Self-administration of the isomers of pentobarbital and secobarbital by rhesus monkeys

Previous studies have shown that the isomers of pentobarbital and secobarbital have behavioral effects that are qualitatively similar to those of the racemic mixture, but that the S-(-) isomers are more potent than the R-(+) isomers. The present study was designed to compare the reinforcing effects of the isomers of these compounds to those of the racemic mixtures in monkeys experienced in the intravenous self-administration of barbiturates. Rhesus monkeys (N = 3) were prepared with indwelling intravenous catheters and allowed to self-administer racemic pentobarbital in 1-hour sessions under a fixed ratio 5 schedule. When responding was stable, various doses of (+,-) pentobarbital, (+,-) secobarbital and single doses of both isomers of these compounds were substituted for the baseline drug in a mixed order. All of the compounds functioned as positive reinforcers in all monkeys. R-(+) isomer were self-administered at higher rates than the racemic mixtures which were self-administered at higher rates than the S-(-) isomers. The results demonstrate that both isomers of these barbiturates can function as positive reinforcers.     

Overdosage with pentobarbital and secobarbital: assessment of factors related to outcome

Factors related to clinical outcome following acute overdosage with pentobarbital or secobarbital were assessed in a series of 162 patients hospitalized during the period 1962 to 1975. The mean ingested dose was 2 Gm (range 0.2 to 10.0 Gm), and plasma barbiturate concentrations ranged from 2.0 to 72.0 microgram/ml. Serious intoxication was common. Intubation and assisted ventilation were required in 59 per cent of patients, and 23 per cent developed clinically important hypotension. Four patients died, all relatively young females. Multiple regression and discriminant function analyses, performed on a subset of 88 patients for whom complete data were available, indicated that plasma barbiturate concentration and/or ingested dose were the most important correlates of serious intoxication among identifiable variables available on admission. Coingestion of other central nervous system depressants, such as ethanol, had no obvious effect on outcome. The present study suggests that measurement of plasma barbiturate concentrations is of value in identifying patients at risk of developing serious intoxication after overdosage with pentobarbital or secobarbital.     

Effect of sodium pentobarbital on behavioral thermoregulation in rats and mice

In this study on behavioral thermoregulation, male Sprague-Dawley rats were given intraperitoneal (IP) injections of sodium pentobarbital in doses of 0, 1, 5, 10 or 15 mg/kg and male CBA/J mice were given doses of 0, 5, 10, 15 or 30 mg/kg. The animals were immediately placed in a temperature gradient which allowed them to select their preferred ambient temperature (Ta). The preferred Ta of rats increased following an injection of 10 mg/kg sodium pentobarbital, whereas, the barbiturate had no effect on the preferred Ta of mice. In another study, male rats and mice were given sodium pentobarbital in doses of 0, 5, 10 and 15 mg/kg and then placed into a temperature-controlled environmental chamber set at 30 degrees C for mice and 25 degrees C for rats (i.e., their approximate preferred Ta when dosed with sodium pentobarbital). Colonic temperatures were taken one hour after injection. Sodium pentobarbital induced dose dependent hypothermia in rats at 25 degrees C and hyperthermia in mice at 30 degrees C. These data suggest a direct or indirect block of heat gain/conserving effectors in rats treated with sodium pentobarbital which results in hypothermia and an appropriate compensatory selection of a warmer Ta.     

Behavioral effects of hashish in mice

Adult mice were treated from parturition to weaning of their first litter with a hashish extract containing 40% delta 9-tetrahydrocannabinol (delta 9-THC), 45% cannabidiol, 9% cannabinol, and 6% other cannabinoids. Oral administrations of 20 mg delta 9-THC/kg three times a week decreased the weight gain of pups from days 3-6 and 6-10 significantly, resulting in about 15% lower body weights on days 6 and 10 compared with control sucklings. Other parameters of development such as the general appearance of the pups were little affected, except for a slight tendency by day 13, when some additional control pups already had both eyes open. The effects of hashish in sucklings might be caused by drug intake with mother's milk, as well as by a decreased lactation of drugged dams. In addition, our pup retrieving tests at the day 3, 1.5-2 h after the second application of hashish extract, showed a decrease in the mother's locomotive and nonsocial activities and pointed to at least transient impairment of the maternal behavior. By day 10, after the fifth administration of hashish extract, a partial tolerance occurred, with normal care for the young, but still decreased nonsocial activities of the drugged dams. Thus our experiments showed distinct effects of cannabis on mice litters when the parents were drugged postnatally during the period of lactation only.     

Behavioral effects of hashish in mice

The acute and subchronic effects of hashish extract (20mg ⁹-THC/kg) on the behavior of male mice encountering a control partner was studied by ethological methods. A single administration of the extract resulted in general sedation, suppressing all the individual and social activities with the exception of some submissive elements. The locomotive and the overall activity of drugged males was drastically reduced and immobility occurred frequently. After four applications, tolerance to the sedative effects had developed and behavioral drug effects were recognizable. Drugged males showed an increase in nonsocial activities as well as in submissive behavior and flight, whereas social investigation was less frequent. Sexual and aggressive behavior was not significantly affected by the drug and immobility no longer occurred.In spite of behavioral changes after a single or repeated drug treatment, drugged males became dominant in about half the experiments. The nest-building behavior of males was disturbed in the same way after one or four drug applications. Drugged males generally refrained from carrying and working up the nesting material.The acute behavioral effects of hashish extract are compared to those described in previous papers and the difference between acute and subchronic drug effects is discussed.     

Behavioral tolerance to stimulating effects of pentobarbital: A within-subject determination

Squirrel monkeys were trained to press a lever under a multiple schedule of food presentation. In one stimulus condition responses that terminated interresponse times greater than 28 sec were followed by food presentation. In the other stimulus condition, an interval schedule of food presentation was presented that provided approximately the same frequency and distribution of food delivery as that observed under the interresponse-time schedule. Except when it was administered for the first time, 5.6 mg/kg sodium pentobarbital produced reliable increases in responding during the interresponse-time schedule. Behavioral tolerance to the rate-increasing effect was assessed in individual subjects by first administering the drug daily following each session, and then giving it daily before each session. Following post-session drugging, the effects of 5.6 mg/kg were not changed, but tolerance developed when the drug was administered pre-session. The way in which tolerance developed was consistent with the reinforcement-loss hypothesis.     

Behavioral effects of PCBs in mice

A single i.p. administration to mice of Fenclor 54 (PCB) resulted in various behavioral deficits. PCB significantly reduced locomotor activity and exploratory behavior at dosages of 150 and 300 mg/kg. Dose dependent increased latencies were also found at the same dosages in the "traction test" while in the rota rod test the dosage of 300 mg/kg of PCB only caused a significant increase in mean number of falls off the rod. Furthermore daily dietary administration of PCB (1, 10, 100 ppm) to male mice during a 21-day isolation period was inversely proportional to the amount of aggressive behavior shown, and directly proportional to the amount of non-social behavior ("indifference"). This supports former findings reporting anti-androgenic like effects of PCBs.     

Behavioral effects of hashish in mice

Within groups of three adult male mice the acute and subchronic effects of hashish extract (20 mg ⁹ - THC/kg) on social dominance, food dominance, and sexual interactions with a female were investigated. An initial drug treatment of only the dominant male weakened his social position, but dominance was regained after treatment 2 or 3. In contrast, a persistent change in dominance was found when only the male which was dominant in the feeding test was treated with the extract. Simultaneous drug treatment of all three males did not affect the social dominance relationship but resulted in a reversible change in food dominance. The original feeding order was reestablished after drug treatment 3. Upon meeting an estrous female, no male of the group was distinctly dominant in mating. After treatment 1 was given to all members of the group, all types of behavior were impaired and total activity was significantly reduced. After treatment 2, animals showed tolerance to the sedative effects, and after treatment 3, sexual behavior was even more frequent in drugged animals than in controls. The results are discussed in relation to a possible dependence of behavioral drug effects and tolerance development on the experimental situation. Present Address: I.C.I.P.E. Research Centre, PO Box 30772, Nairobi, Kenya     

Behavioral effects of hashish in mice

The acute and subchronic effects of hashish extract (20 mg ⁹-THC/kg) on the social interactions between two drug-treated residents and an untreated intruder male were investigated. In this analysis 28 different behavioral elements were recorded.A single drug application suppressed all categories of behavior, except submissive behavior and flight, in dominant and subordinate residents. Treated animals were less active than controls and immobility was very frequent. An elevated total activity, due to an increase in non-social activities, was observed in the untreated intruder males of this group. Social investigation as well as submissive behavior and flight were reduced in these animals.On introduction of an untreated male after the fourth drug treatment of the residents, the drugged males showed tolerance to the sedative and most of the other behavioral effects of the drug, and intruder males behaved quite normally.The formation of a dominant-subordinate relation within the group was influenced neither by a single nor by repeated drug treatment.The acute and subchronic effects of hashish extract on social, especially aggressive behavior of males are compared to those described in previous papers and the variation in the results of the different studies is discussed.     

Effects of pentobarbital and cocaine in rats expecting pentobarbital

Rats received extensive exposure to pentobarbital in a distinctive environment, and were subsequently tested for tolerance to the sedative effects of pentobarbital either in the distinctive environment or in an environment previously associated only with saline. Rats tested when expecting pentobarbital (i.e., in the usual drug environment) were tolerant, but rats tested when not expecting the drug (i.e., in the saline environment) were not tolerant. These results extend demonstrations of conditional tolerance to the general behavioral arousal effects of a sedative hypnotic. Subsequently, the same rats were administered cocaine either when expecting pentobarbital or when not expecting pentobarbital. Rats administered cocaine when expecting pentobarbital exhibited more intense forms of cocaine-induced behavior than rats administered cocaine but not expecting pentobarbital. These results establish the phenomenon of conditional cross-potentiation between conditional drug states and unconditional drug-effects.     

Behavioral effects of arecoline in rats

Summary Effects of arecoline (0.25–4 mg/kg) were studied on several behavioral schedules in rats. It usually decreased the responses, especially at high doses, in schedules including spontaneous motor activity, FR (water and food) and FI (food) reinforcement, DRL and shock avoidance. Slight enhancement of responses was observed at low doses in spontaneous activity, FR (food) reinforcement, FI reinforcement and shock avoidance. Arecoline methiodide had negligible and insignificant effects.The depressant effect of arecoline (2 mg/kg) in the spontaneous activity schedule could be antagonized by scopolamine (0.25 and 0.1 mg/kg), but not by methylscopolamine (0.5 mg/kg) and mecamylamine (2 mg/kg). On the other hand, arecoline induced behavioral depression under FR water and food reinforcement could neither be antagonized by scopolamine (0.025–0.1 mg/kg) that itself caused depression, nor by mecamylamine (2 mg/kg).Supported by a Grant No. U100472 from the U. S. Public Health Service.     

Comparative inhalation toxicity of ethyltoluene isomers in rats and mice

The C9 alkylbenzenes, composed mostly of ethyltoluenes and trimethylbenzenes, comprise 75–90% of the naphtha fraction of crude oil. Occupational and environmental exposure to C9 alkylbenzenes occur via inhalation. We conducted short-term inhalation studies on the ethyltoluene isomers (2-, 3- or 4-) to select one isomer for more comprehensive studies. Male Hsd:Sprague Dawley rats and female B6C3F1/N mice (n?=?10) were exposed by nose-only inhalation to 2-, 3- or 4-ethyltoluene (0, 1000 or 2000?ppm) or cumene (a reference compound: 0, 500 or 1000?ppm) 3?h/day, 5?days/week, for 2?weeks. Clinical observations included abnormal gait and delayed righting reflex. Rats and mice exposed to 2000?ppm 2-ethyltoluene and mice exposed to 2000?ppm 4-ethyltoluene were euthanized early in moribund condition; no exposure-related deaths were observed with 3-ethyltoluene or cumene. Histopathology of selected tissues revealed that the nose and liver (rats and mice) and lung (mice only) to be toxicity targets. In the mouse lung, all compounds except 4-ethyltoluene produced bronchial and bronchiolar hyperplasia. In rats and mice, 2-ethyltoluene was the only compound to produce lesions in the nose and liver: in mice, squamous metaplasia and neutrophilic inflammation of the respiratory epithelium and atrophy and degeneration of the olfactory epithelium were observed in the nose and centrilobular hypertrophy and necrosis were observed in the liver. In rats, 2-ethyltoluene exposure produced atrophy of the olfactory epithelium in the nose and centrilobular necrosis in the liver. Based on mortality, body weight effects and histopathology, the 2-ethyltoluene isomer was the most potent isomer.     

Behavioral effects of apomorphine isomers in the rat: Selective locomotor-inhibitory effects of S(+)N-n-propylnorapomorphine

The optical isomers of apomorphine (APO) and N-n-propylnorapomorphine (NPA) were evaluated behaviorally in the rat. Both R(-) isomers induced motor-excitatory effects and strong stereotyped sniffing, licking, and gnawing, as has been reported previously. The S(+) isomers selectively inhibited locomotor activity and did not induce stereotypy or catalepsy. These actions of the S(+) aporphines were selective against locomotor activity stimulated by low doses of R(-) isomers. (+)NPA (ID₅₀=0.2 mg/kg) was 20 times more potent than (+)APO (ID₅₀=4 mg/kg) in antagonizing the locomotor arousal-inducing effects of (-)APO (at ED₅₀=0.3 mg/kg). (+)NPA also inhibited spontaneous locomotor activity much more potently (ID₅₀=3.0 mg/kg) than did (+)APO (ID₅₀>50 mg/kg). Neither S(+) aporphine had a significant effect against stereotypy induced by the R(-) isomers, even at high doses (up to 30 mg/kg). Inhibition of the effects of (-)APO by (+)NPA appeared not to be due to altered uptake of (-)APO into brain. These results suggest that S(+)NPA or its congeners and analogs may have selective antidopaminergic actions in limbic rather than striatal areas of mammalian brain.     

Behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rats and mice.

The characteristics of the behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM or STP) were compared with those of mescaline and methamphetamine in rats and mice. DOM significantly increased locomotor activity in an open-field situation at 0.5-1.0 mg/kg i.p., but at doses above 5 mg/kg i.p. caused biphasic changes, i.e. an initial decrease followed by an increase in motility and exploratory behavior. This hyperactivity was not accompanied by simultaneous increase in rearing. Besides, DOM induced head twitches in rats as well as in mice at doses above 0.1 mg/kg i.p., and marked backward locomotion only in rats at doses larger than 5 mg/kg i.p. The occurrence of backward locomotion might be attributable to the initial decrease in general activity. Behavioral effects of DOM were different from those of either mescaline or methamphetamine although they resembled those of mescaline in some respects.     

Hepatic effects of xylidine isomers in rats.

The effect of repeated (4 weeks) oral administration of 2,4-, 2,5- or 2,6-xylidine (at dose levels of 400--500 mg/kg/day) on the morphology and microsomal drug metabolising enzyme activity of the liver was studied in rats. All 3 isomers caused hepatomegaly which was considered to be due to proliferation of the smooth endoplasmic reticulum. Decreases in glycogen content and glucose-6-phosphatase activity were demonstrated histochemically. Biochemical investigations showed increases in microsomal protein and cytochrome P-450 content in rats dosed with 2,4- or 2,5-xylidine and in glucuronyltransferase activity in rats given 2,4-, 2,5- or 2,6-xylidine. Aniline hydroxylase activity was increased in all treated rats except males dosed with 2,6-xylidine. The results of the study indicate that all isomes of xylidine can be inducers of microsomal drug-metabolising enzyme activity, that they may be metabolised by oxidation and that the xylidine molecule may be eliminated as a conjugate with glucuronic acid.     

Behavioral effects of CGS 8216 alone,and in combination with diazepam and pentobarbital in dogs

Beagle dogs (N=3) responded under a multiple fixed-interval (FI) 300 sec, fixed-ratio (FR) 30 schedule of food presentation. The pyrazoloquinoline derivative CGS 8216, given either intravenously (0.01–3.0 mg/kg) or orally (0.1–30.0 mg/kg) had little effect on either the rate or temporal pattern of responding during either component. Both diazepam (0.3 to 17.5 mg/kg, PO) and pentobarbital (0.1–17.5 mg/kg, PO) produced qualitatively similar effects on behavior. Rates of responding during the FI components first increased, then decreased with increasing doses; both drugs produced only dose-related decreases in the rate of responding during the FR components. CGS 8216 antagonized some of the behavioral effects of diazepam; FI and FR response rates returned to baseline, however the effects of diazepam on quarter-life values were not appreciably altered by CGS 8216. The effects of pentobarbital on schedule-controlled responding were not antagonized by CGS 8216. These results indicate CGS 8216 is a selective benzodiazepine antagonist that does not produce benzodiazepine-like behavioral effects.     

Behavioral effects of arginine in male rats

The effects of aminoacid arginine on conditioned and unconditioned behavior were studied in male rats. Arginine was administered orally at different dose levels. Both acute and subchronic (7 days) treatment schedule was performed. Exploratory behavior of the rats was studied in an open field. Acquisition of active avoidance behavior was studied in the shuttle-box test situation, and retention of passive avoidance reaction was studied in a step-through type of passive avoidance behavior. Acute administration of arginine failed to affect the acquisition and the retention of avoidance responses, and exploratory behavior of the rats. A 7-day treatment with the aminoacid caused an increase in ambulation of rats of Wistar strain, and a facilitation of acquisition and retention of avoidance responses in rats of CDR strain with poor learning capacity. It is possible that behavioral effects or arginine depend on its involvement in nucleic acid synthesis.     

Behavioral effects of ethanol inhalation in rats

Behavioral effects of ethanol inhalation were studied on two fixed-ratio (FR) liquid-reinforced schedules and a continuous reinforcement (CRF) schedule intracranial self-stimulation (SS) in rats using the inhalational behavioral chamber designed in our laboratory. In the FR-24 schedule ethanol caused a decrease of reinforcement rate at 161 ppm and higher concentrations. In the FR-50 schedule decreases of the rate were observed at 102 ppm and 203 ppm. In the SS behavior ethanol produced a decrease in the rate of reinforcement at 603 ppm and higher concentrations. In rats of this schedule, blood ethanol concentrations were measured to be 393 micrograms/ml and 545 micrograms/ml after exposure to 600 ppm and 1200 ppm of ethanol respectively. Acute tolerance to ethanol was observed in these experiments, particularly in the FR-24 schedule. Thus ethanol inhalation could produce adequate blood concentrations so as to produce behavioral effects.     

Behavioral effects of amphetamine in streptozotocin-treated rats

Experimentally-induced diabetes can modify the behavioral and neurochemical effects of drugs acting on dopamine systems, possibly through insulin-related regulation of dopamine transporter activity. In this study, several behavioral procedures were used to examine possible changes in sensitivity to amphetamine and other drugs in rats rendered diabetic by a single injection of streptozotocin. Conditioned place preference developed to food (Froot Loops) in both control and diabetic rats, demonstrating that conditioned place preference with tactile stimuli can occur in streptozotocin-treated rats. Baseline locomotion was lower in streptozotocin-treated as compared to control rats, although amphetamine significantly increased locomotion in all rats. Conditioned place preference developed to amphetamine regardless of whether rats had received streptozotocin or saline. A second study compared the potency of drugs to decrease lever pressing maintained by food, before and after streptozotocin treatment. Gamma-hydroxybutyrate and amphetamine were less potent after streptozotocin while the potency of raclopride, quinpirole, ketamine, haloperidol and cocaine was not significantly changed by streptozotocin. While markedly affecting locomotion, body weight and blood glucose, streptozotocin only modestly affected sensitivity to the behavioral effects of amphetamine and other drugs; these results fail to confirm previous reports of decreased behavioral actions of stimulants in diabetic rats.