Depressant Effects Of Ethanol Research Articles

Ethanol's disruptive effects upon early breathing plasticity and blood parameters associated with hypoxia and hypercapnia

Early ethanol exposure affects respiratory neuroplasticity; a risk factor associated with the Sudden Infant Death Syndrome. High and chronic ethanol doses exert long-lasting effects upon respiratory rates, apneic episodes and ventilatory processes triggered by hypoxia. The present study was performed in 3–9-day-old rat pups. Respiratory processes under normoxic and hypoxic conditions were analyzed in pups intoxicated with different ethanol doses which were pre-exposed or not to the drug. A second major goal was to examine if acute and/or chronic early ethanol exposure affects blood parameters related with hypercapnic or hypoxic states. In Experiment 1, at postnatal day 9, animals previously treated with ethanol (2.0 g/kg) or vehicle (0.0 g/kg) were tested sober or intoxicated with 0.75, 1.37 or 2.00 g/kg ethanol. The test involved sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. Motor activity was also evaluated. In Experiment 2, blood parameters indicative of possible hypoxic and hypercapnic states were assessed as a function of early chronic or acute experiences with the drug. The main results of Experiment 1 were as follows: i) ethanol's depressant effects upon respiratory rates increased as a function of sequential treatment with the drug (sensitization); ii) ethanol inhibited apneic episodes even when employing the lowest dose at test (0.75 g/kg); iii) the hyperventilatory response caused by hypoxia negatively correlated with the ethanol dose administered at test; iv) ventilatory long-term facilitation (LTF) during recovery normoxia was observed in pups pre-exposed to the drug and in pups that received the different ethanol doses at test; v) self-grooming increased in pups treated with either 1.37 or 2.00 g/kg ethanol. The main result of Experiment 2 indicated that acute as well as chronic ethanol exposure results in acidosis-hypercapnia. The results indicate that early and brief experiences with ethanol are sufficient to affect different respiratory plasticity processes as well as blood biomarkers indicative of acidosis-hypercapnia. An association between the LTF process and the acidosis-hypercapnic state caused by ethanol seems to exist. The mentioned experiences with the drug are sufficient to result in an anomalous programming of respiratory patterns and metabolic conditions.

Neonatal sensitization to ethanol-induced breathing disruptions as a function of late prenatal exposure to the drug in the rat: Modulatory effects of ethanol's chemosensory cues

Preclinical and clinical studies have systematically demonstrated abrupt changes in fetal respiratory patterns when the unborn organism is exposed to the effects of maternal ethanol intoxication. In subprimates, chronic exposure to this drug during gestation and infancy results in marked alterations of the plasticity of the respiratory network. These alterations are manifested in terms of an early incapability to overcome deleterious effects of hypoxic events as well as in terms of sensitization to ethanol's depressant effects upon breathing patterns. It has also been demonstrated that near term rat fetuses process ethanol's chemosensory cues when the drug contaminates the amniotic fluid and that associative learning processes occur due to the temporal contiguity existing between these cues and different ethanol-related physiological effects. In the present study during the course of late gestation (gestational days 17–20), pregnant rats were intragastrically administered with either 0.0 or 2.0g/kg ethanol. Seven-day-old pups derived of these dams were evaluated in terms of respiration rates (breaths/min) and apneas when subjected to different experimental conditions. These conditions were defined by postnatal exposure to the drug (intragastric administrations of either 0.0, 0.5, 1.0 or 2.0g/kg ethanol), postadministration time of evaluation (5–10 or 30–35min) and olfactory context at test (no explicit ambient odor or ethanol ambient odor). The results, obtained via whole body plethysmography, indicated that brief prenatal experience with the drug sensitized the organisms to ethanol's depressant effects particularly when employing the higher ethanol doses. In turn, presence of ethanol odor at test potentiated the above mentioned respiratory alterations. Prenatal treatment with ethanol was not found to alter pharmacokinetic profiles resulting from postnatal exposure to the drug or to affect different morphometric parameters related with lung development. These results indicate that even brief exposure to the drug during late gestation is sufficient to sensitize the organism to later disruptive effects of the drug upon breathing responsiveness. These deficits are potentiated through the re-exposure to the olfactory context perceived in utero which is known to be associated with ethanol's unconditioned effects. As a function of these observations it is possible to suggest a critical role of fetal sensory and learning capabilities in terms of modulating later ethanol-related breathing disruptions.

NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol

The NR2B subunit of N-methyl d-aspartate glutamate receptors influences pharmacological properties and confers greater sensitivity to the modulatory effects of ethanol. This study examined behavioral responses to acute ethanol in a conditional knockout mouse model that allowed for a delayed genetic deletion of the NR2B subunit to avoid mouse lethality. Mice lacking the NR2B gene (knockout) were produced by mating NR2B[f/f] mice with CAMKIIa-driven tTA transgenic mice and the tetO-CRE transgenic mice. Adult male and female offspring representing each of the resultant genotypes (knockout, CAM, CRE and wildtype mice) were tested for open-field locomotor activity following acute low- and high-dose ethanol challenge as well as loss of righting reflex. Findings indicate that male and female mice lacking the NR2B subunit exhibited greater overall activity in comparison to other genotypes during the baseline locomotor activity test. NR2B knockout mice exhibited an exaggerated stimulant response to 1.5 g/kg (i.p.) and an exaggerated depressant response to 3.0 g/kg (i.p.) ethanol challenge. In addition, NR2B knockout mice slept longer following a high dose of ethanol (4.0 g/kg, i.p.). To evaluate pharmacokinetics, clearance rates of ethanol (1.5, 4.0 g/kg, i.p.) were measured and showed that female NR2B knockouts had a faster rate of metabolism only at the higher ethanol dose. Western blot analyses confirmed significant reduction in NR2B expression in the forebrain of knockout mice. Collectively, these data indicate that the NR2B subunit of the N-methyl d-aspartate glutamate receptor is involved in regulating low-dose stimulant effects of ethanol and the depressant/hypnotic effects of ethanol.

Modulation of the respiratory depressant effect of ethanol by 5-hydroxytryptamine

Modulation of the respiratory depressant effect of ethanol by 5-hydroxytryptamine

Ethanol inhibits voltage-gated sodium channels in cultured superior cervical ganglion neurons

To determine whether actions on sodium channels contribute to ethanol's depressant effects on the autonomic nervous system, the acute effects of ethanol on Na+ currents in primary cultured superior cervical ganglion were examined by whole-cell patch clamp recordings. Ethanol inhibited Na+ currents concentration dependently, and decreased action potential firing. Ethanol (100 mM) did not affect activation curve, but resulted in a left shift of the inactivation curve and prolonged the recovery from inactivation. This finding indicates that the channels in the inactivated state are more susceptible to ethanol than those in the resting state. For the first time, this study demonstrates acute inhibitory effects of ethanol on sodium channel gating in sympathetic neurons.

Relationship Between Ethanol’s Acute Locomotor Effects and Ethanol Self‐Administration in Male Long‐Evans Rats

Human studies have suggested an important relationship between ethanol sensitivity and risk of alcoholism. These studies have led some to hypothesize that a low initial sensitivity to ethanol's depressant effects and/or an elevated response to ethanol's stimulant effects may represent important risk factors associated with the development of abusive drinking behavior. Unfortunately, elucidating neurobiologic mechanisms that may underlie these relationships between ethanol sensitivity and ethanol drinking have been hampered by difficulties in modeling some of these interactions in animals. In this study, we re-examined some of these relationships in an outbred strain of rats using continuous access two-bottle choice drinking and a limited-access operant procedure that engenders pharmacologically relevant levels of ethanol intake and permits the discrete assessment of appetitive and consummatory measures of ethanol drinking behavior. Twenty-three male Long-Evans rats were habituated to a locomotor activity box and then tested for their response to a stimulant (0.5 g/kg) and depressant (1.5 g/kg) ethanol dose. Rats were then trained to complete a lever pressing requirement to gain access to 10% ethanol for 20-minute sessions conducted 5 d/wk for 5 weeks. Appetitive behavior was assessed after 2.5 and 4.5 weeks using 20-minute extinction trials in which ethanol was not presented and lever responses were recorded. Home-cage ethanol preference was also assessed prior to and immediately following the 5-week self-administration regimen using a continuous access, two-bottle choice procedure. A significant increase in home-cage ethanol preference was observed following the self-administration procedure, however, neither measure of ethanol preference correlated with average daily ethanol intake during the operant self-administration sessions or with initial sensitivity to ethanol's stimulant or depressant effects. Notably, a significant negative correlation was observed between sensitivity to ethanol's locomotor depressant effect and daily intake during the operant self-administration sessions. No significant relationships were noted between sensitivity to ethanol's locomotor effects and extinction responding. The results of these studies suggest that the well-established relationship between a low level of response to ethanol and increased ethanol consumption reported in human studies can be observed in an outbred rodent strain using a limited-access operant self-administration procedure, but not with home-cage ethanol drinking.

Desipramine potentiation of the acute depressant effects of ethanol: Modulation by α2-adrenoreceptors and stress

Ethanol exerts effects on the brain noradrenergic system, and these are thought to contribute to the sedative/hypnotic (depressant) effects of ethanol. Recent studies suggest that the norepinephrine transporter (NET) plays an important role in modulating ethanol's depressant effects. The aim of the present study was to further characterize this role. Transporter blockers with varying affinity for NET versus the serotonin transporter (desipramine > fluoxetine > citalopram) were tested for their ability to alter ethanol's depressant effects, and for comparison, hypothermic effects. Effects of desipramine on another depressant, pentobarbital, were examined. Desipramine potentiation of ethanol's depressant effects was assessed following depletion of brain norepinephrine via N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) treatment, or depletion of brain 5-HT via para-chlorophenylalanine methyl ester hydrochloride (PCPA) treatment. The effects of co-administration of either the selective α2-adrenoreceptor agonist (dexmedetomidine) or the selective α2-adrenoreceptor antagonist (atipamezole) on desipramine's effect on ethanol's depressant effects were examined. Given the close link between stress, ethanol and norepinephrine, desipramine potentiation of ethanol's depressant effects was tested following repeated forced swim stress. Results showed that desipramine, but not SERT-selective doses of citalopram or fluoxetine, strongly potentiated the depressant (not hypothermic) effects of ethanol. These effects were mimicked by dexmedetomidine and blocked by atipamezole, but not by depletion of either norepinephrine or 5-HT. Desipramine potentiation of ethanol's depressant effects was abolished following repeated stress. Present findings further support a major role for NET and the α2-adrenoreceptor in modulating the depressant effects of ethanol, with possible implications for understanding the role of noradrenergic dysfunction in stress-related alcoholism.

Decreased Ethanol Preference and Consumption in Dopamine Transporter Female Knock-Out Mice

Background: It is commonly believed that the mesolimbic dopamine (DA) system participates in the etiology of alcoholism. One of the most important regulators of DA synaptic transmission is the DA transporter (DAT). We examined the effects of the genetic reduction or deletion of DAT on voluntary ethanol consumption and ethanol-induced sedation. Methods: Ethanol preference and consumption were assessed in the two-bottle choice paradigm, and the depressant effects of ethanol were evaluated by measuring sleep time after acute injection of ethanol. Results: The latent period to lose the righting reflex was shorter in both knock-out mice (DAT-KO) and heterozygote mice (HET) than in wild-type (WT) mice. No significant difference was found among the three genotypes in the ethanol blood concentration at the onset of regaining the righting reflex. Females of all genotypes consumed more fluid than males of the same genotype. HET and DAT-KO females had increased total fluid consumption compared with WT females. DAT-KO males had increased fluid consumption compared with WT and HET males. Ethanol preference and consumption were not different among male mice of different genotypes. WT and HET females demonstrated significantly higher ethanol consumption than males. HET female mice did not differ from WT mice in ethanol preference. There was no difference between HET and WT mice in the preference for saccharin or quinine solutions. DAT-KO females avoided ethanol, and their consumption and preference were lower than in WT and HET females, despite markedly increased total intake. DAT-KO mice also demonstrated altered taste preference for saccharin and quinine. Conclusions: Partial deletion of DAT results in increased fluid consumption in female mice but does not change ethanol preference in either sex. Complete deletion of DAT reduces ethanol preference in female mice; this may be due to a combination of the pharmacological actions of DAT deletion and alterations in fluid consumption and taste discrimination.

Decreased Ethanol Preference and Consumption in Dopamine Transporter Female Knock‐Out Mice

It is commonly believed that the mesolimbic dopamine (DA) system participates in the etiology of alcoholism. One of the most important regulators of DA synaptic transmission is the DA transporter (DAT). We examined the effects of the genetic reduction or deletion of DAT on voluntary ethanol consumption and ethanol-induced sedation. Ethanol preference and consumption were assessed in the two-bottle choice paradigm, and the depressant effects of ethanol were evaluated by measuring sleep time after acute injection of ethanol. The latent period to lose the righting reflex was shorter in both knock-out mice (DAT-KO) and heterozygote mice (HET) than in wild-type (WT) mice. No significant difference was found among the three genotypes in the ethanol blood concentration at the onset of regaining the righting reflex. Females of all genotypes consumed more fluid than males of the same genotype. HET and DAT-KO females had increased total fluid consumption compared with WT females. DAT-KO males had increased fluid consumption compared with WT and HET males. Ethanol preference and consumption were not different among male mice of different genotypes. WT and HET females demonstrated significantly higher ethanol consumption than males. HET female mice did not differ from WT mice in ethanol preference. There was no difference between HET and WT mice in the preference for saccharin or quinine solutions. DAT-KO females avoided ethanol, and their consumption and preference were lower than in WT and HET females, despite markedly increased total intake. DAT-KO mice also demonstrated altered taste preference for saccharin and quinine. Partial deletion of DAT results in increased fluid consumption in female mice but does not change ethanol preference in either sex. Complete deletion of DAT reduces ethanol preference in female mice; this may be due to a combination of the pharmacological actions of DAT deletion and alterations in fluid consumption and taste discrimination.

Differential sensitivities of TTX-resistant and TTX-sensitive sodium channels to anesthetic concentrations of ethanol in rat sensory neurons.

Ethanol at concentration of 200 mM induces anesthesia in experimental animals and depresses neurotransmission in isolated spinal cords. To determine whether actions on primary afferent nerve terminals contribute to ethanol's depressant effects on spinal cord, a study was undertaken to test whether ethanol blocks sodium currents (I(Na)) in dorsal root ganglion neurons (DRGn). Whole-cell patch clamp was used to examine I(Na) in DRGn isolated from 1- to 15-day-old rats. At a holding potential of -80 mV ethanol (200 mM) decreased peak tetrodotoxin-resistant (TTX-R) and tetrodotoxin-sensitive (TTX-S) I(Na) by 19.0% +/- 2.7 (mean +/- SEM) and 8.5% +/- 2.2, respectively. Maximal available I(Na) was reduced to 82 +/- 4% (TTX-R) and 93 +/- 1% (TTX-S) of control. Steady-state inactivation curves were shifted in the hyperpolarizing direction by 2.1 +/- 0.2 mV (TTX-R) and 1.1 +/- 0.1 mV (TTX-S). At prepulse potentials of -30 mV (TTX-R) and -70 mV (TTX-S), these shifts contributed an additional 17 +/- 1% (TTX-R) and 7 +/- 1% (TTX-S) reduction in available I(Na). Ethanol thus selectively induced both voltage-independent and voltage-dependent block of TTX-R I(Na) in DRGn. Because DRGn TTX-R sodium channels are associated with small-diameter primary afferent fibers, these results are consistent with a role for ethanol actions on sodium channels in depression of nociceptive-related neurotransmission in spinal cord.

Evidence for the involvement of dopamine receptors in ethanol-induced hyperactivity in mice

Based on the hypothesis that drugs of abuse increase locomotor activity through mechanisms related to reinforcement, i.e. the mesolimbic dopamine (DA) system, ethanol-induced hyperactivity might provide a screening model to investigate the effect of ethanol on reward pathways. In the present study, ethanol had bidirectional effects on locomotion in mice: hyperactivity at low doses (2-3 g/kg) and sedation at high doses (4-5 g/kg). Such high doses induced a loss of righting reflex (LRR). The stimulant effect of ethanol was blocked by the D2/D3 antagonists, haloperidol (0.2 mg/kg) and tiapride (30-60 mg/kg), and by the D1 antagonist, SCH 23390 (0.03 mg/kg) whereas the non selective DA antagonist, clozapine decreased ethanol-induced hyperactivity at a dose (1 mg/kg) which also decreased activity in control animals. Unlike haloperidol and clozapine which potentiated LRR induced by ethanol, the selective DA antagonists, tiapride and SCH 23390, had no effect. Pretreatment with the D2/D3 agonist, quinpirole (0.1-0.3 mg/kg), reduced hyperactivity induced by ethanol presumably by stimulation of pre-synaptic receptors but did not change LRR. The D1 full agonist, SKF 81297 which produced hyperactivity by itself and the D1 partial agonist, SKF 38393, did not specifically affect ethanol-induced activities. The results indicate that activation of D1 and D2/D3 DA receptors is implicated in ethanol-induced hyperactivity whereas other mechanisms might mediate the sedative effects of ethanol. Tiapride and haloperidol, both used in the management of alcohol dependence, might exert beneficial effects by counteracting the reinforcing effects of ethanol. Tiapride's lack of interaction with the depressant effects of ethanol may account for its better tolerance in alcoholic patients.

14-86 - Evidence for the involvement of dopamine receptors in ethanol-induced hyperactivity in mice

Summary Based on the hypothesis that drugs of abuse increase locomotor activity through mechanisms related to reinforcement, i.e. the mesolimbic dopamine (DA) system, ethanol-induced hyperactivity might provide a screening model to investigate the effect of ethanol on reward pathways. In the present study, ethanol had bidirectional effects on locomotion in mice: hyperactivity at low doses (2–3 g/kg) and sedation at high doses (4–5 g/kg). Such high doses induced a loss of righting reflex (LRR). The stimulant effect of ethanol was blocked by the D 2 /D 3 antagonists, haloperidol (0.2 mg/kg) and tiapride (30–60 mg/kg), and by the D[ antagonist, SCH 23390 (0.03 mg/kg) whereas the non selective DA antagonist, clozapine decreased ethanolinduced hyperactivity at a dose (2 mg/kg) which also decreased activity in control animals. Unlike haloperidol and clozapine which potentiated LRR induced by ethanol, the selective DA antagonists, tiapride and SCH 23390, had no effect. Pretreatment with the D 2 /D 3 agonist, quinpirole (0.1–0.3 mg/kg), reduced hyperactivity induced by ethanol presumably by stimulation of pre-synaptic receptors but did not change LRR. The D 1 full agonist, SKF 81297 which produced hyperactivity by itself and the D 1 partial agonist, SKF 38393, did not specifically affect ethanol-induced activities. The results indicate that activation of D 1 and D 2 /D 3 DA receptors is implicated in ethanol-induced hyperactivity whereas other mechanisms might mediate the sedative effects of ethanol. Tiapride and haloperidol, both used in the management of alcohol dependence, might exert beneficial effects by counteracting the reinforcing effects of ethanol. Tiapride's lack of interaction with the depressant effects of ethanol may account for its better tolerance in alcoholic patients.

Methamphetamine facilitates ethanol-induced depressions in cerebellar purkinje neurons of prazocin- or DSP4-treated rats

Methamphetamine (MA) and ethanol (EtOH) are two commonly abused drugs. Previous behavioral studies indicated that MA may synergistically alter EtOH responses. In the present study, we found that local application of MA did not potentiate ethanol-induced depressions of the spontaneous activity of Purkinje neurons in urethane-anesthetized rats. We and others previously found that, in cerebellar Purkinje neurons, EtOH and gamma-amino-butyric acid (GABA)-mediated depressions can be enhanced by norepinephrine (NE) acting via beta-adrenergic receptors while these responses are decreased by activation of alpha-adrenergic receptors. In the present experiment, after blocking alpha-adrenergic receptors with prazocin, MA significantly enhanced EtOH responses in most of neurons studied. It has been reported that MA may directly and indirectly enhance alpha-adrenergic and beta-adrenergic receptor-mediated responses. The present study may suggest that MA can negatively modulate (antagonize) the depressant effects of ethanol via the alpha-adrenergic receptor, which oppose the positive modulatory mechanism (potentiation of EtOH depression) via actions of the beta-adrenergic receptors. We found that lesioning NE neurons with N-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a selective noradrenergic neurotoxin, enhance the MA-facilitated ethanol responses, suggesting that this action of MA may not require NE. Since it has been reported that MA increases serotonin (5-HT) and catecholamine release from their nerve terminals, MA may potentiate EtOH depressions by facilitating the release of NE and 5-HT. Taken together, our data suggested that MA may modulate EtOH responses via catecholaminergic and serotonergic mechanisms in cerebellar Purkinje neurons.

Operant rate depressant effects of ethanol in mice selectively bred for differential neurosensitivity to ethanol.

Few studies have investigated genetic differences in the effects of ethanol on operant schedule-controlled behaviors. The use of genetically defined populations in sensitive measures of complex behavior can help determine genetically covarying responses to ethanol as well as environmental contexts important for demonstrating genetic differences. The purpose of the present study was to investigate the rate depressant effects of ethanol on two lines of mice selectively bred for increased, LS/Ibg (LS), and decreased, SS/Ibg (SS), sensitivity to the acute narcotic effects of ethanol. Ethanol dose-dependently decreased high rates of behavior maintained by fixed ratio responding for water in both the LS and SS mice. Interestingly, the LS and SS mice did not differ in the rate depressant effects of ethanol under these conditions despite the sensitivity of this measure to the CNS effects of drugs and the very large differences between these lines in sensitivity to numerous other ethanol-related effects. While the SS mice were slightly less sensitive, and LS mice tended to show a low dose rate increasing effect, none of the differences were significant as ED50 values for rate depression differed by only 2.5 percent. The results of this experiment demonstrate that sensitivity to the effects of ethanol on fixed ratio responding for water is not genetically related to the acute narcotic effects of ethanol. In addition, the findings show that previously reported differences in operant ethanol self-administration between these two lines of mice are not due to differential sensitivity to the direct effects of ethanol on reinforced behavior.

Acute effects of ethanol and ethanol plus furosemide on pancreatic capillary blood flow in rats

The effects of intravenous ethanol and ethanol plus furosemide on pancreatic capillary blood flow (PCBF) were investigated using a laser-Doppler flowmeter. Forty Sprague-Dawley male rats were divided into 4 groups: (1) control, (2) 80% ethanol, (3) 80% ethanol plus furosemide, and (4) furosemide. Mean arterial blood pressure and heart rate were monitored. Levels of serum amylase, calcium, electrolytes, ethanol, and furosemide (groups 3 and 4) were measured, and samples of pancreatic tissue were obtained. The ethanol and furosemide levels were statistically different (p < 0.05). PCBF significantly decreased (p < 0.05) in group 2, increased (p < 0.05) in group 3, and did not differ (p > 0.05) between groups 1 and 4. Histopathologic analysis revealed swollen acini in group 2 and sparse focal necrosis without acinar swelling in group 3. The depressant effect of ethanol on PCBF may be the result of its direct action on pancreatic cells causing edema and capillary compression rather than on primary vascular control mechanisms that adjust blood flow. Furosemide counters this effect.

Gender differences in the effects of ethanol on C57BL/6 mice

The influence of gender on the stimulatory and depressant effects of ethanol was examined in C57BL/6 (C57) mice. In Experiment 1, locomotor activity was assessed in young (2-month-old) male and female mice injected intraperitoneally (IP) with stimulatory (1.5 g/kg) or depressant (2.5 g/kg) doses of ethanol. Both the stimulatory and the depressive effects of ethanol were greater in young male than female C57 mice, and the gender difference was unrelated to blood ethanol concentration (BEC). In Experiment 2, older (9-month-old) male and female mice were given ethanol (2.5 g/kg) either by IP injection or gavage to determine if the gender differences in BEC and ethanol effects observed in the first experiment depended upon the route of ethanol administration. In this experiment, ethanol reduced locomotor activity more in males than females whether given by gavage or IP injection, and the males had higher BECs than females at the time of testing. Thus, the differences in the behavioral effects of ethanol appeared to be related to BEC. The greater depressive effect of ethanol on older male mice in this experiment is consistent with an earlier report of prolonged ethanol-hypnosis in older male C57 mice. Therefore, differences in BEC could account for the gender differences in the behavioral effects of ethanol on older but not young mice. The gender difference in BEC of mice obtained in the present and earlier reports is opposite to that reported for humans. Although the present study does not clarify what accounts for this species difference, it eliminates the route of administration as a plausible explanation, and establishes that females were less affected than males to either the stimulatory or the depressive effects of ethanol.

Purinergic modulation of ethanol-induced sleep time in long-sleep and short-sleep mice

The long-sleep (LS) and short-sleep (SS) mice were selectively bred for differences in sensitivity to the depressant effects of ethanol. In addition to their differential sensitivity to ethanol, they are also differentially sensitive to purinergic agonists and antagonists. This suggests that there may be differences in the purinergic systems of these lines of mice which may aid in understanding how they differ in ethanol sensitivity. We have investigated whether these drugs are capable of modifying acute ethanol sensitivity as measured by ethanol-induced loss of the righting response (ethanol sleep time), waking blood and brain ethanol concentrations, and blood ethanol elimination rate. The purinergic agonists cyclohexyladenosine (CHA), L-phenylisopropyladenosine (PIA), 2-chloroadenosine (CAD), and N-ethylcarboxamidoadenosine (NEC) increased sleep time in both LS and SS mice, however, LS mice were generally more affected than SS. The LS and SS mice were also differentially sensitive to the purinergic antagonists, theophylline and caffeine. Blood and brain ethanol concentration on awakening suggested that CNS sensitivity to acute ethanol administration was altered by pretreatment with agonists but not antagonists. Two agonists, CHA and NEC, significantly lowered ethanol elimination in both lines of mice while PIA, CAD, and the antagonists theophylline, and caffeine were without affect on elimination rate. These data support previous observations that adenosine-mediated systems may be involved in the modulation of ethanol sensitivity.

Differential interactions of Ro 15-4513 with benzodiazepines, ethanol and pentobarbital

The effects of the imidazobenzodiazepine Ro 15-4513 in combination with three CNS depressants (ethanol, benzodiazepine agonists and pentobarbital) were examined in three different experiments. Full antagonism of classical benzodiazepines by Ro 15-4513 was seen in all three situations. Partial antagonism of ethanol occured in the pull up test of muscle relaxation in rats, but not in the inhibition of ultrasounds produced in rat pups by mild stress. The depressant effect of ethanol on twitching of the urethane-anaesthetised rat suprahyoid muscles was reversed. No attenuation of the effects of pentobarbital was seen in any test.

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/kg d-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.

Ethanol-induced analgesia

The effect of ethanol (ET) on nociceptive sensitivity was evaluated using a new tail deflection response (TDR) method. The IP injection of ET (0.5 – 1.5 g/kg) produced rapid dose-dependent analgesia. Near maximal effect (97% decrease in TDR) was produced with the 1.5 g/kg dose of ET ten minutes after injection. At ninety minutes post-injection there was still significant analgesia. Depression of ET-induced nociceptive sensitivity was partially reversed by a 1 mg/kg dose of naloxone. On the other hand, morphine (0.5 or 5.0 mg/kg IP) did not modify ET-induced analgesia, while 3.0 minutes of cold water swim (known to produce non-opioid mediated analgesia) potentiated ET-induced analgesic effect. The 0.5 g/kg dose of ET by itself did not depress motor activity in an open field test, but prevented partially the depression in motor activity produced by cold water swim (CWS). Thus the potentiation by ET of the depression of the TDR produced by CWS cannot be ascribed to the depressant effects of ET on motor activity.