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The effect of acute ethanol (EtOH) exposure on 5-HT3 receptor-mediated ion current was examined in whole-cell patch-clamp recordings from NCB-20 neuroblastoma cells. The physiologic and pharmacologic properties of 5-HT-activated ion current in NCB-20 cells indicated that it was mediated by 5-HT3 receptors. EtOH potentiated 5-HT3 receptor-mediated current in a concentration-dependent manner at concentrations (25-100 mM) which are achieved during EtOH intoxication in vivo.

Several evidences indicated the involvement of L- and N-type calcium channels in behavioral effects of drugs of abuse, including ethanol. Calcium channels are implicated in ethanol-induced behaviors and neurochemical responses. Calcium channel antagonists block the psychostimulants induced behavioral sensitization. Recently, it is demonstrated that L-, N- and T-type calcium channel blockers attenuate the acute locomotor stimulant effects of ethanol. However, no evidence indicated the role of calcium channels in ethanol-induced psychomotor sensitization. Therefore, present study evaluated the influence of cilnidipine, an L/N-type calcium channel blocker on acquisition and expression of ethanol-induced locomotor sensitization. The results revealed that cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) attenuates the expression of sensitization to locomotor stimulant effect of ethanol (2.0g/kg, i.p.), whereas pre- treatment of cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) during development of sensitization blocks acquisition and attenuates expression of sensitization to locomotor stimulant effect of ethanol. Cilnidipine per se did not influence locomotor activity in tested doses. Further, cilnidipine had no influence on effect of ethanol on rotarod performance. These results support the hypothesis that neuroadaptive changes in calcium channels participate in the acquisition and the expression of ethanol-induced locomotor sensitization.

Medical management for alcohol abuse has limitations. Alcohol consumption activates N-methyl-d-aspartate receptors and release of nitric oxide which can be inhibited by minocycline as it readily crosses blood brain barrier and may have effect on alcohol consumption. Thus, study objective is to evaluate the effect of minocycline on rewarding property, extinction and the reinstatement phenomenon induced by alcohol in a model of conditioned place preference (CPP) in mice.To evaluate rewarding effects of alcohol, CPP procedure consisted of 4 parts, including adaptation (day 1), pre-conditioning test (day 2), conditionings with alcohol (days 3, 5, 7 and 9) or saline (days 4, 6, 8 and 10) and postconditioning test (day 11) conducted on 11 consecutive days. The groups included were saline treated group (alcohol control), naltrexone - 1mg/kg (positive control), and minocycline in the doses of 10, 30 and 50mg/kg. To evaluate the effect of minocycline on alcohol relapse, CPP procedure consisted 6 parts, the first 4 were the same as enumerated above followed by extinction (days 12-16) and reinstatement phase (day 17).The time spent in alcohol paired compartment by different groups, revealed that minocycline and naltrexone significantly attenuated alcohol-induced place preference compared to alcohol control (p<0.05). Pretreatment with minocycline and naltrexone blocked reinstatement of extinguished CPP.Minocycline may have a role in attenuating the rewarding property of alcohol and prevent alcohol relapse.

Complex Regional Pain Syndrome (CRPS) is a musculoskeletal pain condition that often develops after limb injury and/or immobilization. Although the exact mechanisms underlying CRPS are unknown, the syndrome is associated with central and autonomic nervous system dysregulation and peripheral hyperalgesia symptoms. These symptoms also manifest in alcoholic neuropathy, suggesting that the two conditions may be pathophysiologically accretive. Interestingly, people assigned female at birth (AFAB) appear to be more sensitive to both CRPS and alcoholic neuropathy. To better understand the biobehavioral mechanisms underlying these conditions, we investigated a model of combined CRPS and alcoholic neuropathy in female rats. Animals were pair-fed either a Lieber-DeCarli alcohol liquid diet or a control diet for ten weeks. CRPS was modeled via unilateral hind limb cast immobilization for seven days, allowing for the other limb to serve as a within-subject control for hyperalgesia measures. To investigate the role of circulating ovarian hormones on pain-related behaviors, half of the animals underwent ovariectomy (OVX). Using the von Frey procedure to record mechanical paw withdrawal thresholds, we found that cast immobilization and chronic alcohol drinking separately and additively produced mechanical hyperalgesia observed 3 days after cast removal. We then examined neuroadaptations in AMPA GluR1 and NMDA NR1 glutamate channel subunits, extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) in bilateral motor and cingulate cortex across all groups. Consistent with increased pain-related behavior, chronic alcohol drinking increased GluR1, NR1, ERK, and CREB phosphorylation in the cingulate cortex. OVX did not alter any of the observed effects. Our results suggest accretive relationships between CRPS and alcoholic neuropathy symptoms and point to novel therapeutic targets for these conditions.

Cortical spreading depression is a neural phenomenon present in several animal species. Spreading depression features, like velocity of propagation, depends on several chemical and metabolic factors, as for example, anti-oxidants. Here we studied spreading depression-velocity changes in weaned rat-pups born from dams treated on a daily basis, either during gestation or lactation, with a carotenoid ethanolic extract (30 microg/kg/day) prepared from shrimp waste (heads). These pups were compared with age-mated ones, whose mothers were treated either with the vehicle (ethanol) or with distilled water. Compared to the distilled water-group (mean values, in mm/min, per hour of recording ranging from 3.02+/-0.26 to 3.15+/-0.27 [treatment during gestation; n=7], and from 3.03+/-0.25 to 3.22+/-0.30 [lactation; n=11]), ethanol-treated rats displayed higher spreading depression-velocities (from 3.74+/-0.06 to 3.82+/-0.08 [gestation; n=7], and from 4.26+/-0.32 to 4.33+/-0.34 [lactation; n=11]; p<0.05). Compared to the ethanol-group, carotenoid-treatment lead to lower spreading depression-velocities (p<0.05), ranging from 3.38+/-0.09 to 3.42+/-0.12, n=7 (gestation) and 3.58+/-0.13 to 3.62+/-0.17, n=12 (lactation). Carotenoid-treatment during lactation was shown to be significantly more effective than that during gestation (p<0.05), in lowering spreading depression-velocity. The results suggest a protective action of shrimp carotenoids against the ethanol effects on spreading depression. This protective effect could be related to the carotenoid antioxidant properties, as previously indicated by evidence showing spreading depression-effects of other antioxidants.

Ethanol is a widely consumed substance throughout the world. During development it can substantially damage the human fetus, whereas the developing brain is particularly vulnerable. The brain damage induced by prenatal alcohol exposure may lead to a variety of long-lasting behavioral and neurochemical problems. However, there are no data concerning the effects of developmental ethanol exposure on the glutamatergic system, where extracellular glutamate acts as signaling molecule. Here we investigated the effect of ethanol exposure for 2h (concentrations of 0.0%, 0.1%, 0.25%, 0.50%, and 1.00%) in embryos at 24h post-fertilization (hpf) by measuring the functionality of glutamate transporters in the brain of adult (4 months) zebrafish. However, ethanol 0.1%, 0.25% and 0.50% decreased transport of glutamate to 81.96%, 60.65% and 45.91% respectively, when compared with the control group. Interestingly, 1.00% was able to inhibit the transport activity to 68.85%. In response to the embryonic alcohol exposure, we found impairment in the function of cerebral glutamate transport in adult fish, contributing to long-term alteration in the homeostasis glutamatergic signaling.

Acute alcohol challenge suppresses the mismatch negativity (MMN) component of the auditory event-related potential (ERP), however, the transmitter systems underlying MMN generation/mediating this effect have remained vague. To test adenosinergic contribution, 12 healthy social drinkers participated in four sessions, ingesting: (1) placebo pill and placebo beverage; (2) caffeine (100 mg) and placebo beverage; (3) placebo pill and alcohol (0.55 g/kg in 10% (v/v) solution); or (4) both caffeine and alcohol. ERP measured during a dichotic-listening task disclosed increased MMN and P3b peak latencies, and diminished amplitude of processing negativity (PN) with alcohol, however, only the increase in MMN peak latency was significantly antagonized by caffeine. The results suggest that A1 and A2a receptors play a role in the generation of, and mediate partly the suppressant effect of ethanol on, the MMN.

The neurobiological mechanisms underlying how general anesthetics render a patient's unconsciousness (hypnosis) remains elusive. The role of the cerebellum in hypnosis induced by general anesthetics is unknown. Gabra6100Q allele Sprague-Dawley (SD) rats have a naturally occurring single nucleotide polymorphism in the GABAA receptor α6 subunit gene that is expressed exclusively in cerebellum granule cells.We examined the loss of righting reflex (LORR) induced by isoflurane, and ethanol in Gabra6100Q rats compared with those in wild type (WT) SD rats. We also examined the change of c-Fos expression induced by isoflurane exposure in cerebellum granule cells of both mutant and WT rats.Gabra6100Q rats are more sensitive than WT rats to the LORR induced by isoflurane and ethanol. Moreover, isoflurane exposure induced a greater reduction in c-Fos expression in cerebellum granule cells of Gabra6100Q rats than WT rats.Based on these data, we speculate that cerebellum may be involved in the hypnosis induced by some general anesthetics and thus may represent a novel target of general anesthetics.

The in vivo sensitivity of presynaptic 5-HT(1A) receptors (autoreceptors and heteroreceptors) modulating the synthesis of 5-hydroxytryptophan/serotonin (5-HTP/5-HT) and 3,4-dihydroxyphenylalanine/dopamine (DOPA/DA) in rat brain was investigated after ethanol treatment and withdrawal. In saline-treated rats as well as in acute ethanol (2 g/kg, intraperitoneally (i.p.), 2 h)- and chronic ethanol (2 g/kg for 7 days)-treated rats, a low dose of the 5-HT(1A) receptor agonist 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT; 0.1 mg/kg, i.p., 1 h) did not decrease the synthesis of 5-HTP in brain (except modestly in striatum; 20% after the chronic treatment) or that of DOPA in striatum. In contrast, in chronic ethanol-withdrawn rats (24 h), 8-OH-DPAT significantly decreased the synthesis of 5-HTP in the hippocampus (29%), cerebral cortex (41%) and striatum (33%) and that of DOPA in the striatum (28%). Similar effects were induced by the mixed 5-HT(1A) agonist/D(2) antagonist buspirone (1 mg/kg, i.p., 1 h) which also decreased 5-HTP synthesis in the hippocampus (24%), cerebral cortex (36%) and striatum (35%) of chronic ethanol-withdrawn rats. These results indicate that chronic ethanol and more clearly the spontaneous withdrawal from chronic ethanol induce supersensitivity of 5-HT(1A)-auto/heteroreceptors modulating the synthesis of 5-HT and DA in rat brain.