Role of context in ethanol tolerance and subsequent hedonic effects.

Two groups of male Sprague-Dawley rats received ethanol dose-effect tests for FR30, food-reinforced operant performance, in each of two environmental contexts, before and after a period of daily presession ethanol or saline injections. During the latter period, context alternated daily. The ethanol group received ethanol prior to sessions for one context and saline, prior to sessions for the other context. The saline group always received presession saline. The ethanol, but not the saline, group displayed robust tolerance to ethanol's rate-decreasing effects, with no difference between tests in each context. Both groups then received training and testing in an ethanol-conditioned place preference task. The saline group displayed significant avoidance of the compartment paired with ethanol. The ethanol group displayed no initial aversion for the ethanol compartment and, with extended conditioning, showed a significant increase in time spent in the ethanol compartment. We suggest that this tolerance represents context-independent, learning to compensate for ethanol-induced effects, and that this tolerance subsequently blocked the conditioned place aversion evident in nontolerant controls, thereby enhancing the estimates of ethanol's reward properties.     

Historical factors in the development of ETOH-conditioned place preference.

Three groups of male Sprague-Dawley rats were conditioned with ethanol (ETOH) and water in a Conditioned Place Preference task. To assess the contribution of prior drug/behavioral history on the relative hedonic valence of ETOH, the three groups differed in the task demands and degree of prior ETOH exposure. One group was trained to self-administer 20% w/v ETOH in a home-cage self-administration task using a "Samson sucrose-fading" procedure prior to place conditioning trials (Group SA/CPP). A second group was initially trained in a two-choice ETOH-Saline drug discrimination (DD) task and subsequently conditioned in the place preference paradigm (Group DD/CPP). The third group of rats had no history of drug exposure and were experimentally naive prior to the place learning task (Group NH/CPP). Group SA/CPP developed a significant conditioned place preference; Group DD/CPP failed to demonstrate either a preference or aversion, whereas the Group NH/CPP demonstrated a significant place aversion. Data suggest that both present and past contingencies contribute to the algebraic summation of ETOH's hedonic valences.     

A drug discrimination analysis of ethanol-induced behavioral excitation and sedation: the role of endogenous opiate pathways

The drug discrimination technique was used to characterize the biphasic behavioral effects of ethanol (ETOH) and examine the role of opiate pathways in mediating ETOH's excitatory (EX) and sedative (SED) phase effects. Forty Sprague-Dawley rats were trained to perform ETOH vs. saline discriminations during either ETOH's EX (6 min post-dose) or SED (30 min post-dose) phase of action in a double-lever food reinforced operant paradigm. After animals had achieved the required performance criterion, dose-response and phase-generalization tests were conducted in each group. In addition, preliminary studies were conducted to examine the effect of naloxone (NLX) pretreatment on discrimination of ETOH's EX and SED phase stimulus effects. Results of generalization testing demonstrate that discrimination of ETOH was dose-dependent and there was no generalization between phases regardless of the initial training condition. NLX pretreatment significantly attenuated discrimination of ETOH's EX phase effects but was ineffective in antagonizing ETOH's SED effects. These data demonstrate that the stimulus properties of ETOH are phase-dependent and suggest that opiate pathways are critical for the expression of ETOH's EX phase behavioral effects.     

Ro 15-4513 does not antagonize the discriminative stimulus- or rate-depressant effects of ethanol in rats

Female rats, trained to discriminate between IP administered 1.2 g/kg ethanol (ETOH) and the saline vehicle (12 ml/kg), did not press the nondrug associated lever in tests with ETOH (0.9 and 1.2 g/kg) plus the purported amethystic imidazo benzodiazepine Ro 15-4513 (3 and 10 mg/kg) as examined at two intervals after ETOH administrations viz. 7.5 and 15 min. The two doses of Ro 15-4513 were administered 5 min prior to ETOH. Response times were increased in tests with the combination. ETOH in expired air was not different in the two drug conditions, i.e., ETOH singly and together with Ro 15-4513, irrespective of the dose combinations examined. Rats trained to press a bar (FR-10 operant behavior) for sweetened water disclosed increases in the time used to obtain the reinforcer after treatments with ETOH and Ro 15-4513. Thus, Ro 15-4513 did not seem to reverse any of the behaviors examined in this study.     

A rat model of neurobehavioral sensitization to toluene.

Some individuals report that, following either a single high-level or repeated lower-level exposures to chemicals (initiation), subsequent exposure to very low concentrations of chemicals (triggering) produces a variety of adverse effects, including disruption of cognitive processes. Our objective was to model this two-step process in a laboratory animal. Two groups of 16 rats, eight male and eight female, received whole-body inhalation exposure to toluene, either at 80 ppm for 6 h/day for 4 weeks (Repeat group) or to 1600 ppm for 6 h/day on one day only (Acute group). Two other groups (Trigger group and Clean group) of 16 were sham-exposed. After 17 days without toluene exposure, the Acute, Repeat and Trigger groups began a series of daily toluene 'trigger' exposures (10 ppm for 1 h) followed immediately by testing on an operant repeated-acquisitions task requiring learning within and across sessions. The Clean group was sham-exposed prior to operant testing. Trigger or sham exposures and operant testing continued 5 days/week for 17 sessions. Analysis of variance revealed a variety of statistically significant (P < 0.05) differences between treatment groups. Furthermore, the patterns of differences between groups differed (P < 0.05) for female and male rats. For example, male rats of the Trigger group made the most responses, and female rats of the Repeat group responded most slowly. The observation of important changes in the operant behavior of female and male rats previously exposed to toluene, at relatively low concentrations (80 or 1600 ppm) and then later re-exposed at very low concentrations (10 ppm), is consistent with the experiences of humans reporting cognitive difficulties following acute or chronic exposures to chemicals.     

Aversive attributes of ethanol can be attenuated by dyadic social interaction in the rat

Forty-eight male Sprague-Dawley rats were conditioned with either water or 4 g/kg ethanol in a standard drug place-learning task. In addition to the drug treatment, the opportunity for social interaction with either a sober or intoxicated conspecific was varied across groups (N = 8 rats/group). Ethanol produced a robust conditioned place aversion. The opportunity for dyadic social interaction with either a sober or intoxicated cohort attenuated the aversive attributes of ethanol. However, the initial preference scores did not significantly shift in water-conditioned rats in isolation or given access to either a sober or intoxicated cohort. These data are similar to clinical reports and suggest that social factors can influence the aversive affective properties of ethanol.     

Fat-preferring rats consume more alcohol than carbohydrate-preferring rats

Rats with a genetic preference for alcohol (ETOH) have been found to consume more dietary fat then ETOH nonpreferring rats. We therefore hypothesized that rats selected on the basis of fat and carbohydrate (CHO) preferences would differ in ETOH intake. Patterns of macronutrient self-selection were determined by allowing rats to select diets from separate sources of CHO, fat and protein. Subsequently, CHO- and fat-preferring groups were formed. All rats were then returned to a lab chow diet and trained to drink ETOH (4-12%) during one hour of access per day. Food restriction was used only in the first three weeks of the procedure. On the final drinking sessions, water and ETOH were alternated on a daily basis. Fat-preferring rats consumed significantly more ETOH than water; CHO-preferring rats consumed approximately equal amounts of ETOH and water. Furthermore, fat-preferring rats consumed more ETOH than CHO-preferring rats. This study suggests that there may be a common mechanism underlying diet preference and oral intake of ETOH.     

Absence of tolerance to the aversive stimulus properties of ethanol following oral ethanol self-administration

Depending on the situation, ethanol can serve as a reinforcer in one paradigm and an aversive stimulus in another. The relationships between the two stimuli are not clear, particularly the behavioural adaptation following chronic ethanol exposure. We report on two experiments using an oral-self administration (OSA) paradigm and a conditioned taste aversion (CTA) paradigm. Male Wistar rats were exposed to ethanol using either the OSA or the CTA paradigm, and the consequences were examined in the same groups of rats by performing the other corresponding experiment. Thus, sensitisation or tolerance to the respective stimulus properties of ethanol would be detectable. For OSA experiments, rats were presented, under a free-choice setting, tap water and an ascending series of ethanol concentrations (2–10%) for up to 4 days per concentration. The amounts of ethanol and water consumed in 23-h sessions were measured. For CTA, a two-bottle procedure was employed. Distinctively flavoured solutions (saccharin or saline) were paired with IP injections of either ethanol (1.5 g/kg) or saline (1 ml/kg). Tests for aversion were made after two pairings, when both solutions were presented simultaneously for 10 min. At low concentrations of ethanol, drinking solution consumption was high, decreasing gradually with increasing concentrations; however, daily intake of orally self-administered ethanol remained stable. No significant differences could be established between the two groups tested. Ethanol preference [EtOH/EtOH + H₂O] was attenuated in rats experienced with the CTA procedure before the OSA experiment. Injections of ethanol produced marked CTAs, even in rats that had consumed ethanol in the OSA experiment. The absence of tolerance to the aversive stimulus effects suggests that this stimulus property may not play a significant role in the consumption of ethanol.     

Differential effects of ethanol on luteinizing hormone, follicle stimulating hormone and prolactin secretion in the female rat

Serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (Prl) levels were determined in ovariectomized rats following short-term (3 day) ethanol (ETOH) administration. ETOH was given either as an ETOH-saline solution, or via a liquid diet regimen (Bio-Serve, Inc.). Rats receiving the ETOH-saline solution (3.0 g ETOH/kg) were injected via a permanent gastric cannula every 8 hr for 3 consecutive days, while control animals received injections of saline only. Each animal receiving the liquid diet regimen was provided with 40 ml of the ETOH or the isocaloric control diet ad lib during the lights-off period, followed by 40 ml of the respective diet via the gastric cannula (4 injections of 10 ml each) equally divided over the lights-on period. Additional control animals were cannulated and maintained on Lab Chow and water, but were left untreated. Both groups of ETOH-treated rats had significantly lower serum LH levels with significantly higher Prl levels when compared to values in their respective control animals. By contrast, ETOH failed to alter FSH levels. These data indicate that ETOH can differentially affect LH, FSH, and Prl secretion following short-term ETOH exposure. The dissociation observed between LH and FSH secretion following ETOH supports the hypothesis that there are separate hypothalamic control mechanisms for LH and FSH secretion.     

The influence of acute ethanol exposure on growth hormone release in female rats.

This study investigates the site (hypothalamic or pituitary) at which ethanol (ETOH) alters GH release in female rats. Both the hypothalamic response to clonidine (CLON), an alpha 2-adrenergic agonist, and the pituitary response to growth-hormone releasing hormone (GRH) were tested. Jugular cannulae were inserted for drug administration and undisturbed blood sampling. ETOH was injected IP 24 and 1 h before experimentation. In animals receiving saline or ETOH (1, 2, or 3 g/kg), there was no response to CLON and no difference in GH levels between groups. On the other hand, there was a significant surge in GH release in response to a high dose of GRH (1000 ng/kg) in both saline controls and in ETOH (3 g/kg) animals. Although there was no difference in the height of the surge between groups, baseline GH levels were higher in animals that received ETOH. In response to a low dose of GRH (250 ng/kg) the GH surge was only significant in the ETOH animals. In animals receiving somatostatin antiserum (anti-SRIF; 0.5 ml) in combination with the low GRH dose, the surge in GH levels was significant in both saline and ETOH animals, however, the surge was higher in saline compared to ETOH animals. The results of this study suggest that: 1) ETOH alters the SRIF system (release of reception) in female rats and that this interaction is evident when GRH concentration is low, and 2) ETOH may also inhibit GH release by interfering with the GRH system, however, the site of this influence most likely does not involve an alpha 2-GRH component.     

Concentrations of ethanol in rebreathed air of rats: correlation with the discriminative stimulus effects of ethanol

We modified the method of Pohorecky and Brick (14) for determination of ethanol (ETOH) concentrations in rebreathed air of rats. Rats were injected with different doses (1-2 g/kg) of ETOH and both arterial blood and rebreathed air samples were collected at various time intervals (15-120 min) after administration. We found a very good correlation (r = .96) between ETOH concentrations in arterial blood and in rebreathed air; the blood/breath conversion factor (+/- SEM) was 3241 +/- 55. In the second part of the study, rats were trained to discriminate between IP administered ETOH (1.2 g/kg) and the saline vehicle (12 ml/kg). Training occurred 15 min after administrations. Once trained to reliably differentiate between ETOH/saline training sessions, different doses (0.6, 0.9 and 1.2 g/kg) of ETOH were examined at various time intervals (1, 7.5, 15, 30, 60, 120 and 240 min) after administrations on certain test days. The results indicated a good correlation (r = .65) between the discriminative stimulus effects of ETOH and the concentrations measured in rebreathed air. The behavioral effects as well as the concentrations of ETOH in rebreathed air have a fast onset. The peak occurred 7.5 min after injection, and both the stimulus effects and concentrations of ETOH were time- and dose-dependent.     

EFFECT OF PRENATAL EXPOSURE TO ETHANOL ON ADULT ETHANOL PREFERENCE AND RESPONSE TO ZIMELIDINE IN RATS

The effects of prenatal ethanol (ETOH) exposure (2.8–3.5g/kg per day) on subsequent adult ETOH preference and on ETOHconsumption after treatment with zimelidine, a serotonin uptakeinhibitor, were investigated. Pregnant rats were exposed toan ETOH/saccharin solution in the first, second, third, allthree, or none, of the trimesters of the gestation period. Asadults, the offspring were subjected to a 40-day screening procedureto determine ETOH preference (greater than 50% of total dailyfluid consumption) over water (experiment 1). Only animals whichpreferred ETOH were included in experiment 2, in which theyreceived either five daily injections of zimelidine (20 mg/kg)or comparable volumes of Ringer's solution. Results indicatedthat although there were no differences between groups in termsof ETOH preference, a significant difference was evident inETOH intake after zimelidine treatment. All groups of rats showeda significant decrease in ETOH intake from baseline levels whengiven zimelidine. However, only rats prenatally exposed to ETOHin the first trimester demonstrated a significant decrease inETOH drinking when compared to controls. These results suggestthat early prenatal ETOH exposure, even in moderate doses, mayinduce central neurochemical alterations that are salient enoughto be detected in adulthood.     

Operant ethanol self-administration after nicotine treatment and withdrawal.

The effects of chronic intermittent administration of nicotine (NIC) and withdrawal on operant ethanol (EtOH) self-administration were tested in Long-Evans rats (n = 8). EtOH self-administration (10% v/v, Fixed Ratio 4 reinforcement schedule) was induced by the sucrose-substitution procedure. Then the animals were divided into two groups of four rats matched on EtOH self-administration and the locomotor activity following an injection of NIC (0.35 mg/kg, SC) or saline was measured. The groups then received 9 days of injection of either NIC (0.35 mg/kg) or saline and then motor activity was retested using the initial NIC dose. This was followed by 17 days of NIC injections (0.6 mg/kg) or saline injections. A final locomotor test using the higher NIC dose was then conducted. The initial acute administration of NIC had no effect on motor activity compared to saline (measured by the number of horizontal movements). However, after the repeated treatment, the group of animals injected chronically and acutely with NIC showed motor activation in comparison with the animals injected chronically with saline and injected acutely with NIC only on the days of activity testing. At the end of the chronic NIC treatment, operant EtOH self-administration was not changed. However, 6 days after the NIC injections were concluded, a change in the pattern of responding for EtOH was observed in the NIC group, showing a decrease in the mean rate of responding during the first half of the operant self-administration session. When both groups were again tested for locomotor activity at the end of the operant self-administration experiment, the increased motor activity in the NIC group was still observed. The results suggest that alterations in the nicotinic system may affect EtOH self-administration, but this appears to be only modulatory, even with a significant change in locomotor response to NIC following chronic NIC administration.     

Wheel Running Simultaneously Induces CTA and Facilitates Feeding in Non-deprived Rats

Previous findings indicate that wheel running can have either an aversive or an appetitive effect. That is, wheel running for 30 min induces conditioned taste aversion (CTA) in rats trained while hungry and thirsty but facilitates feeding in non-deprived rats. In Experiment 1, wheel running was also found to be effective in producing CTA in non-deprived rats. Therefore, Experiment 2 tested whether wheel running produces the aversive and appetitive effects simultaneously. During each of four training trials, two groups of non-deprived rats were given a flavored solution to drink for 10 min. Then those in the wheel group were put in running wheels for 30 min whereas those in the cage group spent 30 min in small cages. Finally, all rats were given a 60-min feeding test. After the first trial, the wheel group drank less flavored solution than the cage group during each of the remaining trials. The wheel group also ate more than the cage group on each feeding test. These results indicate that wheel running produces CTA and facilitates eating at the same time. A role for the mesolimbic dopamine reward system in these effects was considered.     

Persistence of tolerance in the P line of alcohol-preferring rats does not require performance while intoxicated

Persistence of tolerance was measured seven days after a single ethanol injection (2.5 g/kg b. wt.) in the alcohol-preferring P line of rats with and without testing in a shock-motivated jump task during the initial ethanol exposure. P rats were trained to jump 50 cm to avoid shock and were assigned to one of three groups. On day 0, group E/J (n = 8) was injected with ethanol and tested on the jump task until recovery to criterion (37.5 cm), while group S/J (n = 21) was injected with saline and was tested yoked to an E/J rat. Rats in the E/NJ group (n = 19) received ethanol but were not tested on day 0. Seven days later, all rats received 2.5 g ethanol/kg and were tested to criterion. Recovery times on day 7 were significantly longer (p less than 0.05) for rats in the S/J group (169 +/- 7 min) than for the E/J (141 +/- 11 min) and E/NJ (145 +/- 6 min) rats. Blood ethanol concentrations at recovery for the E/NJ group were higher than the S/J group on day 7 and higher than the E/J group on day 0 (p less than 0.05). The results indicate that the persistence of tolerance manifested by the P rats is an inherited behavioral trait that requires only ethanol exposure.     

Ethanol and the pulsatile release of luteinizing hormone, follicle stimulating hormone and prolactin in ovariectomized rats

Conscious ovariectomized rats were administered either saline or an ethanol (ETOH)-saline solution via a permanent intragastric cannula, and plasma LH, FSH and PRL were measured by RIA of jugular blood samples drawn every 10 min through an indwelling silastic catheter. Control injections of saline into the gastric cannula did not modify any of the plasma hormone concentrations. Animals which were administered ETOH, showed marked decreases in the plasma concentrations of LH. Compared to basal levels, a significant decrease in the area under the secretion curve of LH occurred during the initial hour after ETOH administration. This decline continued with the lowest levels of plasma LH being detected at approximately 1.5 hours following the ETOH injection. Additionally, no LH pulses were detected in any of the ETOH-treated animals during the second hour after ETOH; thus, reducing the number of LH pulses observed in ETOH vs. saline-injected animals. Comparable increases in the area under the LH curve occurred following a challenge dose of LHRH in both saline and ETOH-injected rats, indicating that pituitary responsiveness was the same for both groups. In contrast to LH, ETOH did not significantly alter the pattern of FSH secretion, as represented by the area under the curve and the number of FSH pulses. In addition to the differential effects of ETOH on the pulsatile release of LH and FSH, the present data also indicate that these two gonadotropins have different secretory patterns. With regard to PRL, ETOH-injected animals showed a significant elevation in plasma PRL levels during the first hour following ETOH administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

A role for taste aversion learning in FLA-57 induced reductions of voluntary alcohol intake

It has been proposed by Amit, Brown and colleagues that the reduction in voluntary alcohol intake observed after the administration of FLA-57 in rats can be attributed to decreased NE levels produced by FLA-57. Our studies investigated whether a conditioned taste aversion could better explain this phenomenon. In the key study, two groups of rats were injected with FLA-57 or Ringers before drinking alcohol for five days, while a third group was injected with FLA-57 before exposure to intragastrically intubated (untasted) alcohol in amounts identical to those in the tasted group. Results showed that only the FLA-57 group that tasted alcohol reduced subsequent voluntary alcohol intake. When a CTA was precluded, allowing only for an effect due to reduced NE, no reduction was observed. This suggests that FLA-57 reduces VAI, not via reduced NE levels, but by a conditioned taste aversion. A second study, utilizing saccharin instead of alcohol, generally supported this conclusion. While these results support a CTA explanation, it is possible that under other conditions FLA-57 might produce a central pharmacological effect.     

溴氰菊酯对染毒孕鼠仔鼠生长发育的影响及中药干预作用

目的:观察溴氰菊酯(DM)雌性大鼠孕期染毒对子代生长发育的影响及补肾健脾复方助孕3号对DM发育毒性的干预作用。方法:将妊娠大鼠分为对照组及3个染毒组,染毒组自妊娠第1~15天经口灌服1/20LD50DM(6.93 mg/kg),另灌服生理盐水、成人等效剂量中药液及牛磺酸溶液(0.2 g/kg)。待孕鼠分娩后观察仔鼠不同时点的体格发育及生长发育情况。结果:DM染毒各组仔鼠在不同时点的体重、身长均显著低于对照组,出毛、张耳、雄性仔鼠睾丸下降时间等生长发育指标也与对照组有显著差异。但各组性别比无显著性差异。结论:溴氰菊酯具有发育毒性,可通过胚胎胎盘转运,对子代的生理发育产生不良影响,但不影响子代性别;等效剂量的中药和牛磺酸不能有效干预溴氰菊酯的发育毒性。     

Do rat strain differences in ethanol consumption reflect differences in ethanol sensitivity or the preparedness to learn?

Three strains of rats (Wistar, Sprague-Dawley, Long-Evans; n = 10/strain) were trained to drink various concentrations of ethanol (ETOH) in the rats' home cage in daily 30-min drinking sessions using a modified “Samson” sucrose-fading procedure. Wistar and Sprague-Dawley rats were similar in their voluntary intake of a wide range of ETOH concentrations and both of these strains drank considerably more ETOH than the Long-Evans strain. For comparison purposes only, pharmacological pretreatment tests were later conducted with the Sprague-Dawley strain of rats using a maintenance concentration of 20% w/v ETOH. Low-dose ETOH pretreatments increased (125% of control), and high-dose ETOH pretreatments decreased the subsequent voluntary consumption of ETOH. Low-dose nicotine pretreatments increased ETOH consumption to 148% of control intake, and high doses of nicotine decreased ETOH consumption. Both opiate antagonists, naloxone and naltrexone, produced dose-dependent decreases in ETOH consumption. The dopamine antagonist, haloperidol, produced dose- and time-dependent increases in voluntary ETOH consumption. The strain differences in voluntary ETOH consumption described in the present study differ from those previously described by other labs. We suggest that this strain-dependent disparity between laboratories, with respect to ETOH consumption/preference tasks, may reflect genetic differences in the preparedness to condition (learn) voluntary ETOH consumption rather than genetic differences in ETOH's reward/reinforcement attributes.     

Prenatal ethanol exposure leads to greater ethanol-induced appetitive reinforcement

Prenatal ethanol significantly heightens later alcohol consumption, but the mechanisms that underlie this phenomenon are poorly understood. Little is known about the basis of ‘this effect of prenatal ethanol on the sensitivity to ethanol’s reinforcing effects. One possibility is that prenatal ethanol exposure makes subjects more sensitive to the appetitive effects of ethanol or less sensitive to ethanol’s aversive consequences. The present study assessed ethanol-induced second-order conditioned place preference (CPP) and aversion and ethanol-induced conditioned taste aversion (CTA) in infant rats prenatally exposed to ethanol (2.0 g/kg) or vehicle (water) or left untreated. The involvement of the κ opioid receptor system in ethanol-induced CTA was also explored. When place conditioning occurred during the ascending limb of the blood–ethanol curve (Experiment 1), the pups exposed to ethanol in utero exhibited greater CPP than untreated controls, with a shift to the right of the dose–response curve. Conditioning during a later phase of intoxication (30–45 min post-administration; Experiment 2) resulted in place aversion in control pups exposed to vehicle during late gestation but not in pups that were exposed to ethanol in utero. Ethanol induced a reliable and similar CTA (Experiment 3) in the pups treated with vehicle or ethanol during gestation, and CTA was insensitive to κ antagonism. These results suggest that brief exposure to a moderate ethanol dose during late gestation promotes ethanol-mediated reinforcement and alters the expression of conditioned aversion by ethanol. This shift in the motivational reactivity to ethanol may be an underlying basis of the effect of prenatal ethanol on later ethanol acceptance.