-preferring and non-preferring rats.

Recent intracerebral microdialysis studies of different rat brain regions have shown that an acute ethanol injection induced a rapid dose-dependent increase in taurine microdialysate content during the first 60-min period. In taurine-supplemented rats, a reduced aversion for high ethanol doses was observed in a place conditioning paradigm, suggesting that taurine may be implicated in the regulation of some adverse effects of ethanol. The present study compares the effects of acute ethanol injections (1.0 and 2.0 g/kg, i.p.) on taurine nucleus accumbens microdialysate content in Sardinian ethanol-preferring (sP) and Sardinian ethanol-non-preferring (sNP) rats. While neither saline nor 1.0 g/kg ethanol injections had significant effect on taurine microdialysate concentration, 2.0 g/kg ethanol administration induced a rapid and significant increase in taurine microdialysate content in both sP and sNP rats. However, this ethanol-induced taurine release was significantly reduced in sP rats by comparison to sNP rats. As taurine is suggested to be released by brain cells to modulate different ethanol adverse effects, this lower taurine responsiveness to ethanol in sP rats by comparison to both sNP and Wistar rats may be a relevant indicator of reduced ethanol aversive effects in such animals and therefore be related to their higher alcohol consumption.     

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.     

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.     

Influence of fluoxetine and paroxetine in behavioral sensitization induced by ethanol in mice

The serotonergic system is involved in depression, anxiety and alcoholism. The rewarding properties of ethanol, mainly its anxiolytic and stimulant effects, as well as the development of dependence on ethanol have been related to the serotonergic system. Consequently, the use of selective serotonergic reuptake inhibitors (SSRI) has been proposed in the treatment of alcoholism. In this study we investigated whether acute administration of the SSRIs fluoxetine or paroxetine is able to (i) reverse the behavioral effects induced by chronic ethanol consumption, and conversely, (ii) to determine whether acute ethanol is able to substitute for the chronically induced behavioral effects of fluoxetine or paroxetine. Four groups of male Swiss mice (n=60/group) received daily i.p. saline, ethanol (2 g/kg), fluoxetine (10 mg/kg) or paroxetine (5 mg/kg) for 27 days. On the 28th day, each group was challenged with saline, ethanol, fluoxetine or paroxetine. The 14 groups (SS, SE, SP, SF, EE, ES, EP, EF, PP, PE, PS, FF, FE, and FS) were then tested in open field, activity cage and plus-maze. EP and EF groups were able to reverse the behavioral sensitization to the psychomotor stimulant effects of chronic ethanol administration. In contrast, a sensitized stimulatory effect was observed in chronically fluoxetine- or paroxetine treated mice challenged with ethanol (PE and FE). An anxiolytic effect was observed whether ethanol was substituted for SSRI or, conversely, SSRI was substituted for ethanol. SSRIs facilitated ethanol-induced locomotor sensitization, although SSRIs by themselves are unable to produce the locomotor stimulation similar to that induced by ethanol. Finally, SSRIs are unable to interfere in the ethanol anxiolytic effect.