Penile constitutive nitric oxide synthase expression in rats exposed to unpredictable chronic mild stress: role of inflammation.

Chronic psychological stress cause erectile dysfunction (ED). Considering recent evidence that tumor necrosis factor-α (TNF-α) levels are increased in serum of patients with ED, the present study investigated the effects of infliximab (a TNF-α blocker) on endothelial nitric oxide synthase (eNOS) and neuronal NOS (nNOS) immunoreactivity of rat penile corpus cavernosum in unpredictable chronic mild stress (UCMS). Male adult rats were randomly divided into three groups (n=8 per group): Control, UCMS and UCMS+infliximab. Control and UCMS groups received physiological saline, UCMS+infliximab group received infliximab (5 mg kg-1 per week, intraperitoneally) during 8 weeks of UCMS. UCMS and UCMS+infliximab groups were subjected to different types of stressors, which were randomly applied four to five times during this time period. After 8 weeks, penile eNOS and nNOS expressions were determined immunohistochemically. In UCMS group, nNOS and eNOS immunoreactivity was found to be decreased in penile corpus cavernosum compared with the control group. Whereas in infliximab treatment group eNOS and nNOS immunoreactivity increased compared with the UCMS group. These findings support that UCMS decreases penile constitutive NOS expression via TNF-α, which may contribute to the development of ED. Blockage of TNF-α actions may represent an alternative therapeutic approach for ED in chronic psychological stress.

Effects of chronic low- and high-dose ethanol intake on the nitrergic relaxations of corpus cavernosum and penile nitric oxide synthase in the rabbit.

Epidemiological evidence showed that chronic ethanol consumption is a major risk factor in the development of impotence. The present study investigated the effects of carbachol-, electrical field stimulation (EFS)-, sodium nitroprusside (SNP)- and papaverine-induced relaxant responses in the isolated corpus cavernosum tissues from rabbits submitted to an 12-week course of chronic low (5% v/v) or high ethanol intake (30% v/v). Increased carbachol- and EFS-induced relaxant responses but not SNP and papaverine, were observed in low ethanol-fed rabbits compared with controls. However, impaired carbachol- and EFS-induced relaxant responses were observed in high ethanol-fed rabbits compared with control rabbits. There were no significant differences in SNP- and papaverine-induced relaxant responses between control and high ethanol-fed rabbits. In addition, decreased neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS) immunoreactivity in penile tissue were found in high ethanol-fed rabbits, but increased the immunoreactivity in low ethanol-fed group, compared with control group. These results suggest that alterations in nitric oxide (NO) production within the cavernous tissue in the high ethanol-fed rabbits are, at least in part, responsible for the erectile dysfunction.

Effects of long-term treatment with fluoxetine and venlafaxine on rat isolated vas deferens.

Antidepressant therapy is considered as one of the factors leading to male infertility. In this study, the effects of long-term treatment with fluoxetine or venlafaxine were investigated on electrical field stimulation (EFS, 1-64 Hz), noradrenaline (10(-8) to 10(-4) M), serotonin (10(-8) to 10(-4) M), adenosine 5'-triphosphate [ATP (10(-8) to 10(-4) M)] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of rat isolated vas deferens strips. Serotonin-induced contractile responses were significantly increased in the epididymal portion of the vas deferens obtained from the fluoxetine-treatment group, whereas in the prostatic portion there was no change. However, venlafaxine treatment had no effect on serotonin responses in the either portion of the vas deferens. Both fluoxetine and venlafaxine treatment significantly inhibited ATP-evoked contractions of the prostatic and epididymal portions of the rat vas deferens, but had no effect on EFS, noradrenaline- and KCl-evoked contractions of the vas deferentia in both portions. In conclusion, these results suggest that chronic treatment with fluoxetine and venlafaxine affects vas deferens motility. Purinoceptors may, at least in part, responsible for the impaired motility in chronic treatment of venlafaxine and fluoxetine.

Changes in the neurogenic and endothelium-dependent relaxant responses of rabbit corpus cavernosum smooth muscle after cavernous nerve neurotomy.

The present study was conducted to investigate the reactivity of the corpus cavernosum smooth muscle after unilateral cavernous nerve neurotomy in rabbits. Rabbits (18) were randomly divided into two groups: sham-operated (n = 9) and those subjected to unilateral neurotomy of a 5-mm segment of the cavernous nerve (n = 9). The reactivity of the corpus cavernosum tissue from the neurotomized and sham groups was studied in organ chambers at 4 weeks postoperation. In the neurotomized group, endothelium-dependent relaxation of the corpus cavernosum smooth muscle to carbachol was significantly increased when compared to the sham group. In addition, the sensitivity (i.e., pD(2)) of neurotomized strips to carbachol was also increased when compared to controls. Electrical field stimulation-induced neurogenic relaxation was significantly reduced in the neurotomized group. Relaxation to the nitric oxide (NO) donor sodium nitroprusside and to papaverine was similar in the cavernosal tissue of both groups. There was no change in agonist potency. Furthermore, neurotomy had no effect on KCl-induced contractile responses. When tissue contraction was induced with phenylephrine to study relaxation to various stimuli, the tension induced was similar in the neurotomized and the sham control groups. We conclude that unilateral, chronic cavernous nerve neurotomy causes significant functional changes to the penile erectile tissue of rabbits, which may contribute to the development of impotence.

Investigation of enhancement effects of nicotine on cholinergic neurotransmission in isolated rabbit gastric fundus: role of antioxidants.

Nicotine, which is tobacco alkaloid, still induces interests for researchers because of smokers addiction to nicotine. Nicotine having influence on the neuronal acetylcholine receptors (nAChRs) increases release of most certain neurotransmitters from the nerve endings. Also, nicotine, affecting the mitochondrial respiratory chains, contributes to the formation of reactive oxygen species. In the present study, we investigated the effects of nicotine on smooth muscles of gastric fundus on the electrical field stimulation (EFS) that induces transition contraction via stimulation nAChRs. In addition, we aimed to investigate the interaction between release of acetylcholine, induced by nicotine, and the effects of reactive oxygen species. Therefore, the effects of allopurinol (10(-6)-10(-5) M), deferoxamine (10(-4) M) and mannitol (10(-4)-5 x 10(-3) M) were tested on the transient contraction induced by nicotine. In conclusion, mannitol (5 x 10(-3) M) significantly reduced contractile response to nicotine on EFS only in high concentration. Whereas in small concentrations mannitol (10(-4) M) statistically did not cause any results. Deferoxamine and allopurinol also did not have any significant response.

Effects of diabetes and elevated glucose on nitrergic relaxations in the isolated duodenum of the rat.

Nitrergic relaxations of the isolated duodenum, induced by streptozotocin, were investigated in the experimental 8-week diabetes rat model. The effects of elevated glucose were also examined in the incubated duodenal muscles (in Krebs-Henseleit solution containing 44 mM glucose for 6 h) taken from nondiabetic rats. The relaxations induced by electrical field stimulation (EFS) and nicotine were significantly reduced in diabetic rats compared with control rats. Incubating of duodenal tissues in medium containing elevated glucose revealed significantly impaired relaxations to EFS and nicotine compared to responses obtained after normal glucose incubation. However, the relaxant responses to sodium nitroprusside and papaverine were similar in all groups. Incubating in hyperosmolar solutions containing sucrose, the relaxant responses were not affected. In conclusion, impairment of NO-mediated relaxations in diabetes may be related to hyperglycemia. The alterations caused by elevated glucose are not due to a hyperosmotic effect because the same concentration of sucrose had no effect on the relaxations.

Secondhand tobacco smoke impairs neurogenic and endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle: improvement with chronic oral administration of L-arginine.

The first goal of this study was to examine the effect of secondhand smoking on neurogenic, endothelium- and cGMP-dependent relaxant responses of rabbit corpus cavernosum smooth muscle. Our second goal was to determine whether such an effect can be prevented by oral administration of L-arginine. Male New Zealand rabbits were divided into control, chronic passive cigarette smoking and L-arginine treatment groups. Relaxant or contractile responses in isolated corpus cavernosum smooth muscle strips were determined by using in vitro muscle technique. There was no significant difference in the relaxant response of the strips to papaverine, sodium nitroprusside and contractile response to KCl among the groups. Relaxant responses to acetylcholine and electrical field stimulation and contractile response to phenylephrine were significantly decreased in the strips of the smoking group than that of the control group. The impaired relaxations of strips were markedly improved by treatment of L-arginine, but the contractile responses to phenylephrine were not affected. These data indicate that secondhand smoking may impair both neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle, and may contribute to the etiology of impotence. Chronic dietary supplementation with L-arginine offsets the impairment of neurogenic and endothelial relaxation. Therefore, we suggest that secondhand smoking exposure to cigarette produces selective impairment of neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle via a mechanism related to the decreased production and/or availability of nitric oxide.

Impaired esophageal reactivity in adriamycin-induced rat esophageal atresia: an in vitro study.

PURPOSE: The aim of this study was to investigate the reactivity of lower esophageal smooth muscle in the Adriamycin-induced esophageal atresia (EA) rat model. METHODS: The fetuses were divided into 3 groups. The control group was exposed to saline. The second group comprised fetuses that were exposed to Adriamycin but in whom EA did not develop. The third group comprised of fetuses that were exposed to Adriamycin and EA was observed. The reactivity of distal esophageal strips was studied in organ chambers. RESULTS: The tension was similar in all groups precontracted with carbachol for the study of relaxation to serotonin. Relaxation of lower esophageal strips to serotonin was comparably unaffected in the control and Adriamycin-no EA groups, whereas it was significantly inhibited in the EA group with decreased E(max) and pD(2) values. Contractile responses of esophageal smooth muscle to carbachol or 80 mmol/L KCl and relaxant responses to papaverine were similar in all groups. No change in agonist potency was observed among the groups. CONCLUSIONS: Our study showed impairment of serotonin-receptor-mediated relaxation; but not of cholinoceptor-mediated contraction of the lower esophageal smooth muscle in the EA. Thus, impaired relaxant responses may be, at least in part, a contributing factor in the esophageal dismotility seen in EA.

Chronic ethanol consumption impairs adrenoceptor- and purinoceptor-mediated relaxations of isolated rat detrusor smooth muscle.

OBJECTIVE: To investigate the effects of chronic ethanol consumption on the reactivity of detrusor smooth muscle. MATERIALS AND METHODS: Eight male rats received ethanol (7.2% v/v) in a modified liquid diet for 4 weeks. Two control groups were assessed; eight rats in one group were fed sucrose and received a liquid diet, and 12 rats in the second group received standard rat chow and water for 4 weeks. The reactivity of detrusor smooth muscle strips from ethanol-fed animals and control animals was evaluated in organ chambers. RESULTS: The relaxation response elicited by isoprenaline or adenosine was unaffected in the both control groups while it was significantly inhibited, with decreased maximum responses and pD2 values, in the ethanol-fed group. Contractile responses of detrusor smooth muscle to carbachol or 80 mmol/L KCl and relaxant responses to papaverine were similar in the control groups and the ethanol-fed group. There was no change in agonist potency among the groups. CONCLUSION: Chronic ethanol consumption impairs beta-adrenoceptor- and purinoceptor-mediated relaxation but not cholinoceptor-mediated contraction of the rat detrusor smooth muscle. Thus, it appears that different regulatory mechanisms are involved in ethanol-induced alterations in beta-adrenergic, purinergic and muscarinic receptors in detrusor strip.

Blood pressure and vascular reactivity to endothelin-1, phenylephrine, serotonin, KCl and acetylcholine following chronic alcohol consumption in vitro.

Ethanol has been reported to cause hypertension, the mechanism of which is unknown. Therefore, the effect of chronic ethanol consumption on vascular responsiveness and blood pressure was investigated. Systolic blood pressure was recorded weekly by tail-cuff method. Aortic rings from rats fed chow ad libitum or pair-fed liquid diets containing either ethanol (7.2% v/v) or isocaloric carbohydrate for 4 weeks were placed in organ chambers for isometric tension measurement. There was a mild but significant elevation of the systolic blood pressure in the alcohol-fed rats by week 1 compared to baseline measurements and this remained higher. No significant changes in reactivity of rat isolated aortas to phenylephrine, serotonin, endothelin-1 (ET-1) and KCl were seen in chronic ethanol consumption. In addition, the sensitivity (i.e. pD2) of alcohol-fed aortic rings to the vasoconstrictors was also unchanged compared to controls. Chronic ethanol consumption, however, increased relaxation to acetylcholine with increased pD2 values, but did not alter relaxation to sodium nitroprusside, a cyclic guanosine monophosphate (cGMP)-dependent direct smooth muscle dilator. The results indicate that chronic ethanol consumption significantly potentiates endothelium-dependent relaxations in aortic rings, probably through interference with the production and/or the release of nitric oxide (NO) or adaptive alterations in muscarinic receptors on the endothelial cells, and that increased vascular responsiveness to several vasoconstrictors is not a mechanism responsible for the blood pressure elevation in the chronic alcohol consumption in rats.

Effects of the specific phosphodiesterase inhibitors on alloxan-induced diabetic rabbit cavernous tissue in vitro.

An experimental study was done to examine a potential role of phosphodiesterase (PDE) inhibitors in the treatment of diabetic erectile dysfunction. Relaxant effect of specific PDE inhibitors were measured in strips of corpus cavernosum smooth muscle taken from control and diabetic groups. Diabetes mellitus was induced in New Zealand white rabbits using alloxan. Penises excised from diabetic rabbits 8 weeks after the induction of diabetes mellitus. In the organ bath strips from control and diabetic rabbit corpus cavernosum were precontracted and increasing doses of several PDE inhibitors were added. In the precontracted rabbit cavernous tissue, sulmazole and zaprinast specific PDE V inhibitors were equally potent and efficacious in vitro but amrinone, a specific PDE III inhibitor, exhibits low relaxant effects. All PDE inhibitors tested showed a similar relaxation effect on corpus cavernosum smooth muscle from control and 8-week diabetic rabbits. The present study provides the possibility of using selective PDE III and V inhibitors in the treatment of diabetic impotence.

Antidepressant, anxiogenic, and antinociceptive properties of levofloxacin in rats and mice.

Levofloxacin, an optically active isomer of ofloxacin, is a fluorinated quinolone with a broad spectrum of antibacterial activity. Fluoroquinolones have been used for the treatment of bacterial infections for many years. Although they were considered as relatively safe drugs, various adverse effects have recently been reported along with increase in the usage of new-generation fluoroquinolones. In the present study, some of the central nervous system (CNS)-related side effects of levofloxacin were clarified in animals. Our results suggested that: levofloxacin (10-20-40 mg/kg i.p.) had no depression-like effect in the forced swimming test (FST) in rats; exerted anxiety-like effect in the elevated plus maze test in rats; did not alter the locomotor activity in rats; had no apparent effect on sleep latency but shortened the sleeping time on pentobarbital sleeping time in mice; and showed analgesic activity in acetic acid writhing and hot plate test in mice.

Impaired neurogenic and endothelium-dependent relaxant responses of corpus cavernosum smooth muscle from hyperthyroid rabbits.

We investigated the effect of hyperthyroidism on the responsiveness of the rabbit corpus cavernosum smooth muscle. In male albino rabbits, hyperthyroidism was established by oral feeding of L-thyroxine at increasing dosages (150-450 microg/kg) over an 8-week period. This treatment produced a stable hyperthyroid state as indicated by the increased serum T4 levels. The reactivity of corpus cavernosum tissue from hyperthyroid animals and euthyroid control animals was studied in organ chambers. Hyperthyroidism caused impaired neurogenic and endothelium-dependent relaxant responses with decreased Emax and pD2 values. However, hyperthyroidism had no effect on both phenylephrine- and KCl-induced contractile responses and sodium nitroprusside- and papaverine-induced endothelium-independent relaxant responses, and there was no change in agonist potency. These data indicate that hyperthyroidism may impair both neurogenic and endothelium-dependent relaxation of corporal smooth muscle, and may contribute to the etiology of impotence.

Effects of experimental obstructive jaundice on contractile responses of dog isolated blood vessels: role of endothelium and duration of bile duct ligation.

1. We examined the effects of experimental obstructive jaundice caused by bile duct ligation (BDL) on vascular smooth muscle function, as well as the underlying mechanisms involved, by recording responses to noradrenaline (NA), 5-hydroxytryptamine (5-HT) and acetylcholine (ACh) in canine isolated renal arteries and to NA in isolated mesenteric arteries in vitro. All studies were performed 7 days after the onset of BDL in renal arteries and 3, 7 and 15 days after the onset of BDL in mesenteric arteries. 2. The maximum contraction evoked by both NA and 5-HT was significantly attenuated with no change in agonist potency (pD2 value) in renal arteries with endothelium obtained from 7 day BDL dogs when compared with those from sham-operated controls (SO). However, the reduction almost disappeared when the endothelium was removed. In contrast, no change in the responsiveness of renal arteries to KCl could be detected at 7 day BDL. Endothelium-dependent relaxations produced by ACh were significantly increased in renal artery rings from 7 day BDL dogs, but the endothelium-independent relaxations produced by papaverine in BDL preparations were not changed when compared with SO controls. 3. At 7 and 15 days after BDL, the Emax values of the mesenteric ring of BDL dogs to NA were significantly lower than that of SO controls, whereas 3 days after surgery there was no significant difference. The pD2 values in arteries obtained from 15 day BDL animals were significantly lower than those obtained from SO control animals. However, no significant changes in pD2 values were seen 3 and 7 days after the onset of BDL. 4. In conclusion, it is suggested that enhanced production and/or release of nitric oxide, mainly of endothelial origin, is associated with reduced vascular responses to contractile agents in experimental obstructive jaundice and that this effect is related to the duration of obstructive jaundice. These results may explain, at least in part, a cause of hypotension that leads to renal failure in patients with obstructive jaundice.

Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats.

RATIONALE: There is some strong evidence about the role of nitric oxide (NO) as an intercellular messenger in central physiological mechanisms. NO is synthesized from L-arginine by nitric oxide synthase (NOS), as a response to activation of N-methyl-D-aspartate (NMDA) receptors by excitatory amino acids. NMDA receptor antagonists also produce antidepressant-like actions in preclinical models. OBJECTIVE: In the present study, the involvement of NO in the mechanism of depression was investigated. 7-Nitroindazole (7-NI) (15, 30, 60, 90 mg/kg IP), a selective inhibitor of neuronal NOS was examined. METHODS: The Porsolt forced swimming test (FST) has been used as a test for screening new antidepressant agents. RESULTS: 7-NI dose-dependently decreased the immobility time in FST, but produced no significant change in locomotor activity in naive rats. Neither L-arginine, nor D-arginine (100 mg/kg) affected the immobility time in the FST or revealed any effect on locomotion. L-Arginine but not D-arginine, given 10 min before 7-NI, reversed the 7-NI-induced effect on immobility time. CONCLUSIONS: Our findings suggest that NO might be an important modulator of depression in rats.

Investigation on the mechanism involved in the effects of agmatine on ethanol-induced gastric mucosal injury in rats.

Effects of agmatine, an endogenous metabolite formed by decarboxylation of L-arginine, on ethanol-induced gastric mucosal injury were investigated in rats. Agmatine at 1 and 10 mg/kg i.p doses significantly increased ethanol-induced gastric mucosal injury. This effect of agmatine was abolished completely by pretreatment with idazoxan, an imidazoline receptor-antagonist and alpha2 receptor- antagonist, (0.5 mg/kg i.p), partly by yohimbine, an alpha2 receptor- antagonist, (1 mg/kg i.p) but not by L-arginine, a precursor of nitric oxide, (500 mg/kg i.p). Our results suggest that agmatine had a potent ulcerogenic effect mediated, at least in part, by both alpha2-adrenoceptors and imidazoline receptors.

Effects of exogenous testosterone on isolated rabbit corpus cavernosum penis.

AIM: To study the effects of exogenous excess of testosterone on the constricting effect of phenylephrine and endothelium-dependent and -independent relaxing effects of different agonists in the corpus cavernosum penis (CCP). METHODS: Specimens of the CCP were obtained from rabbits testosterone for 1 and 2 months and untreated for 2 months after testosterone-treatment for 2 months. Preparations were mounted between two parallel platinum electrodes in organ baths. Responses to phenylephrine, carbachol, and sodium nitroprusside were obtained by adding the reagent cumulatively to the bath. RESULTS: The phenylephrine-induced contractions were decreased with no change in agonist potency (pD2 value) after both 1 and 2 month testosterone-treatment and did not return to control values in corpus cavernosum obtained from rabbits untreated for 2 months after testosterone-treatment for 2 months. Testosterone treatment for 1 or 2 months increased the endothelium-dependent relaxations induced by carbachol and decreased the relaxations elicited by electric stimulation but did not affect the relaxations induced by sodium nitroprusside. These relaxant responses to carbachol and electric stimulation did not return to control values in corpus cavernosum obtained from rabbits untreated for 2 months after testosterone-treatment for 2 months. There were no significant changes in the pD2 values calculated by agonist-induced relaxation responses in all testosterone-treatment groups compared with control group. CONCLUSION: The exogenous excess of testosterone plays an important role in erectile function by a direct action on the relaxant and contractile responses of CCP.

Evidence of relaxant effect of omeprazole in rabbit corpus cavernosum in vitro.

The present experiments were designed to investigate the effects of omeprazole, a H(+)-K+ ATPase inhibitor, on corporal smooth muscle tone in vitro. All spontaneous contractile activity in the corpus cavernosum was blocked following omeprazole (0.1 mM-1 mM) administration. However atropine (1 microM), Nw-nitro L-arginine methyl ester (L-NAME, 30 microM) or indomethacin (10 microM) did not affect the spontaneous contraction. Omeprazole (10 microM-1 mM) concentration-dependently induced relaxation in corporal smooth muscle precontracted with 10 microM phenylephrine or 80 mM KCl. Pretreatment of corporal tissue with L-NAME (30 microM), indomethacin (10 microM), ammonium chloride (7.5 mM), sodium acetate (7.5 mM), tetraethyl ammonium chloride (0.5 mM) or glibenclamide (1 microM) had no effect on the omeprazole induced relaxant responses. Nimodipine, an L-type Ca++ channel blocker, relaxed corporal strips precontracted with 80 mM KCl. Collectively, these results indicate that the inhibition of spontaneous contraction and the relaxation of precontracted corporal smooth muscle by omeprazole is probably mediated by the blockade of calcium channels. Further work is needed to determine the cellular mechanism(s) of action by which omeprazole acts on corpus cavernosum smooth muscle.

Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses.

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.

Dextromethorphan attenuates ethanol withdrawal syndrome in rats.

The effects of dextromethorphan (DM), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, have been investigated on ethanol withdrawal signs in rats. Ethanol (7.2% v/v) was given to rats in a liquid diet for 16 days. DM (10, 20, and 40 mg/kg) and saline were injected intraperitoneally at the third hour of ethanol withdrawal. DM (40 mg/kg) and ethanol dependent saline were also administered to ethanol naive rats. DM (40 mg/kg) did not produce any significant change in locomotor activity in ethanol naive rats. The effects of DM on locomotor activity and total ethanol withdrawal score were evaluated at the fourth and sixth hours of ethanol withdrawal. DM inhibited locomotor hyperactivity at these periods. DM also reduced total ethanol withdrawal score from the fourth hour to the sixth hour, and it significantly decreased audiogenic seizures. Seizure susceptibility after chronic ethanol exposure may be dependent upon sensitization or upregulation of NMDA processes and NMDA receptors. Our results suggest that inhibition of NMDA receptors by DM alleviates signs of ethanol withdrawal.