Alterations in dopamine metabolism by intraperitoneal ethanol in rats selected for high and low ethanol preference: A 3-methoxytyramine study

Effects of an ethanol dose (1 g/kg, IP) on the metabolism of dopamine (DA) in the nucleus accumbens, striatum and hypothalamus of ethanol-naive alcohol-preferring (AA) and alcohol-avoiding (ANA) rats were studied. Rats were sacrificed by focused-beam microwave irradiation of the brain 20 minutes after ethanol administration, and the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), assumed to reflect DA metabolism, and of 3-methoxytyramine (3-MT), assumed to reflect DA release, were measured using gas chromatography-mass spectrometry. Basal striatal DOPAC and HVA concentrations were higher in the AA rats in comparison with ANA rats. Ethanol increased HVA, but not DOPAC, concentration in the nucleus accumbens and striatum, but not in the hypothalamus. There was a significant rat line × ethanol treatment interaction with respect to HVA concentration in the nucleus accumbens. The increase in HVA was higher in the AA than ANA rats. Basal 3-MT concentration was not changed by ethanol, except in the nucleus accumbens, where a significant rat line × ethanol treatment interaction was found. A decrease in 3-MT concentration was only detected in the ANA rats. After inhibition of monoamine oxidase with pargyline hydrochloride (75 mg/kg, IP, 10 min before sacrifice), 3-MT accumulation was decreased by ethanol, especially in the nucleus accumbens of both AA and ANA rat lines as well as in that of nonselected Wistar rats. The results suggest that 1) DA metabolism to DOPAC and HVA is dissociable from DA release as reflected by 3-MT production, 2) ethanol, if anything, reduces DA release, and that 3) the AA and ANA rats differ in their basal DA metabolism and in the ethanol effects thereupon, but not in ethanol-induced changes in DA release.     

不同暴露时间TiO2纳米粒子对雌性小鼠脑单胺类神经递质的影响

目的探讨小鼠鼻腔滴注二氧化钛（TiO2）纳米粒子对脑中单胺类神经递质的影响。方法以50mg／kg的剂量给CD雌性小鼠隔天鼻腔滴注不同粒径大小的TiO：（25、80和155nm）水悬浮液（浓度为10^5mg／L）,同时设定对照组。分别在暴露2、10、20和30d后用电感耦合等离子体质谱仪分析小鼠脑组织中钛元素的含量,采用反相高效液相色谱-电化学检测法测定暴露20和30d后小鼠脑中单胺类神经递质的含量。结果在暴露10d时,小鼠脑中钛的含量上升较快,25nm组小鼠脑中钛的含量即达到（1059．3±293.5）ng／g;在暴露20d之后,脑中钛的含量有一定降低,仍维持在较高水平,25nm组中钛的含量下降为（654.7±269．2）ng／g。暴露30d时钛含量没有明显改变。由于吸入的TiO2粒子在小鼠脑中的蓄积,导致80nm和155nm组中小鼠脑中去甲肾上腺素（NE）和5-羟色胺（5-HT）含量在暴露20d时明显升高,而多巴胺（DA）、3、4-双羟苯乙酸（DOPAC）、高香草酸（HVA）和5-羟吲哚乙酸（5-HIAA）的含量有一定下降。结论吸入的TiO2颗粒可以经鼻黏膜吸收入脑并能蓄积于小鼠的脑组织中,影响脑中单胺类神经递质的代谢。     

Effects of scheduled access on ethanol intake by the alcohol-preferring (P) line of rats

The effects of scheduling the availability of ethanol on its voluntary consumption by the selectively bred alcohol-preferring P rats were examined under three conditions: unrestricted 24 hr/day access (Condition A), access limited to a continuous 4 hr/day (Condition B), and access limited to 1 hr every 3 hr, 4 times/day (Condition C). Food and water were always available. Daily alcohol intakes (mean +/- SEM) with Conditions A, B and C were 6.9 +/- 0.2, 2.1 +/- 0.2 and 4.4 +/- 0.2 g/kg, respectively, while the intake per hour of availability increased from 0.3 +/- 0.03 under Condition A to 1.1 +/- 0.4 g/kg under condition C. The amount of ethanol consumed per drinking episode under Conditions A, B and C were 1.1 +/- 0.1, 2.1 +/- 0.2 and 1.1 +/- 0.03 g/kg, respectively. Mean blood alcohol concentrations (BACs), determined periodically during the dark cycle of Condition A and five minutes after drinking episodes under Conditions B and C, were 59 +/- 10, 61 +/- 7 and 62 +/- 7 mg%, respectively. When unlimited access was reinstated after Condition C, daily alcohol consumption returned to a level similar to that under the initial Condition A (7.2 +/- 0.5 g/kg). When the ethanol concentration was increased from 5 to 20% (v/v) under Condition C, the amount of ethanol consumed per episode at 5% was significantly less than at the 10, 15 and 20% concentrations, and the volume consumed was significantly lower at the 20% concentration than at the 5, 10 and 15% concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alcohol stimulates the release of dopamine and serotonin in the nucleus accumbens.

The effects of acute IP administration (0.5, 1.0 or 2.0 g/kg) and local perfusion (25, 50 or 100 mM) of ethanol on the extracellular concentrations of dopamine (DA), serotonin (5-HT) and their metabolites in the nucleus accumbens (ACC) of the rat were studied with in vivo microdialysis coupled with a small-bore HPLC electrochemical detection procedure. The IP administration of 1.0 and 2.0 g/kg ethanol significantly (p less than 0.05) increased the extracellular levels of DA and 5-HT in the ACC whereas the 0.5 g/kg dose caused no change. In general, the extracellular levels of the 3 monoamine metabolites were not altered by IP ethanol except for a slight increase in the levels of homovanillic acid following the 2.0 g/kg dose. Local perfusion of 50 and 100 mM ethanol (but not 25 mM) through the microdialysis probe markedly increased (170-200% of control) the extracellular levels of DA in the ACC. Only the 100 mM concentration of ethanol altered the extracellular levels of 5-HT (2-fold increase), 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid. Addition of 100 microM ICS 205-930 (a 5-HT3 antagonist) to the perfusate markedly reduced the 100 mM ethanol-stimulated release of DA and 5-HT. Overall, the data suggest that ethanol can stimulate the release of both DA and 5-HT in the ACC and that the action of ethanol within the ACC may be mediated in part by 5-HT3 receptors.     

Effects of ethanol and low-carbohydrate diet on contents of noradrenaline, dopamine, serotonin and their metabolites in rat brain]

Effects of ethanol consumption and intake of low-carbohydrate (low-CHO) diet on noradrenaline (NA), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5HT) and its metabolite, 5-hydroxyindoleacetic acid (5HIAA) contents in six brain regions of rats were investigated. 1) Change of DA neuron Ethanol-containing control diet (hypercaloric ethanol diet) did not affect DA content in any area of brain, but decreased HVA in cortex and hypothalamus and increased DOPAC and HVA in midbrain. Low-CHO diet increased DA content in striatum, DOPAC and HVA in midbrain, but decreased DOPAC in hippocampus and hypothalamus, and HVA in cortex, pons and medulla, hippocampus and hypothalamus. Ethanol-containing low-CHO diet (isocaloric ethanol diet) increased DA level in striatum, DOPAC and HVA in midbrain, but decreased HVA in cortex, hippocampus, striatum and hypothalamus. These results suggest that i) hypercaloric ethanol diet has an opposite effect to carbohydrate on DA metabolism: hypercaloric ethanol diet and lowered carbohydrate intake per se enhance DA metabolism in midbrain, whereas inhibit it in cortex and hypothalamus, ii) lowered carbohydrate intake also declines DA metabolism in pons and medulla and hippocampus, whereas enhances DA synthesis in striatum, iii) the combined effect of ethanol and carbohydrate intake on DA metabolism is inhibited each other in the rats of isocaloric ethanol diet feeding, and this diet decreased DA metabolism in striatum. 2) Change of 5HT neuron Hypercaloric ethanol diet did not affect the contents of 5HT and 5HIAA in any region of brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

OCCURRENCE IN VIVO OF 5-HYDROXYTRYPTOPHOL IN THE BRAIN OF RATS TREATED WITH ETHANOL

The effect of ethanol (EtOH) on the release of dopamine (DA)and 5-hydroxytryptamine (5-HT) and the efflux of their metabolites,3, 4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindol-3-ylaceticacid (5-HIAA) and 5-hydroxytryptophol (5-HTOL) from the striatumof the freely moving rat were studied in vivo using brain microdialysis.Striatal DA and 5-HT release was maximally enhanced at firstfraction after the administration of EtOH (2 g/ kg, i.p.). Thelevel of the DA-oxidized metabolite, DOPAC, decreased significantly.In the 5-HT metabolic pathway, the oxidized metabolite, 5-HIAA,did not show significant changes, whereas levels of the biogenicalcohol 5-HTOL were increased to 180% at 90 min following EtOHadministration. It is suggested that EtOH, most probably viaacetaldehyde, could shift 5-HT metabolism from the oxidativeto the reductive pathway in the rat brain.     

Extracellular dopamine and serotonin after ethanol monitored with 5-minute microdialysis.

In order to determine potential rapid changes in extracellular dopamine (DA) and 5-hydroxytryptamine (serotonin, 5-HT) during the first 5-10 min after ethanol, intracerebral microdialysis coupled with microbore HPLC was used. Ethanol at the doses of 0.5, 1, and 2 g/kg was administered IP and extracellular DA and 5-HT in 5-min dialysates from the nucleus accumbens (NAC) of freely moving rats were determined. Ethanol at all doses significantly increased extracellular DA and 5-HT. DA and 5-HT peaked at 10, 15, 20 min and 20, 20, 55 min following 0.5, 1, and 2 g/kg, respectively. Based on previous reports showing that brain or blood ethanol levels peaked within 10-20 min after administration, the results indicate that peak increases in extracellular DA and 5-HT in the NAC occurred at approximately the same time, with the DA time course more temporally correlated with the blood or brain alcohol concentration curve reported in the literature. These results support the concept that the reinforcing properties of ethanol derive, at least in part, from its ability to stimulate DA release in the NAC. In addition, the present data are not in opposition with a role of 5-HT in the ethanol reinforcing effect.     

拟除虫菊酯对大鼠脑黑质纹状体系统多巴胺及其代谢产物的影响

目的 初步探讨拟除虫菊酯类农药对雄性SD大鼠脑黑质纹状体多巴胺(DA)系统的毒性作用及其可能机制。方法 采用不同剂量的溴氰菊酯(DM,6.25、12.50 mg/kg)、氯菊酯(PM,200、400mg/kg)给雄性SD大鼠连续10 d经口灌胃给药后,HPLC荧光检测法分别检测其脑黑质、纹状体内DA及其代谢产物3,4-二羟基苯乙酸(DOPAC)、3-甲氧基-4-羟基苯乙酸(HVA)的含量。结果 给药各组大鼠纹状体内DA含量都有不同程度的下降,且12.50 mg/kg DM组(6.14±0.57μg/g湿重)与对照组(9.46±1.95 μg/g湿重)的差异有统计学意义(P<0.05);200、400 mg/kg PM组和6.25、12.50 mg/kgDM 4个组的DA更新率[(DOPAC HVA)/DA]与对照组相比,分别增加了133.33％、166.67％、166.67％和266.67％,差异均有统计学意义(P<0.05或P<0.01);而黑质内DA及其代谢产物水平均无明显变化。结论 DM可能抑制酪氨酸羟化酶合成DA,使其在纹状体内的含量下降,PM和DM都可以加强DA的代谢。     

Striatal and hypothalamic neurotransmitter changes during ethanol withdrawal in mice

The alterations in striatal and hypothalamic GABA, DA and its metabolites DOPAC and HVA, and in hypothalamic NE were investigated immediately after ethanol removal and during the withdrawal phase following 10 or 30 days of chronic ethanol administration. After 10 days of ethanol, GABA levels were increased immediately after ethanol removal in both the corpus striatum and the hypothalamus. The concentration of striatal DA was increased at days 2 and 3 of withdrawal and was unchanged at any other time. There was no change in the concentration of DOPAC and HVA in the hypothalamus at any time during withdrawal. Striatal DOPAC and HVA levels were increased only at day 7 of withdrawal after 10 and 30 days of ethanol feeding which was associated with a return of striatal DA to control levels. The concentration of NE in the hypothalamus was increased at days 1, 2 and 7 of withdrawal. After 30 days of ethanol, striatal GABA was increased only at day 7 of withdrawal whereas striatal DA levels were only increased at days 2 and 3 of withdrawal. Hypothalamic NE was markedly increased at days 2, 3 and 7 of withdrawal. The increase in DA concentration associated with no change in DOPA accumulation following inhibition of DOPA decarboxylase and a decrease in the striatal disappearance of DA after alphamethylparatyrosine (alpha-MT) suggests the presence of a hypodopaminergic state. On the other hand an increase in the disappearance of NE in the hypothalamus after alpha-MT suggests an increased NE turnover and a hyperadrenergic state during withdrawal. The increase in striatal GABA at day 7 of withdrawal after 30 days of ethanol may be a rebound phenomenon and may reflect the presence of a hypogabaergic state which has been shown to occur during ethanol withdrawal.     

Effects of successive intrastriatal methylmercury administrations on dopaminergic system

The present study was carried out in order to determine the effects of intrastriatal administration of different doses (40 microM, 400 microM, and 4mM) of methylmercury (MeHg) on dopaminergic system of rat striatum. Experiments were performed in conscious and freely moving rats using brain microdialysis coupled with liquid chromatography. Intrastriatal administration of MeHg produced significant increases in dopamine (DA) striatal levels (907+/-7%, 1870+/-319%, and 7971+/-534% for the doses of 40, 400 microM, and 4mM, with respect to basal). The increase in DA levels was associated with significant decreases in extracellular levels of its main metabolites dihydroxyphenylacetic acid (DOPAC) and homovallinic acid (HVA) (65.0+/-3.0% and 52.2+/-1.3%, respectively) using the dose of 4mM MeHg, whereas nonsignificant changes in metabolite levels were observed with the doses of 40 and 400 microM MeHg. A second infusion of 4mM MeHg 24h after first infusion also produced a rise of DA levels, but this increase was very small as compared with that produced by first infusion (7971+/-534% versus 985+/-186%). This second infusion of 4mM MeHg also decreased DOPAC and HVA levels, but this decrease was not significant as compared with that observed after first infusion (65.0+/-3.0% and 52.2+/-1.3% versus 62.4+/-5.2% and 63.4+/-7.4%, respectively). We discuss these effects based on a stimulated DA release and/or a decreased DA intraneuronal degradation.     

Alcohol inhibition of suckling-induced prolactin release in lactating rats: threshold evaluation

Prolactin release in response to suckling was examined in primiparous lactating rats two hours after alcohol administration. Litters were adjusted to eight pups on lactation day 2 and dams were implanted with an atrial catheter on day 6. On day 10, pups were separated from the mother at 0800 h. An extension was attached to the catheter at 1100 h. Following removal of a baseline blood sample an hour later, rats were infused with alcohol doses of 0, 0.5, 1.0, 2.0 or 2.5 g/kg body weight. Two hours later, pups were returned to dams. Subsequent blood samples were obtained 10, 30, 60, 120 and 180 min after the onset of suckling. Following 10 min of suckling, plasma prolactin for groups of rats infused with alcohol at 2.0 and 2.5 g/kg body weight were lower than control, 0.5 and 1.0 g/kg groups. The blood alcohol level (BAL) for the 2.0 g/kg group was 94 +/- 8 mg% and for the 2.5 g/kg group was 162 +/- 4 mg%. After 30 min, the BAL for the 2.5 g/kg group was 134 +/- 5 mg% and plasma prolactin was suppressed in this group compared to control, 0.5 and 1.0 g/kg groups. The BAL for the 2.0 g/kg group after 30 min of suckling was 74 +/- 9 mg% but prolactin was not significantly lower than controls. We conclude that in rats, alcohol inhibition of suckling-induced prolactin release is directly correlated to the BAL. The threshold BAL which effectively inhibits this prolactin release is lower than the human legal intoxication level.     

Effects of perinatal exposure to bisphenol A on brain neurotransmitters in female rat offspring

Pregnant Sprague-Dawley (CD IGS) rats were orally administered doses of bisphenol A (BPA) at 4, 40, and 400 mg/kg, from gestation days 6 to postnatal day 20. Neurotransmitters such as dopamine (DA) and serotonin (5HT) were extracted from the brains of dams and female offspring, and measured using liquid chromatography. BPA at 400 mg/kg was toxic and dosed rats died. At 3 wk after birth, brain levels of 3,4-dihydroxyphenylacetic acid (DOPAC, a DA metabolite), homovanillic acid (HVA, a DA metabolite), 5HT, 5-hydroxyindoleacetic acid (5HIAA, a 5HT metabolite) in female offspring were increased and the HVA/DA ratio was high in some brain areas of BPA-treated groups as compared with controls. At the age of 6 wk, levels of choline (Ch) in BPA-treated groups at 4 and 40 mg/kg were higher than control in all of eight brain areas. No changes were observed in acetylcholine (ACh) contents. In 9-wk-old offspring, changes in monoamines and metabolites were scattered and not great. At 3 wk after delivery, levels of 5HIAA in some brain areas of dams treated with BPA were higher than in control dams. Dose dependent increases in HVA and the HVA/DA ratio of the occipital cortex, and in the HVA/DA ratio of the frontal cortex were observed. The turnover of DA and 5HT was accelerated in 3-wk-old offspring and dams. BPA possesses very weak estrogenic activity. Changes in cerebral neurotransmitters observed in offspring and dams in this study may have been related to the estrogenic activity of BPA. However, further investigation is needed to examine the contribution of hormonal activity to such neurotransmitter changes.     

Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats

Neurochemical and neuropharmacological studies were undertaken to assess the involvement of CNS serotonin (5-HT), dopamine (DA) and GABA systems in regulating the alcohol-drinking behavior of two lines of rats selectively bred for their high alcohol-seeking behavior, namely the alcohol-preferring P line and the high alcohol-drinking HAD line of rats. Neurochemical data indicate that high alcohol-seeking behavior (when compared with data from rats with low alcohol-seeking characteristics) is associated with: a) lower (10-20%; p less than 0.05) contents of 5-HT in certain limbic regions (e.g., nucleus accumbens, frontal cortex, hypothalamus and hippocampus); b) a lower (10-15%; p less than 0.05) content of DA in the nucleus accumbens; c) higher (20-35%; p less than 0.05) densities of 5-HT1A binding sites in some limbic regions (e.g., medial nucleus accumbens, medial prefrontal cortex and ventral hippocampus); and d) a greater (20-50%) density of GABA axon terminals in the nucleus accumbens. Furthermore, the acute administration of high doses of ethanol appears to increase the activity of the 5-HT and DA projections to the nucleus accumbens of the P line of rats (as indicated by the 20-30% elevated tissue levels of 5-HT and DA metabolites following IP ethanol administration); neuronal tolerance to alcohol appears to develop in both these monoamine pathways, as suggested by an attenuated effect on metabolite levels by a challenge dose of ethanol given to P rats that had been chronically drinking alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nimodipine's effect on alcohol disposition in mice

Adult Binghamton Heterogeneous male mice received either nimodipine (5 mg/kg in saline) or vehicle 10 minutes prior to ethanol (1.02 g/kg) administration. Blood samples were obtained at 2, 10, 30, 60 and 120 minutes following the alcohol injection for determination of ethanol content. Although mean blood alcohol concentrations (BACs) were similar for both groups, nimodipine increased the variance in blood alcohol levels. Therefore, while nimodipine may alter alcohol pharmacokinetics through its interaction(s) with the genetic characteristics of the individual animal, the ability of this calcium slow channel blocking agent to enhance the psychotropic effects of alcohol cannot be due to altered absorption or elimination of the intoxicant.     

The acute dose-related effects of ethanol on right ventricular function in anesthetized dogs.

The acute dose-related effects of small to moderate doses of ethanol on right ventricular functioning were studied on 18 anesthetized, artificially ventilated dogs in 39 sessions. Diluted ethanol (from 25-37.5%) was infused during 40 minutes, yielding total doses of 1.0 g/kg (n = 15), and 1.5 g/kg (n = 12) with corresponding venous blood ethanol peak concentrations of 1.38 +/- 0.25 and 2.41 +/- 0.31 mg/ml, respectively. Heart rate increased up to 16% in groups receiving ethanol. In the control group receiving the equivalent volume of saline (n = 12) heart rate decreased 14%. Pulmonary arterial systolic pressure increased from 24 +/- 3 to 27 +/- 3 mmHg and diastolic pressure from 11 +/- 2 to 14 +/- 4 mmHg (p less than 0.05) when the ethanol dose was 1.0 g/kg. The pulmonary arterial resistance increased from 620 +/- 135 to 805 +/- 185 dyn.s.cm-5 (p less than 0.01). The peak dP/dt decreased maximally by 20% with increasing ethanol doses. Stroke volume decreased maximally by 14% but due to the increase in heart rate, cardiac output even increased. The changes in end-diastolic volume and pressure were not significant. Hence, the ethanol increased heart rate and afterload of the right ventricle but depressed the myocardium.     

Nefazodone attenuates the behavioral and neurochemical effects of ethanol

This study evaluated the influence of nefazodone, a combined 5-HT_2A receptor antagonist and 5-HT reuptake inhibitor, on the behavioral and neurochemical effects of ethanol in nonselected male Wistar rats. In microdialysis experiments, ethanol (2.5 g/kg, IP) increased extracellular accumbal dopamine levels by 36% (p = 0.0073) compared to baseline levels, and elevated the maximal DOPAC and HVA levels by 26% (p = 0.0093) and 52% (p = 0.0010), respectively. Nefazodone (50 mg/kg, SC) per se increased accumbal dopamine levels by 28% (p = 0.0199), but, when injected 40 min before ethanol, reduced the ethanol-induced elevation of accumbal dopamine overflow (p = 0.0132) and decreased the ethanol-induced HVA levels (p = 0.0159). In an ethanol(6% v/v)/water free-choice paradigm, nefazodone (50 mg/kg, SC) decreased ethanol intake by 51% (p = 0.0251) and preference by 22% (p = 0.0251) in high- but not low-preferring rats from a nonselected Wistar strain. These results show that nefazodone modulates the mesolimbic dopamine system in a dopamine activity-dependent manner, and influences the neurochemical and behavioral effects of ethanol in the rat.     

Evaluation of toluene exposure via drinking water on levels of regional brain biogenic monoamines and their metabolites in CD-1 mice

Toluene, a potentially neurotoxic substance, is found in trace amounts in groundwater. Adult male CD-1 mice were continuously fed drinking water ad libitum containing 0, 17, 80, and 405 mg/liter toluene. After a 28-day treatment, animals were tested for endogenous levels of the biogenic monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their respective metabolites. 3-methoxy-4-hydroxymandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in six discrete brain regions. The maximum toluene-induced increases of biogenic amines and their metabolites generally occurred at a toluene concentration of 80 mg/liter. In the hypothalamus, a major NE-containing compartment, the concentrations of NE significantly increased by 51, 63, and 34% in groups dosed with 17, 80, and 405 mg/liter, respectively. Significant increases of NE were also observed in the medulla oblongata and midbrain. Concomitantly, concentrations of VMA increased in various brain regions. Concentrations of DA were significantly higher in the corpus striatum and hypothalamus. Alterations in levels of DA metabolites, DOPAC and HVA, were marginal. Toluene significantly increased concentrations of 5-HT in all dissected brain regions, except cerebellum, and increased the 5-HIAA levels in the hypothalamus, corpus striatum, and cerebral cortex.     

Differential motivational properties of ethanol during early ontogeny as a function of dose and postadministration time.

While appetitive reinforcement effects of ethanol are easily detected in rat neonates, such phenomena rarely have been observed in older infants. Recently, Molina et al. [Molina, J. C., Ponce L. F., Truxell, E., & Spear N. E. (2006). Infantile sensitivity to ethanol's motivational effects: ethanol reinforcement during the third postnatal week. Alcohol Clin Exp Res 30, 1506-1519] reported such effects of ethanol in 14-day-olds using a second-order conditioning procedure. Infants also appear to be sensitive to biphasic reinforcement or general motivational effects of ethanol, with appetitive effects seeming to occur early in the state of intoxication and aversive effects predominant during late stages, but tests have been inconclusive. The present study examined the possibility of biphasic motivational effects of ethanol during infancy through the use of second-order conditioning procedures. Preweanling rats (14 days old) experienced intraoral water infusions (conditioned stimulus, CS) either 5-20 or 30-45 min after administration of 0.5 or 2.0 g/kg i.g. ethanol. Pups were then exposed to the CS while over a novel texture (second-order phase). Tests of tactile preference for that texture followed. Locomotive, thermal, hormonal (corticosterone release), and pharmacokinetic patterns likely to underlie the acquisition of ethanol-mediated conditioning were also examined in subsequent experiments. Intraoral CSs paired with either early or late effects of low-dose ethanol (0.5 g/kg, blood ethanol concentration: 40 mg%) became positive second-order reinforcers. Appetitive effects were also exhibited by pups exposed to the CS during commencement of the toxic episode induced by a 2.0 g/kg ethanol dose, 5-20 min after administration of ethanol, whereas aversions emerged when CS presentation occurred 30-45 min postadministration time (blood ethanol concentrations: 157 and 200 mg%, respectively). Overall, the results indicate that infants rapidly detect differential motivational properties of ethanol as a function of dose or drug postadministration time. Relatively neutral stimuli associated with these properties are later capable of acting as either positive or aversive reinforcers. Thermal and motor responses that accompany ethanol intoxication do not seem to be directly associated with differential hedonic properties of the drug at this stage of development.     

Effects of ethanol on the dorsal raphe nucleus and its projections to the caudate putamen.

The objective of this study was to examine the effects of intraperitoneal injection of ethanol on the activity of the dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) system and its projections to the rostral caudate putamen (CPu) and determine whether rapid tolerance to the effects of ethanol develops in this system. Adult, male, Wistar rats were used in these experiments. In experiment 1, a microdialysis procedure was used to determine (a) the effects of acute intraperitoneal administration of ethanol (1.75 and 2.5 g/kg) on the extracellular levels of 5-HT in the rostral CPu and (b) whether rapid tolerance develops to these effects. In experiment 2, firing rates of 5-HT neurons were determined in the DRN after intraperitoneal administration of 2.5 g/kg of ethanol. The results of the microdialysis experiments indicated that the 2.5-g/kg dose significantly (P < .005) increased the extracellular levels of 5-HT to 150%-160% of baseline. Compared with findings for rats pretreated with saline 24 h earlier, prior treatment 24 h earlier with 2.5 g/kg of ethanol had no effect on the extracellular levels of 5-HT produced by a challenge dose of 2.5 g/kg of ethanol. Contrary to the effects in the CPu, intraperitoneal administration of 2.5 g/kg of ethanol significantly (P<.005) decreased the firing rates of 5-HT neurons in the DRN to approximately 50% of control. Overall, the results suggest to us that there is a dissociation between the effects of acute administration of ethanol on 5-HT cell body neuronal activity and 5-HT synaptic activity. The higher extracellular levels of 5-HT in the CPu may be due to increased release of 5-HT from a direct or an indirect action of ethanol, a result of inhibiting 5-HT reuptake, or related to both of these mechanisms. In addition, the findings suggest to us that rapid tolerance did not develop to the effects of ethanol on the 5-HT system within the CPu.     

Subclinical effects of groundwater contaminants. II. Alteration of regional brain monoamine neurotransmitters by benzene in CD-1 mice

Benzene, a common groundwater contaminant, possesses neurotoxic and behavioral effects. Male, adult CD-1 mice were continuously fed drinking waterad libitum containing 0, 31, 166 and 790 mg/L benzene for four weeks. Endogenous levels of the catecholamines norepinephrine (NE) and dopamine (DA), the catecholamine metabolites 3-methoxy-4-hydroxymandelic acid (VMA), 3,4-di-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the indoleamine serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), were measured by high-performance liquid chromatography (HPLC) in six discrete brain regions. In the hypothalamus, the brain region richest in NE, concentrations of NE increased by 40, 58 and 61% when mice received doses at 31, 166 and 790 mg/L, respectively. Significant increases of NE were also observed in the medulla oblongata and cerebellum. Dopamine concentrations increased significantly in the hypothalamus and corpus striatum. Increases of catecholamine metabolites were seen in a number of brain regions: midbrain (DOPAC), corpus striatum (VMA, DOPAC, HVA), cerebral cortex (VMA) and cerebellum (VMA). Benzene ingestion significantly increased 5-HT concentrations in the hypothalamus, corpus striatum, midbrain, cerebral cortex and medulla oblongata. Concomitant with increases of 5-HT, 5-HIAA increased in corpus striatum, midbrain, cerebral cortex and medulla oblongata. The findings indicate that oral ingestion of benzene by CD-1 mice induced both synthesis and catabolism of the monoamine neurotransmitters investigated.