Effects of cocaine and fenfluramine on progressive-ratio performance

Pigeons obtained food on a progressive-ratio schedule that required 8 additional responses for each successive reinforcement. The number of responses in the final completed ratio of the session was defined as the breaking point. When cocaine was administered (IM, 5 min presession), the breaking point increased and then decreased as a function of increasing doses (0.3-10 mg/kg). In contrast, across the same range of doses of fenfluramine, the breaking point only decreased. At doses of each drug that decreased the breaking point, the high running rate of responding was interrupted by pauses. At doses of cocaine that increased the breaking point, the running rate was also disrupted, but the disruption was characterized by lower, irregular rates rather than pausing. The increases in breaking point observed at 3 mg/kg of cocaine were no longer seen when fenfluramine was administered at the same time.     

Effects of prenatal ethanol exposure in C57BL mice on locomotor activity and passive avoidance behavior

The purpose of this study was to examine the long-term behavioral effects of prenatal ethanol exposure in C57BL mice. Pregnant mice received free access to a liquid diet containing 25% ethanol-derived calories (EDC) from gestation days 6 to 18. Control animals were pair-fed an isocaloric 0% EDC diet during the same period of time. An additional control group was included that was maintained on standard lab chow and water throughout pregnancy. At 30 days of age, female offspring were tested for spontaneous locomotor activity in an open field under two lighting conditions (dim or bright illumination). Male off-spring were tested in a passive avoidance task at 25 days of age. The activity results demonstrated that the 25% EDC female progeny were more active than controls. This hyperactivity was observed under both lighting conditions, despite the fact that all groups evidenced suppressed activity when tested under bright lights. With regard to passive avoidance behavior, male EtOH-exposed offspring required a greater number of trials to reach criterion than controls. Additionally, they exhibited shorter latencies to enter the shock-associated chamber after receiving a single shock. Taken together, these results confirm our previous findings and demonstrate that C57BL mice are sensitive to both the deleterious behavioral and morphological consequences of prenatal ethanol exposure.     

Effect of clonidine,amphetamine, and their combinations on the locomotor activity of CD-1 and C57BL/6 mice

Clonidine inhibited the exploratory motor activity of C57BL/6 mice non-habituated to the testing conditions. In CD-1 mice clonidine did not depress exploratory activity but did elevate the basal locomotor activity of animals both non-habituated and habituated to testing conditions. Amphetamine increased the locomotor activity of many C57BL/6 mice and conversely inhibited the locomotion of many CD-1 mice. In both strains, amphetamine in doses up to 2 mg/kg was unable to alter effects produced by clonidine. Results suggest that the locomotor activity of C57BL/6 mice is more sensitive than that of CD-1 mice to drugs affecting the central noradrenergic system.     

Voluntary ethanol drinking in C57BL/6J and DBA/2J mice before and after sensitization to the locomotor stimulant effects of ethanol

RATIONALE: Drug-induced sensitization has been associated with enhanced drug self-administration and may contribute to drug addiction. OBJECTIVES: We investigated the possible association between sensitization to the locomotor stimulant effects of ethanol (EtOH) and voluntary EtOH consumption. METHODS: Mice of the EtOH-avoiding DBA/2J (D2) and EtOH-preferring C57BL/6J (B6) inbred strains were offered the choice of an EtOH solution versus tap water (EtOH-experienced) or just water (Na), and voluntary consumption was measured. Mice from each condition then received repeated EtOH or saline injections, and locomotor responses were measured. Subsequently, all mice were offered the choice of EtOH versus water, and voluntary consumption was again measured. A subsequent study examined relative susceptibility of D2 and B6 mice to EtOH-induced locomotor sensitization. RESULTS: Voluntary EtOH consumption induced locomotor sensitization to an EtOH challenge in B6 mice. D2 mice consumed little EtOH, but developed sensitization with repeated EtOH treatments as expected. EtOH consumption was not altered in EtOH-sensitized D2 mice. Unexpectedly, B6 mice developed significant sensitization, and following sensitization, the EtOH-experienced EtOH-sensitized group consumed more EtOH than their EtOH-experienced salinetreated (non-sensitized) counterparts. In an independent study, B6 mice required between three and five EtOH injections to express sensitization, whereas for D2 mice, between one and three EtOH exposures were sufficient. CONCLUSIONS: Development of sensitization to the locomotor stimulant effects of EtOH may be associated with increased EtOH consumption in mice with high initial avidity for EtOH. In the same mice, voluntary EtOH consumption can also produce behavioral sensitization to the effects of EtOH.     

Effects of naloxone on ethanol induced alterations of locomotor activity in C57BL/6 mice

Ethanol (2 g or 3 g/kg) or water vehicle was injected intraperitoneally into C57BL/6 mice 15 min after injections of naloxone, a narcotic analgesic antagonist, or its saline vehicle. Locomotor activity was monitored for 60 min beginning 30 min (Experiment 1) or immediately (Experiment 2) following the ethanol injection. In both experiments, animals injected with the lower dose of ethanol were more active than controls during the second half of the activity test. Animals injected with the high dose of ethanol were less active than controls during the first half of the activity test but returned to control levels or above during the second half of the test. Naloxone at the doses used injected 45 min prior to the activity test (Experiment 1) did not alter locomotor activity and did not influence ethanol induced activity changes. When injected 15 min prior to testing (Experiment 2), however, naloxone alone produced a transient reduction in activity observed only during the first half of testing. During the second half of testing all animals injected with naloxone had activity levels similar to controls and lower than those of animals injected with ethanol in the absence of naloxone. Hence, it appears that naloxone at a dose and time period which does not alter the locomotor activity of mice is capable of blocking ethanol induced excitatory effects.     

Effects of 6-hydroxydopamine and amphetamine on rat mothering behavior and offspring development

Selective CNS dopamine depletion was produced in neonatal female rats by administration of 6-hydroxydopamine and desmethylimipramine. These rats were subsequently tested as adults for maternal behavior toward their own offspring and received d-amphetamine prior to half of these sessions. The effects of early, selective CNS dopamine depletion and its related developmental disruptions on later care of offspring and response to amphetamine were thereby assessed. Pup retrieval, nest building, crouching, and locomotor behaviors were studied in 6-OHDA + DMI treated mothers while offspring were examined with respect to weight, density of fur, age of eye opening, and shuttlebox avoidance learning. Depletion of brain dopamine to 30% of control concentrations was associated with increased crouching time but with no other differences in caregiving, offspring development, or response to amphetamine. Although profound neonatal depletion of dopamine leads to a variety of disturbances in early life, later maternal behavior is adequate and apparently enhanced. The possible role of compensatory brain mechanisms is discussed. Rat behavior     

The effect of amphetamine on delayed response performance in the monkey

The effect of amphetamine on discrete-trial, visual discrimination where response was permitted simultaneously with stimulus presentations or 0, 1, or 3 sec after stimulus presentation, was assessed in the marmoset. An interaction between dose and delay was observed comprising significantly impaired performance after amphetamine under conditions of longer delay. Results are interpreted in terms of loss of response inhibition and increased distraction and are compared with frontal lobe function in the primate.     

Paternal alcohol exposure and hyperactivity in rat offspring: Effects of amphetamine

Locomotor activity of rat offspring sired by fathers treated with 0, 2 or 3 g/kg of alcohol twice daily was assessed at 21, 42 and 90 days of age. Fathers treated with the two lower doses were pair-fed to those treated with the highest dose. Offspring of nontreated ad-lib fed fathers were also evaluated to determine the possible role of paternal stress associated with intubation and pair-feeding. The behavioral response to amphetamine was also examined in 90-day-old male offspring. Paternal alcohol treatment resulted in increased activity at each age for 3 g/kg offspring compared to pair-fed controls. Ad-lib offspring did not differ from 0 g/kg controls at 21 and 42 days of age. The significant effect of paternal alcohol treatment on offspring activity at 90 days, including a significant linear paternal effect, occurred when all amphetamine-treated groups were pooled. The alcohol × amphetamine interaction was not significant, but a significant linear paternal alcohol × linear amphetamine interaction indicated that the paternal alcohol effect on activity was differentially responsive to amphetamine. Subsequent analysis of this interaction indicated a significant linear paternal alcohol trend only at the high dose of amphetamine. These results corroborate a previous report of increased activity on the part of offspring sired by fathers treated with alcohol. The presence of a differential effect of amphetamine suggests that the paternal effect on activity may be mediated by catecholaminergic activity. The absence of significant differences between ad lib and 0 g/kg pair-fed controls indicates that paternal stress/undernutrition does not significantly affect offspring activity.     

乙醇对嗜酒和非嗜酒小鼠体重和肝脏组织形态的影响

目的比较乙醇对嗜酒和非嗜酒小鼠躯体损害的易感性。方法以近交系C57BL/6J小鼠(嗜酒者)和远交系ICR小鼠(非嗜酒者)为实验动物,采用强制性饮酒程序:饮酒组小鼠饮用乙醇溶液8d,乙醇浓度从3%递增至20%。每天检测小鼠体重、摄食量、饮液量和乙醇摄入量。饮用乙醇期间取小鼠肝脏用组织化学方法观察肝脏组织病理学变化。结果乙醇对嗜酒小鼠体重增长的抑制作用明显强于非嗜酒小鼠。乙醇对两组小鼠的摄食量均有抑制作用,抑制程度无显著差异。乙醇抑制非嗜酒小鼠的饮液量,但对嗜酒小鼠无影响。实验期间两组小鼠的饮酒量相当,但嗜酒小鼠的肝脏损伤更为严重。结论嗜酒小鼠对乙醇毒性作用的耐受性弱于非嗜酒小鼠。     

Effects of acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats

Rationale Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity.Objective The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague–Dawley rats.Materials and methods The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus).Results Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects.Conclusion These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating.     

Effects on the acquisition of conditioned avoidance responses and seizure threshold in the offspring of amphetamine treated gravid rats

Female rats with 30 to 70% of conditioned responses in an avoidance conditioning session in a Warner cage, were treated daily during pregnancy with 0.5 mg/kg of d,l-amphetamine administered subcutaneously. They had been mated with males selected with the same criterion who received no treatment.The control group differed from the treated one in that females received the same volume of saline solution instead of the drug.Teratogenic effects of the drug were not observed and there were no differences in either the age of eyes or vaginal aperture or in growth rate determined by the weekly weight between offspring of treated and control mothers.The pups of amphetamine treated mothers had better acquisition and retention of conditioned avoidance responses than those of control mothers when they were 90 days old but no difference was observed at the age of 45 days.On the other hand, offspring of the treated group had a lower hippocampal seizure threshold than the control group.The relation between the mechanisms of learning and seizure are discussed in connection with potassium release by stimulation in the hippocampus.Established Investigator of the Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina.Fellow of the same Institution.     

Alteration of voluntary ethanol and saccharin consumption by the neurosteroid allopregnanolone in mice

RATIONALE: The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, ALLOP) is a positive modulator of gamma-aminobutyric acid type A (GABA(A)) receptors. Recent findings indicate that ethanol (EtOH) and ALLOP share common mechanisms of action and that ALLOP may modulate some of EtOH's abuse-related effects. OBJECTIVES: The present studies investigated whether ALLOP pretreatment altered voluntary EtOH consumption in male and female C57BL/6J mice, and voluntary saccharin and quinine consumption in male C57BL/6J mice. METHODS: Mice had access to two drinking tubes containing water versus 5% or 10% (v/v) EtOH or a tastant for 2 h each day at the beginning of the dark cycle. Following establishment of stable consumption, animals received 2 days of vehicle followed by 3 days of ALLOP injections (0, 3.2, 10, or 17 mg/kg, IP), immediately prior to EtOH or tastant access. RESULTS: Prior to injection, the 2-h baseline dose of the 10% EtOH solution consumed was 1.31 g/kg (expt 1) or 2.46 g/kg (expt 3) for male and 2.21 g/kg (expt 2) for female mice. Baseline intake of the 5% EtOH solution was 0.60 g/kg for males and 0.75 g/kg for females (expt 5). In males, ALLOP administration significantly and dose-dependently increased consumption of both EtOH solutions during the first hour of availability without affecting water intake. In females, ALLOP did not significantly alter EtOH consumption. Lastly, ALLOP significantly increased saccharin, but not quinine, consumption in males (females were not tested). CONCLUSIONS: ALLOP may increase voluntary EtOH consumption in male mice by altering its reinforcing effects. The lack of significant effect on quinine and water consumption suggests that ALLOP does not simply increase consumption of all fluids.     

Phenobarbital during pregnancy alters operant behavior of offspring in C57BL/6J mice.

Offspring of C57BL/6J injected daily with phenobarbital for the last third of pregnancy responded less than control animals when maintained on various fixed ratio schedules of reinforcement. The response decrement became more pronounced as the schedule demands were increased and was noted in offspring of both sexes. The higest dose (80 mg/kg) was less effective than the 2 lower doses (20 mg and 40 mg/kg) in producing the decrement which may reflect a selection factor due to high neonatal mortality previously reported at this dose. The study provides no evidence of the mechanism mediating the long term behavioral abnormality but does clearly extend the finding of such changes to doses which do not produce increased neonatal mortality or noticeable morphological changes.     

Effects of parachlorophenylalanine and amphetamine on habituation of orienting

Parachlorophenylalanine significantly reduced the orienting response to the first presentation of a tone but did not alter the size of responses to subsequent tone presentations nor the rate of habituation. In contrast amphetamine did not alter the orienting response but significantly impaired habituation. It was concluded that there was little evidence for a serotonergic involvement in behavioral habituation, although a role for the catecholamine system could not be excluded.     

A genetic analysis of the hyperthermic response to d-amphetamine in two inbred strains of mice

A genetic analysis of amphetamine-induced hyperthermia was conducted in inbred mice of the strains Balb/c and C₃H and in their F₁F₂ and backcross generations. The results of biometric analysis indicate that the effect of amphetamine on body temperature is genetically determined. The mode of inheritance characterized by a partial dominance (Balb/C over C₃H strain). However, a possible matermal effect of C₃H can overcome the dominant effect in male progenies and inhibit amphetamine hyperthermic effect.     

Effects of amphetamine on the decrement of performance in avoidance conditioning of guinea pigs

Summary A decrement of avoidance response was observed in guinea pigs during a 100 or 300-trial shuttle-bos avoidance session. Amphetamine was very effective in preventing and in counteracting the performance decrement. The results are discussed in relation to the peculiarities of the level of vigilance of this species.     

妊娠期接触酒精对子鼠视皮质神经元数量的影响

目的探讨酒精对C57BL/6小鼠胚胎发育和视皮质神经元数量的的影响。方法妊娠母鼠酒精灌胃直至小鼠出生;采用苏木精-伊红和Nissl染色法观察P0、P7和P14小鼠视皮质神经元密度(ND)和皮层的厚度(CCT)。结果酒精组出现死胎和畸形。晚期胚胎和新生鼠发现多种畸形,如:小头畸形、无脑儿、脊柱脊髓裂等,畸形的出现率为12%。酒精组视皮质的发育明显滞后于对照组,皮质的分层和神经元的极性紊乱。在酒精实验组出现神经元的缺失。在各年龄组,酒精组视皮质神经元的密度均明显低于对照组(P<0.01),而酒精实验组应见皮质的厚度明显比对照组薄(P<0.01)。结论出生前酒精处理诱导视皮质神经元的缺失,此作用具有剂量依赖性和长时程性效应。     

Naltrexone pretreatment decreases the reinforcing effectiveness of ethanol and saccharin but not PCP or food under concurrent progressive-ratio schedules in rhesus monkeys

 The purpose of this experiment was to determine whether attenuation of ethanol consumption by naltrexone is the result of selective changes in the reinforcing effectiveness of drug and non-drug reinforcers. A range of naltrexone doses (0.1–1.0 mg/kg) was administered for 5 days, and the effects on the reinforcing effects of orally delivered 8% (w/v) ethanol, 0.25 mg/ml phencyclidine (PCP), 0.03% (w/v) saccharin and food were studied in eight rhesus monkeys. Food and liquids were available under independent and concurrent progressive-ratio (PR) schedules (ratio range 8–4096) during daily 3-h sessions. Ethanol-maintained responding was attenuated by 0.3 and 1.0 mg/kg doses of naltrexone, while saccharin-maintained responding was decreased at the 1.0 mg/kg dose. Furthermore, there was a significant linear trend that consumption of available ethanol and saccharin was attenuated dose-dependently by naltrexone. Following 5 days of naltrexone pretreatment, ethanol- and saccharin-maintained responding immediately returned to or exceeded baseline levels. Food- and PCP-maintained responding and intake were not significantly affected by any of the naltrexone doses examined. The decreased break point (BP) values for ethanol and saccharin suggest that their reinforcing effects are mediated through opioid reinforcement mechanisms. The lack of naltrexone attenuation of PCP- and food-maintained responding suggests that these reinforcers: 1) are not sensitive to naltrexone antagonism at the doses examined, 2) are mediated by non-opioid reinforcement mechanisms, and/or 3) have less intrinsic palatability. Received: 13 May 1998 / Final version: 28 July 1998     

Fixed-ratio schedules of oral ethanol self-administration in inbred mouse strains

Previous studies of ethanol reinforcement in BALB/cJ and C57BL/6J mice have shown that over a range of concentrations oral ethanol appeared to serve as a reinforcer only for the C57BL/6J mice. In the previous studies BALB/cJ mice maintained rates of responding for ethanol that only slightly exceeded the rates maintained by the vehicle, water. However, the quantity of ethanol consumed with the continuous reinforcement schedule (fixed ratio one) may have led to pharmacologically significant effects, given the high sensitivity to ethanol of this genotype. The present study tested whether and to what extent ethanol would maintain responding under increasing fixed ratio size in these two strains of mice at ethanol concentrations of 0%, 8%, and 16% (w/v). For the C57BL/6J mice, as fixed-ratio size increased from 1 to 2, 4, and 8, there were almost directly proportional increases in response rate at ethanol concentrations of 8% and 16% (w/v), but not at 0%. Post-session blood ethanol levels confirmed intake of pharmacologically significant quantities. The volume consumed per unit of body weight decreased as fixed-ratio size increased. For the BALB/cJ mice, at no condition did ethanol maintain responding at levels that significantly exceeded vehicle maintained responding. BALB/cJ mice did not differ from C57BL/6J mice as fixed-ratio size was increased during vehicle conditions. These results, along with earlier findings, demonstrate that ethanol can serve as a reinforcer for C57BL/6J mice but not in BALB/cJ mice over a range of schedule conditions. They further support the conclusion that genotype is an important determinant of ethanol reinforced behavior.     

Effects of ethanol on pregnant rats and their offspring

Pregnant rats were intubated with either 1.0 or 2.0 g/kg of ethanol daily throughout gestation. Pair-fed vehicle-treated, and nontreated rats fed ad libitum, served as control groups for ethanol-treated animals. Ethanol treatment reduced food and water consumption and attenuated the gain in body weight of pregnant animals relative to nontreated animals fed ad libitum. Litter size, litter weight, and the mean weight per pup were reduced in both the ethanol-treated and pair-fed control groups. There was no evidence of gross malformations in any of the offspring. Since the reduction in litter size and litter weights did not differ significantly between ethanol-treated and pair-fed controls, the effects of treatment with ethanol appeared to be related to a reduction in maternal intake of calories rather than to the direct effect of ethanol on the developing fetus.There were no significant differences between any of the groups of offspring on one-way shock avoidance learning, water maze escape learning, spontaneous alternation, or brightness discrimination learning in tests beginning at 75 days of age. Thus, at the doses of alcohol used in this study, there was no evidence of behavioral teratogenesis comparable to that reported for higher doses in animals or in man characterized by the fetal alcohol syndrome.