The effects of morphine in the consummatory contrast paradigm

Rats shifted from 32% to 4% sucrose show a negative contrast effect, licking significantly less than animals that receive only 4% sucrose. The effects of morphine sulfate (0.5, 1.0, 2.0, 4.0, 8.0, and 16.0 mg/kg) on negative contrast were investigated in four experiments. Contrast was reduced on both the 1st and 2nd postshift day by the 4.0 and 8.0 mg/kg doses, but the effects were less robust than those seen with the benzodiazepines. The effects of morphine on contrast were dissociable from simple increases in sucrose consumption. Naloxone (0.25, 0.5, and 1.0 mg/kg) had no effect on contrast or sucrose intake. However, the contrast-reducing effect of morphine (4.0 mg/kg) was blocked by pretreatment with naloxone (0.50 mg/kg). The results are discussed in terms of other anxiolytic screening paradigms that have obtained “partial anxiolytic effects” using morphine.     

Effects on splenic, hepatic, hematological, and growth parameters following high-dose poloxamer 407 administration to rats

The nonionic surfactant poloxamer 407, NF (PIuronic ^® F-127, NF) has previously been shown to produce marked hyperlipidemia in rats at a dose of 1.5 g/kg for greater than 96 h following a single intraperitoneal (i.p.) injection (Wout et al. J. Parenter. Sci. Technol., 46 (1992) 192–200). In an effort to characterize any potential toxicity of the polymeric vehicle to various organ systems in the rat following multiple i.p. injections, a dose of 0.33 g/kg per day (10% w/w solution) or 1.0 g/kg per day (30% w/w solution) of poloxamer 407 was administered once daily for 4 consecutive days. When compared to control (non-injected) animals, rats injected with 0.33 g/kg per day of poloxamer 407 did not show a significant (p > 0.05) increase or decrease in spleen, liver, or total body weight. A complete blood count (CBC) with a white blood cell (WBC) differential was performed on blood samples collected on day five from rats injected with poloxamer 407 at both doses. The CBC with WBC differentia] was conducted to assess any changes in the WBC count, percent lymphocytes (LY), percent monocytes (MO), percent granulocytes (GR), red blood cell (RBC) count, hemoglobin (HGB), percent hematocrit (HCT), and the mean corpuscular volume (MCV) following administration of poloxamer 407. Rats injected i.p. with a dose of 0.33 g/kgper day of poloxamer 407 for 4 days demonstrated a significant (p < 0.05) increase in the number of MO when compared to controls. Administration of 1.0 g/kg per day of poloxamer 407 to rats for 4 days demonstrated distinct splenomegaly when compared to non-injected control animals. In addition, a significant (p < 0.05) reduction in body weight and significant (p < 0.05) decrease in the percent LY, RBCs, HGB, and percent HCT were noted. Lastly, a significant (p < 0.05) increase in the number of WBCs and the percent MO was observed in this same group of rats. However, rats administered 1.0 g/kg per day of poloxamer 407 for 4 days were observed to have no detectable changes in the values of the MCV, the percent GR, or liver-to-body weight ratio when compared to control animals. Thus, repetitive i.p. injections of poloxamer 407 to rats at a dose of 1.0 g/kg per day for four days results in splenomegaly and a reduction in total body weight. Splenomegaly in rats administered poloxamer 407 at a dose of 1.0 g/kg per day resulted from red pulp expansion due to infiltration of macrophages which contained phagocytized lipids.     

Effect of in vivo antiestrogen pretreatment on rabbit atrial chronotropic response to histamine

The chronotropic response (delta rate) to histamine (1.4 to 18 X 10(-6) M) of isolated atria from antiestrogen (tamoxifen)-pretreated immature female rabbit was investigated. Tamoxifen treatment (1.0 and 10.0 mg/kg/day for 14 days) had no significant effect on the delta rate. The Rmax and D1/2max were not significantly different in the two tamoxifen-treated groups compared to the oil-treated (1.0 ml/kg/day for 14 days) control group. Cimetidine (2.8 X 10(-7) M) inhibited the delta rate to histamine in all groups: control, 27%; tamoxifen (1.0 mg/kg), 38%; and tamoxifen (10.0 mg/kg), 28%. Only the low dose of tamoxifen was found to be estrogenic (uterotropic). We conclude that tamoxifen pretreatment, both at estrogen-agonist and estrogen-antagonist doses, is without effect on atrial chronotropic response to histamine.     

Effects of dopaminergic agents on alcohol consumption by rats in a limited access paradigm

The effects of several dopaminergic drugs on alcohol consumption were studied in free-feeding rats using a limited access paradigm. Ascending doses of amphetamine (0.1, 0.3 and 1.0 mg/kg), haloperidol (0.1, 0.3 and 1.0 mg/kg), SKF 38 393 (a D1 receptor agonist – 0.3, 1.0 and 3.0 mg/kg), quinpirole (LY 171 555, a D2 receptor agonist – 0.03, 0.1 and 0.3 mg/kg), SCH 23 390 (a D1 receptor blocker, 0.003, 0.01, 0.03 and 0.1 mg/kg) and spiperone (a D2 receptor blocker, 0.003, 0.01, 0.03 and 0.1 mg/kg) were administered IP to rats approximately 30 min prior to their 1-h per day access to alcohol. Each dose was administered for 5 successive days, and the effects of the drugs were compared to those of respective saline or 0.4% lactic acid solution controls. Although there was an overall significant dose effect of amphetamine on alcohol consumption, no single dose altered alcohol consumption significantly from baseline. SKF 38 393 specifically decreased alcohol consumption at the highest dose of 3 mg/kg. Quinpirole significantly increased water consumption at the highest dose but had no effect on alcohol consumption. The antagonist haloperidol decreased alcohol consumption but only at doses that also reduced water consumption. The specific antagonists SCH 23 390 and spiperone decreased water consumption at the highest doses tested without modifying alcohol consumption. Taken together, these data suggest that dopamine does not play as critical a role in mediating the reinforcing effects of alcohol (insofar as they are reflected by alcohol consumption) as it does in relation to other psychoactive drugs, particularly the psychomotor stimulants.     

Chlordiazepoxide and ethanol additively reduce gustatory negative contrast

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose has been shown to be reduced by chlordiazepoxide (CDP) and ethanol (ETOH). In a previous experiment, doses of 0.75 and 1.0 g/kg ETOH substantially reduced contrast while doses of 0.25 and 0.5 g/kg ETOH were much less effective. In this study, doses of 6 and 8 mg/kg CDP were shown to attenuate the negative contrast effect while smaller doses (2 and 4 mg/kg) influenced contrast to a lesser degree. Evidence for an additive effect of CDP and ETOH on contrast reduction was obtained when 4 mg/kg CDP and 0.5 g/kg ETOH were administered together.     

Evidence for zolpidem-induced hyperphagia, but not anxiolysis, in a successive negative contrast paradigm

Zolpidem is an imidazopyridine which binds to certain benzodiazepine receptor types with varying degrees of affinity. The effect of zolpidem on successive negative contrast was investigated in three experiments. In each experiment, a contrast group was given brief access to 32% sucrose for 10 days, then shifted to 4% sucrose for 2 days; a procedure that elicits anxiety primarily on the second postshift day. One control group was given only 4% sucrose. Experiments 2 and 3 included a 2% sucrose group as an intake rate-dependent control. In Experiment 1, zolpidem (4.0 and 0.5 mg/kg) dose-dependently reduced contrast on the two postshift days. Contrast occurred during the first postshift consummatory burst. Zolpidem prolonged the first postshift burst equally in both shifted and unshifted groups, suggesting a general facilitation of intake masked by a ceiling effect in controls. In Experiment 2, zolpidem's (4.0 mg/kg) anti-contrast action was equivalent to its hyperphagic effect in the 2% control group. Zolpidem prolonged the first postshift burst equally in all three groups, again consistent with general intake facilitation. In Experiment 3, 8.0 mg/kg zolpidem produced an anti-contrast effect not present in 2% controls on both postshift days. This does not appear attributable to anxiolysis, however, as the effect was equivalent during stressful and non-stressful phases of the postshift period, and zolpidem extended the duration of the first postshift burst equally in all three sucrose groups. Thus, unlike benzodiazepines, zolpidem is not anxiolytic in this paradigm.     

The effects of dose and repeated administration on the longer-term hypophagia produced by amphetamine in rats

Rats are hypophagic approximately 1-3 and 13-27 h after receiving amphetamine (2.0 mg/kg). This study examined how these short- and longer-term phases of hypophagia were affected by repeated administration of different amphetamine doses. Throughout eight five-day tests, the rats could lever press for food pellets for 1-hour periods beginning every three hours. On test day 1, the rats were treated with saline, and on test day 3, they were treated with a dose of amphetamine. Across tests, for one group, treatment on day 3 alternated between 0.0 (saline) and 0.5 mg/kg amphetamine; for a second, group treatment on day 3 alternated between 1.0 and 2.0 mg/kg amphetamine; and for a third group, treatment on day 3 was always 1.0 mg/kg amphetamine. The patterns of food intake following day 1 saline and day 3 treatment were compared. Short-term food intake was abolished by 0.5, 1.0, and 2.0 mg/kg amphetamine, and no tolerance was observed to this effect. Longer-term hypophagia was produced by 1.0 and 2.0 but not by 0.5 mg/kg. Tolerance to longer-term hypophagia was seen when 1.0 mg/kg alone was used as the day 3 treatment, but not when 1.0 and 2.0 mg/kg were alternated across tests as the day 3 treatment. Short- and longer-term hypophagia were dissociated by threshold doses for elicitation and by differential tolerance. Occasional receipt of a higher amphetamine dose may sometimes increase the longer-term hypophagia produced by a lower dose.     

注射用辛芍对神经、呼吸、心血管系统影响的实验研究

目的观察不同剂量的注射用辛芍对试验动物神经系统、呼吸系统、心血管系统的影响，为注射用辛芍用药安全提供试验依据。方法小鼠和大鼠静脉注射注射用辛芍低（2．4g／kg）、中（4．8g／kg）、高（9．6g／kg）剂量，观察其对中枢神经系统的影响；麻醉犬静脉注射低（0．5g／kg）、中（1．0g／kg）、高（2．0g／kg）剂量，观察其对呼吸系统、心血管系统的影响。结果注射用辛芍低、中、高3个剂量对神经系统、呼吸系统的影响与给药前及生理盐水（NS）组相比差异无统计学意义；低、中、高3个剂量对收缩压（SAP）、平均动脉压（MAP）、心电图（PR间期、QRS间期、QT间期、T波）的影响与NS组相比差异无统计学意义；但中、高剂量给药后能显著降低麻醉犬舒张压（DAP）和心率（HR）。提示中、高剂量可使动物心率减慢、血压降低，而低剂量对舒张压（DAP）和心率（HR）无显著性影响。结论注射用辛芍在0．5g／kg剂量应用时比较安全．在应用1．0g／kg及2．0g／kg剂量时应当注意其潜在的减慢心率、降低血压的作用。     

Reproductive toxicity of cabergoline in mice, rats, and rabbits

Cabergoline, a new dopaminergic ergot derivative with potent long-lasting prolactin (PRL)-lowering properties, was assessed using standard reproductive studies in the mouse, rat, and rabbit with oral administration. Because of the compound's pharmacologic activity, several aspects remain incompletely explored in the rat, in which prolactin is the luteotrophic hormone. A fertility study in female rats was possible only at very low doses (0.5, 1, and 2 μg/kg/d) because higher doses completely inhibited implantation. In male rats no adverse effects were seen on male reproductive performance or on the offspring at doses up to 320 μg/kg/d given for 10 weeks prior to mating with untreated females. In a developmental toxicity study in rats treated from day 6 to day 15 of gestation at doses (6.25, 12.5, and 25 μg/kg/d) not exceeding the active dose for inhibition of egg nidation (ED₅₀ = 25 μg/kg), a high incidence of total litter loss occurred as a reflection of inhibition of egg nidation at the highest dose, but embryofetal development was not impaired in litters reaching term. An exploratory study at 30 or 1000 μg/kg/d with treatment from day 5 of gestation or later demonstrated that cabergoline did not affect the maintenance of pregnancy at 30 μg/kg/d given from day 7 or later, or at 1000 μg/kg/d given from day 9. Doses of 500, 2000, and 8000 μg/kg/d (treatment from day 6 to day 15 of gestation) did not inhibit egg nidation in mice and showed no adverse effects on intrauterine development Doses ranging from 5 to 8000 μg/kg/d administered from day 6 to day 18 of gestation in the rabbit were associated with maternal effects, including a reduction in body weight gain and food and water intake starting from 500 μg/kg/d and increased reactivity at the highest doses (4000 and 8000 μg/kg/d). Effects on intrauterine development were restricted to a reduction in mean fetal and placental weights at 4000 and 8000 μg/kg/d. In peri- and postnatal studies in rats (treatment from day 15 or 17 of gestation to weaning) cabergoline did not affect fetal development and parturition up to 100 μg/kg/d, but strongly inhibited milk secretion starting from 10 μg/kg/d, thus leaving unexplored the postnatal phase at higher doses. When neonatal rats (born from untreated dams) were treated directly with cabergoline at 10, 30, and 90 μg/kg/d from day 7 to 13 after birth, treatment was well tolerated up to the highest dose tested (90 μg/kg/d). It was concluded that cabergoline did not impair fertility in the male rat, was not teratogenic in mice and rabbits, did not affect the latter phase of gestation or parturition in the rat, and was not toxic when administered directly to neonatal rats.     

Differences in response to the aversive properties and activity effects of low dose ethanol in LAS and HAS selectively bred rats

Rats selectively bred for high alcohol sleep times (HAS) and those that are less affected (LAS) by hypnotic doses (3.0–3.6 g/kg) of ethanol were tested for differential responses to the aversive effects of 1.0 g/kg ethanol in a conditioned place preference task. Likewise, the effects of 0.3–1.0 g/kg ethanol on spontaneous locomotor activity over a 30-min period, as well as the loss of righting reflex with a higher ethanol dose (3.0 g/kg), were determined in these animals. The LAS rats reacted more aversively to 1.0 g/kg during conditioned place aversion testing than the HAS animals and also had a shorter mean sleeping time following 3.0 g/kg ethanol. Furthermore, dose-related depression of spontaneous motor activity was seen in the HAS animals and not in the LAS animals over a 30-min period using doses of 0.3, 0.6, or 1.0 g/kg (10% w/v) ethanol. Taken together, the results indicate that the intoxicating sequelae of high ethanol doses, such as ataxia and sedation, may not be correlated with the aversive effects of low ethanol doses.     

Evaluation of infrequent dosing regimens with (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine (S-HPMPC) on simian varicella infection in monkeys.

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (S-HPMPC) was able to prevent simian varicella infection in African green monkeys inoculated intratracheally with virus. A dose of 50 mg/S-HPMPC/kg administered intravenously was shown to prevent the development of rash, reduce viremia and protect the monkeys from death. The 50 mg/kg dose was effective when treatments initiated on day 2 post-infection (p.i.) was given as ten daily doses of 5 mg/kg, as 10 mg/kg administered on five days on an alternate-day schedule, as two 25 mg/kg doses given on day 2 and on day 7 p.i., or as a single injection of 50 mg/kg on day 2. The single 50 mg/kg dose was also effective when treatment was delayed until four days p.i., but was ineffective when treatment was delayed until six days p.i. The 50 mg/kg dose was not effective when given orally by gavage. No evidence of toxicity was noted in daily clinical examinations, or in frequent hematology and clinical chemistry tests performed during the clinical evaluation of the infection.     

Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys

Acute dependence on and tolerance to heroin and morphine were assessed in rhesus monkeys using measures of respiration. Respiratory frequency (f) and minute volume (V(e)) were measured in monkeys breathing air or 5% CO(2) in air using a pressure-displacement plethysmograph. Cumulative doses of naltrexone (0.0001-1.0 mg/kg, i.m) did not alter these parameters in untreated monkeys. Twenty-four hours after a cumulative dose of heroin (1 mg/kg, i.m.), naltrexone produced an increase in both f and V(e) when monkeys were breathing air or 5% CO(2). Following 1 to 3 days of treatment with heroin (0.5 mg/kg/day, i.m.) or morphine (16 mg/kg/day, i.m.), naltrexone produced an increase in f and V(e) that was related to the dose of naltrexone and the number of days of agonist administration. Two days following termination of heroin administration, naltrexone-induced respiratory stimulation declined and had disappeared completely by the fifth day. In tolerance studies, heroin (0.032-0.5 mg/kg, i.m.) and morphine (1-16 mg/kg, i. m.) were injected cumulatively each day for three consecutive days. These drugs suppressed f and V(e) to nearly the same extent on day 3 as they had on day 1 of administration. These results suggest that dependence to morphine and heroin can be measured under conditions of acute 1 to 3 day administration conditions in primates using f and V(e) as reliable and quantitative indicators of opioid withdrawal. Under these conditions, tolerance does not occur.     

Alcohol, allopregnanolone and aggression in mice

RATIONALE: Aggressive behavior of certain individual animals can be greatly increased when under the influence of low doses of alcohol. One of alcohol's neurochemical actions that may be relevant to alcohol-heightened aggression (AHA) is its positive modulation of the GABA(A) receptor complex. OBJECTIVE: The objective of this study was to investigate whether alcohol interacts with an endogenous modulator of the GABA(A) receptor complex, the neurosteroid allopregnanolone, in stimulating/heightening aggressive behavior. METHODS AND RESULTS: The first experiment was designed to test the hypothesis that neurosteroid modulators of the GABA(A) receptor complex will increase aggression and to compare these effects with alcohol. Male CFW mice were injected with allopregnanolone, alphaxalone (3-30 mg/kg, i.p.), or alcohol (1.0 g/kg, p.o.) 15 min prior to a 5-min confrontation with an intruder. Moderate doses of alcohol and the neurosteroids increased aggression by ca. 50% above baseline; impaired locomotion was seen only at the highest doses. A second experiment compared AHA and ANA (i.e. alcohol-non-heightened aggression) mice by giving allopregnanolone (1-10 mg/kg) with a simultaneous oral injection of alcohol (0.6 or 1.0 g/kg) or water. When administered with water and the 0.6 g/kg dose of alcohol, allopregnanolone increased the aggression of AHA and ANA mice. Administration of the 1.0 g/kg dose of alcohol in ANA mice prevented allopregnanolone-heightened aggression. In AHA mice, addition of allopregnanolone to 1.0 g/kg alcohol dose-dependently reduced alcohol-heightened aggression, suggesting potentiation of alcohol's suppressive effects on aggression. CONCLUSIONS: The neuroactive steroid allopregnanolone appears to play an important role in alcohol-heightened aggression. Moreover, the upward shift of the aggression-heightening effects of alcohol and the downward shift at the maximally effective alcohol dose by allopregnanolone point to a shared mechanism for both positive modulators of the GABA(A) receptor complex.     

A preliminary assessment of the acute and subchronic toxicity profile of phase2: an alpha-amylase inhibitor

Phase2, which has been reported to reduce body weight by its inhibition of a-amylase, was evaluated for toxicity in young adult male and female Wistar rats (10 animals/dose group). Evaluations included mortality, change in body weight, food consumption pattern, organ weight, and other adverse side reactions as well as hematological, biochemical, and histopathological analyses. Acute toxicity was determined after a single dose of Phase2 by oral gavage at doses of 5.0, 1.0, and 0.5 g/kg body weight. Animals were sacrificed on fourteen days after Phase2 administration. Subchronic toxicity was determined by administering Phase2 daily for 90 days to rats, at doses of 1.0, 0.5, and 0.2 g/kg body weight. These animals were sacrificed on day 90. Acute and subchronic administration of Phase2 did not produce any adverse reactions or any significant change in the loss of body weight as compared to untreated controls, organ weight, and mortality. Administration of Phase2 did not alter the hepatic and renal function, and did not produce any change in the hematological parameters and in lipid profile. Subchronic administration produced a reduction in the food consumption after 77 days (1.0 g/kg body weight). These data indicate that acute and subchronic administration of Phase2 did not produce any toxicity to rats as evident from weight change, mortality, and limited biochemical and histopathological analyses.     

The influence of allopurinol and size of dose on the metabolism of phenylbutazone in patients with gout

Summary Administration of allopurinol 300 mg/day produced minimal changes in the disappearance of phenylbutazone in each of five subjects following single doses (6 mg/kg) in clinical range and caused some prolongation (21%, 52%) of drug half-lives in two of six subjects after single small doses (0.5 mg/kg); mean half-life was not significantly altered by allopurinol at either dose level (means of 52 versus 48 at 0.5 mg/kg and 68 versus 70 h at 6 mg/kg). Size of dose altered half-life when phenylbutazone was used alone; three subjects showed considerably longer half-lives at the higher dose (86 versus 47, 91 versus 41, 65 versus 38 h). Allopurinol caused a greater than 50% prolongation of half-lives in two of five subjects who received single 0.5 g doses of probenecid. These preliminary data do not indicate a need to change the dose of phenylbutazone when subjects are receiving allopurinol.     

Discriminative stimulus properties of cocaine,norcocaine, and N-allylnorcocaine

A discriminative stimulus paradigm was employed to train eight male and female Wistar rats to discriminate 5.0 mg/kg cocaine HCl from 2.0 ml/kg saline. Subjects responded in a two bar operant chamber on an FR 30 schedule for food reinforcement. All sessions followed a 10 minute pretreatment with either saline, the training dose of cocaine, four probe doses of cocaine HCl (1.0, 2.5, 7.5, 10 mg/kg), four probe doses of norcocaine (1.0, 2.5, 5.0, 7.5 mg/kg) or four probe doses of N-allylnorcocaine (5.0, 7.5, 10, 20 mg/kg). All probe doses were tested using an extinction procedure. The three highest doses of cocaine generalized to cocaine while the 1.0 mg/kg dose of cocaine generalized to saline. The two highest doses of norcocaine generalized to cocaine while the 2.5 mg/kg dose of norcocaine resulted in 57% responding on the cocaine lever with the 1.0 mg/kg dose generalizing to saline. Only the highest dose of N-allylnorcocaine was found to generalize to cocaine with the intermediate doses resulting in an intermediate level of responding occurring on the cocaine lever. The 5.0 mg/kg dose of N-allylnorcocaine generalized to saline.     

Sensitivity and tolerance to the motor impairing effects of moderate doses of ethanol

The present study assessed sensitivity and the development of tolerance to the motor impairing effects of moderate doses of ethanol, using an oscillating bar task. Adult male Wistar rats were trained for 5 consecutive days to stay on the oscillating bar for 120 s to avoid a 0.5-mA foot shock. On the 5 consecutive test days, animals were injected once a day with ethanol (ip: 1.0, 1.25, or 1.5 g/kg) and tested at 15 min intervals until recovery to the 120 s criterion. On test day 1, rats in the 1.5 g/kg group took significantly longer to recover (81+/-9 min; mean+/-S.E.M.) than did animals in the 1.25 (49+/-9 min) and 1.0 (29+/-5 min) g/kg groups. Tolerance developed to all doses by test day 3, with the 1.5, 1.25, and 1.0 g/kg groups reaching criterion in significantly shorter times (42+/-8, 31+/-5, and 18+/-2 min, respectively), as compared to test day 1. BACs associated with recovery time on test day 3, for the 1.5 g/kg group, were significantly higher than the BACs associated with recovery time on test day 1. The data suggest that the oscillating bar task can be used to measure the acute ataxic effects of ethanol, across a narrow range of moderate ethanol doses, and, as well, the development of tolerance to the motor impairing effects of these ethanol doses.     

Ethoxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH)-inducing potency and lethality of chlorinated naphthalenes in chicken (Gallus domesticus) and eider duck (Somateria mollissima) embryos

The 7-ethoxyresorufin O-deethylase (EROD)- and aryl hydrocarbon hydroxylase (AHH)-inducing potencies and lethalities of a technical preparation of polychlorinated naphthalenes (PCNs) (Halowax 1014, approximate congener ratio: 20% tetrachloronaphthalenes, 40% pentachloronaphthalenes, 40% hexachloronaphthalenes), a mixture of 50% 1,2,3,5,6,7-hexachloronaphthalene and 50% 1,2,3,4,6,7-hexachloronaphthalene (HxCN-mix), and 1,2,3,4,5,6,7-heptachloronaphthalene (HpCN) were studied in chicken (Gallus domesticus) and eider duck (Somateria mollissima) embryos. Mortality and hepatic EROD activity were determined on day 10 of incubation in chicken embryos exposed to various doses of the PCNs via the air-sacs of the eggs on day 7. The HxCN-mix and Halowax 1014 proved to have both embryolethal and EROD-inducing properties, while the HpCN had low EROD-inducing potency and embryolethality. ED₅₀ values for EROD induction by the HxCN-mix and Halowax 1014 were estimated to be 0.06 mg/kg egg and 0.2 mg/kg egg, respectively. Fifty percent of the chicken embryos died (6/12) when given 3.0 mg/kg of the HxCN-mix while a similar dose of Halowax 1014 caused mortality in 4 out of 12 chicken embryos. The dose-response curve for EROD induction by Halowax 1014 exhibited a decline after the maximal level was reached. When Halowax 1014 (1.0 mg/kg egg) was coinjected with 3,3′,4,4′,5-pentachlorobiphenyl (PCB IUPAC #126) (0.1 μg/kg egg) no additive effects on EROD activity were found, but when the same dose of Halowax 1014 was coinjected with a dose of PCB #126, known to cause maximal induction (1.0 μg/kg egg), the resulting EROD activity was lower than that caused solely by 1.0 μg PCB #126/kg egg. These findings indicate that Halowax 1014 has both EROD-inducing and EROD-inhibiting properties. Mortality and EROD and AHH activities were determined on day 18 (chicken) or day 24 (eider) of incubation in embryos exposed to 1.0 mg/kg egg via the yolksac on day 4 (chicken) or day 5 (eider). The HxCN-mix and Halowax 1014 induced AHH and EROD in both chicken and eider, but the induction rates were higher in the eider embryos. The HxCN-mix and Halowax 1014 caused degenerative hepatic lesions and pericardial oedema in the chicken embryos but not in the eider embryos. The most toxic PCNs tested (the HxCN-mix and Halowax 1014) were approximately of the same EROD-inducing potency as previously found for the most toxic mono-ortho-chlorinated biphenyls (Brunstr?m 1990), and 1000 times less toxic and potent as EROD inducers compared with PCB #126 (Brunstr?m and Andersson 1988). HpCN was considerably less toxic and exhibited a low EROD-inducing potency. The chicken embryos were more sensitive to the hepatotoxic effects produced by Halowax 1014 and the HxCN-mix than the eider duck embryos, while the eider embryos were more responsive in terms of EROD and AHH induction. The two HxCNs studied usually make up approximately 1% of the total quantity of PCNs present in Halowax 1014 [when determined with gas chromatography (flame ionization detection)]. Therefore, the relatively high toxic potency of Halowax 1014 cannot be explained by its content of the two HxCNs. Received 7 June 1993/Accepted 15 September 1993     

Evaluation of the Developmental and Reproductive Toxicity of Chlorpyrifos in the Rat

Chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl)-phosphorothioate),an organophosphate insecticide, was evaluated for its potentialto produce developmental and reproductive toxicity in rats followingoral exposure. Pregnant Fischer 344 rats were given doses of0 (corn oil vehicle), 0.1, 3.0, or 15 mg chlorpyrifos/kg/day,by gavage, on Gestation Days 6 through 15. Maternal effectsnoted at the two higher dose levels included decreased cholinesteraselevels at 3.0 mg/kg/day and cholinergic signs (excessive salivationand tremors), decreased cholinesterase levels, and decreasedbody weight gain at 15 mg/kg/day. No maternal effects were apparentat 0.1 mg/kg/day. Although maternal toxicity was observed atthese two higher exposure levels, no developmental effects werenoted at any dose. In a two-generation reproduction study, Sprague-Dawleyrats were maintained on diets supplying 0, 0.1, 1.0, or 5.0mg chlorpyrifos/kg/day. Parental effects included decreasedplasma, and erythrocyte cholinesterase at 1.0 mg/kg/day, anddecreased plasma, erythrocyte, and brain cholinesterase andhistopathologic alterations of the adrenal zona fasciculataat 5.0 mg/kg/day. The histopathologic alterations of the adrenalwere characterized as very slight to slight vacuolation (consistentwith fatty change) in males, and very slight vacuolation and/oraltered tinctorial properties in females. No effects on thereproductive or fertility indices or on the histopathology ofreproductive tissues were observed at any dose level, and noneonatal effects were observed at 0.1 or 1.0 mg/kg/ day in theF1 or F2 litters. Parental toxicity at the high dose was accompaniedby decreased pup body weight and increased pup mortality inthe F1 litters only. These data show that oral administrationof chlorpyrifos to rats at parentally toxic dose levels wasnot embryolethal, embryo/fetotoxic, or teratogenic and did notadversely affect fertility or the function or structure of thereproductive organs. Although effects on neonatal growth andsurvival were observed at a maternally toxic dose level in onegeneration, this effect was not observed in the subsequent generationand, therefore, may not have been related to treatment.     

Incomplete stimulus generalization from a mixture of d-amphetamine and morphine to different doses of the component drugs

Pigeons were trained to discriminate a mixture of 1.8mg/kg morphine plus 1.0mg/kg d-amphetamine from saline, and then tested for generalization to various doses of d-amphetamine and morphine, alone and in combination. The birds discriminated the drug mixture from saline with more than 90% responding on the drug key. The training doses of morphine (1.8mg/kg) and d-amphetamine (1.0mg/kg), as well as lower doses of these drugs, did not reliably generate responding on the drug key when given in combination with saline. Higher doses of morphine and d-amphetamine did generate responding on the drug key, but not as reliably as the training dose combination. Combination of the training dose of morphine with doses of d-amphetamine higher than those in the training dose combination resulted in somewhat less responding on the drug key than that seen with the training dose combination in one bird. These data and those from other experiments where animals were trained to discriminate drug mixtures can be characterized as the net effect of stimuli produced by the component drugs and interactions between the component drugs.