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.     

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.     

Monkey motor stimulation and altered social behavior during chronic methadone administration

To assess the effects of chronic methadone administration on locomotor, social, and eating behavior of drug-naive individuals under circumstances approximating those of methadone maintenance clinics, we gave single, daily oral doses of methadone to 5 Macaca radiata monkeys living in a social group. We obtained motor activity counts automatically during 6 weeks of baseline, 10 weeks of drug administration, and 3 weeks of post-drug abstinence. Social behaviors of association, dominance, submission, and sexuality were counted 5 days per week, and animal weights, food eaten, and food-reinforced work were recorded. Plasma methadone levels were near those achieved in methadone clinics. Methadone produced mixed stimulation and sedation in the daytime, with stimulation predominating for 4 hrs following administration. At night the subjects moved less while taking the drug. Associative behaviors were reduced by methadone, but dominance, submission, and sexual behaviors were not altered. The monkeys ate less while taking the drug, losing weight and working less for food. In these primates methadone had significant stimulant properties, impaired important social behaviors, and reduced the potency of food as a reinforcer of work. The results are compared with methadone's effects upon humans.     

Behavioral effects in rhesus monkeys of repeated intravenous doses of δ-9-tetrahydrocannabinol

In two separate experiments effects were evaluated of chronic administration of -9-THC (i.v.) on the behavior of rhesus monkeys trained on a multiple schedule of food reinforcement and a shock avoidance schedule. Rapid tolerance to drug effect was observed on avoidance responding; but only partial tolerance on food reinforced responding. Only a minor degree of tolerance was noted on gross behavior. In both experiments, tolerance to the drug carried over a 30-day drugfree period.Research supported by NIMH grant MH 19651.     

Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in non-deprived male rats were investigated. Low doses of 8-OH-DPAT (15–60 g/kg) significantly increased food intake, without affecting drinking, grooming, rearing or locomotion. Microstructural analysis of the elicited feeding behaviour revealed that the rate of eating after 8-OH-DPAT treatment was very similar to that previously reported following 16 h food deprivation. Higher drug doses (250–4,000 g/kg) also elicited feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e. forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15–60 g/kg 8-OH-DPAT. The induction of feeding by a serotonin agonist appears paradoxical, since drugs which enhance brain serotonergic activity usually inhibit feeding.     

The effect of midazolam and β-carboline carboxylic acid ethyl ester on behaviour,steroid hormones and central monoamine metabolites in social groups of talapoin monkeys

Established social groups of talapoin monkeys show rank-related differences in aggressive, social and sexual behaviours and visual monitoring, as well as in endocrine and monoamine profiles. Here we describe the effects on these variables of an anxiogenic drug, -carboline carboxylic acid ethyl ester (-CCE), and an anxiolytic drug (midazolam) given to either dominant or subordinate male talapoins. In dominant animals -CCE increased aggression and visual monitoring but reduced sexual behaviour. Treatment of subordinate animals with -CCE served only to increase visual monitoring. Conversely, treatment with a non-sedative acute dose of midazolam in dominants reduced aggressive behaviour and increased sexual behaviour, whereas in subordinates no behavioural changes were noted. Significant effects on endocrine and neurochemical variables were not seen with the acute drug treatments employed. Nevertheless, the results show that drugs which modulate anxiety produce status-dependent behavioural effects.     

Sociopharmacology of d-amphetamine in Macaca arctoides

This study was designed to assess the effects of acute d-amphetamine pretreatment on the social behavior of a heterosexual group of adult M. arctoides. The dominance status had been previously determined by use of daily group food competition tests. Prior to some sessions amphetamine was administered to a single group member; whereas on other occasions all subjects were drug treated. The effects of both the individual and concurrent pretreatments were compared to those produced by saline. Furthermore, the effects of individual treatment were compared to those following concurrent dosing. The behavior of the group was monitored for one hour after a fifteen minute pretreatment time. Although generally qualitatively similar, the effects of concurrent and individual treatment were in many instances quantitatively different. d-Amphetamine increased vocalization, self-grooming, playing (low doses), social grooming (low doses), and aggression (low doses). At higher doses most forms of social interaction (playing, social grooming) were greatly decreased. Presenting behavior was increased by all doses under both treatment conditions. Mounting was increased to a much lesser extent and only after concurrent dosing. The increased presenting and mounting may be a result of sexual stimulation or perhaps more likely, an indication of increased submissive behavior directed toward more dominant animals.     

Long-term l-Dopa pretreatment of mice: Central receptor subsensitivity or supersensitivity?

The effect of d-amphetamine added to the drinking water on the rate of conditioned lever pressing by rats was determined using fixed-ratio 30 (FR-30) and fixed-interval 2-min (FI-2) schedules of food presentation. After 32 days of gradual increase in drug concentration the average drug ingestion was 13 mg/kg/day. In tests with various doses of d-amphetamine injected before and after the chronic ingestion regimen, the rate-decreasing effects of d-amphetamine on FR responding were attenuated after chronic treatment, indicating development of a two- to three-fold tolerance. However, the rate-decreasing effect of d-amphetamine on FI responding was not altered by chronic ingestion. Since acute amphetamine treatment reduced the reinforcement frequency under the FR but not the FI schedule, these results are consistent with the hypothesis that a behavioral tolerance will develop most readily to drug effects that decrease the frequency of reinforcement. Upon removal of d-amphetamine from the drinking water there was some increase in the rate of FR responding, but no change in FI responding.     

Effects of chronic d-amphetamine on social behavior of the rat: Implications for an animal model of paranoid schizophrenia

Hooded rats in a social colony were given increasing daily doses of d-amphetamine up to 8 mg/kg. Time-lapse 16 mm cinematographically recorded behavior was analyzed for the following: grooming, feeding, sex, sleeping, resting, stereotypy, agonistic behavior, muricidal activity, and the location and movement of each rat. Subordinant rats receiving d-amphetamine actively withdrew from social interactions by retreating to strategically defensible locations in the environment. They remained hypervigilant of other rats and overreacted to their approaches by either fleeing or by defensively rearing and boxing. On the other hand, when the dominant rat received the maximum dose, it seemed totally oblivious to the other rats. The responses to drug treatment in subordinant rats may provide a model for the social behavior of frightened paranoid schizophrenics.NIMH Research Scientist awardee MH 1759     

Differences in D2 dopamine receptor availability and reaction to novelty in socially housed male monkeys during abstinence from cocaine

Rationale

Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration.

Objective

The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object.

Materials and methods

Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes ～270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [¹⁸F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys.

Results

During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object.

Conclusions

Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty—a personality trait associated with low vulnerability to cocaine abuse.     

Alteration of the disruptive effect of fenfluramine on food consumption in the rat by repeated post-session administration of d-amphetamine

The purpose of this study was to determine whether repeated treatment (15 days) with d-amphetamine (AMP) or fenfluramine (FEN), administered after a daily 3 h feeding session (e. g. post-session), would result in tolerance or crosstolerance to the decrement in food consumption induced by treatment with either drug before feeding (e. g. pre-session). Groups of male rats were treated IP with 0.5 ml saline, 1.0, 2.0, or 4.0 mg/kg AMP, or 2.5, 5.0, or 10.0 mg/kg FEN prior to a 3 h feeding session. For the next 15 sessions, the respective groups were treated post-session with saline (0.5 ml), AMP (4.0 mg/kg), or FEN (10 mg/kg). Following the 15 day postsession phase, each group again received this pre-session treatment. The initial pre-session treatment with all dosages of these two drugs produced a significant decrease in food consumption. Tolerance to the food intake suppressant effect of FEN, but not AMP, resulted from repeated post-session treatment with the same agent. Repeated post-session treatment with AMP resulted in a significant decrement in the suppressant activity of FEN on food intake, whereas the corresponding post-session treatments with FEN did not alter the pre-session effects of AMP, except for an enhancement seen with higher AMP doses.     

Acute and chronic effects of δ9-tetrahydrocannabinol on food intake by rats

The effects of intraperitoneally injected ⁹-tetrahydrocannabinol (THC) were compared with d-amphetamine sulfate (d-AMP) on food intake in rats which were given access to food for 6 hrs each day. Food intake was markedly reduced in a dose-related fashion by THC (2.5 and 5.0 mg/kg) in the first 2 hrs after drug administration. This anorexic effect persisted for the next 4 hrs and even on the next day. The anorexic potency of d-AMP (1.25 and 2.5 mg/kg) was approximately twice that of THC in the initial 2-hrs interval after a single dose, but during the next 4 hrs and on the next day there was a compensatory increase in food consumption. Daily administration of THC (2.5 mg/kg) for 9 days greatly decreased food intake and body weight gain of animals which were injected immediately before feeding, but had little effect on animals injected 16 hrs before feeding.     

Hashish extract impairs retention of defeat-induced submissive behavior in mice

The effects of hashish extract on adaptive behavior of male mice were studied in a paradigm which allows the investigation of learning mechanisms in a social context. Mice of the C3H strain, which were not submissive in a confrontation with a nonaggressive DBA mouse on day 1, were defeated on day 2 over 3 min by aggressive, isolated DBA mice, and showed conditioned submissive behavior upon mere contact with a nonaggressive DBA mouse on day 3. A hashish extract containing 38.6–39.4% ⁹-tetrahydrocannabinol ( ⁹-THC), 11.6–12.0% cannabinol and 47.7–48.5% cannabidiol was administered orally in all experiments. Hashish extract given 90 min before defeat on day 2, in dosages corresponding to 1, 5, and 10 mg ⁹-THC/kg, impaired retention of defensive upright, defensive sideways and immobility on day 3 (experiment 1). Experiment 2 showed that the drug (5, and 10 mg ⁹-THC/kg) had no antinociceptive potency in mice and did not modify defeat-induced analgesia. Experiment 3, with drug (5 mg ⁹-THC/kg) or solvent administration on day 2 and day 3, showed that the retention deficit was neither due to state-dependent learning, nor to impaired retrieval. It is suggested that hashish extract administered before learning may interfere with memory processing.     

δ9-Tetrahydrocannabinol: Effects of route of administration on onset and duration of activity and tolerance development

Pigeons trained to key-peck for food reinforcement on a VI 3, were injected either orally, intramuscularly, or intravenously with ⁹-tetrahydrocannabinol and the onset and duration of this drug were determined. Onset of action was much faster for the intravenous route than the other two routes. Speed of and duration of effect were also affected by drag dosage. Using the same methods, the development of tolerance to the behavioral effects were investigated. Tolerance occurred with all three routes at about the same rate.     

Individual differences in the effects of environmental stimuli on cocaine choice in socially housed male cynomolgus monkeys

Rationale

Studies in laboratory animals have demonstrated an influence of environmentally derived stress and enrichment on the reinforcing effects of stimulants.

Objective

To characterize the effects of acute exposure to ethologically valid environmental stimuli on the reinforcing strength of cocaine relative to food in socially housed monkeys.

Materials and methods

Choice between cocaine and food was assessed in subsets of 16 socially housed (4/pen) male cynomolgus monkeys immediately after the following manipulations: (1) treats placed in home cage, (2) a 10-min exposure to a rubber snake, or (3) 3 to 7 days of living in a larger environment without cage mates.

Results

Placing treats in the home cage shifted the cocaine dose–response curve to the left in five monkeys tested and to the right in 4 of 12 animals. The rubber snake significantly shifted the cocaine choice curve to the left in dominant monkeys. Exposure to an enlarged environment decreased cocaine choice in 9 of 15 monkeys; this effect was transient and not related to social rank. Repeated testing did not affect cocaine choice.

Conclusions

Brief exposure to environmental events hypothesized to be stressors or enrichment altered cocaine choice, although not all individuals were affected and the effects were transient. Importantly, the data suggest that implementing positive changes in the environment produced effects that are clinically desirable. Understanding the behavioral and neurobiological mechanisms mediating sensitivity to environmental events in socially housed animals will lead to better treatment strategies for drug addiction.     

Amnesic effects and subjective ratings during repeated dosing of flunitrazepam to healthy volunteers

Summary Flunitrazepam (1 mg) or placebo was administered once daily over a treatment period of 8 days to healthy, male volunteers to study the time course of the effects on memory functions and on subjective ratings of alertness and tension. The plasma level of flunitrazepam increased by approximately 40% (P<0.05) during the treatment period. The mean pre-dose level of flunitrazepam on day 4 and day 8 was approximately 0.005 M, and no residual effects on memory functions were observed. Intake of flunitrazepam decreased the number of freely recalled words by about 85% (P<0.05) and significantly affected the subjects' rating of attention when tested during the first few hours after drug intake on day 1 of treatment. However, no significant effect on the subjects' rating of relaxation was observed. When tested similarly after 8 days treatment, flunitrazepam significantly affected the subjects' rating of relaxation (P<0.01). Furthermore, no tolerance developed for the effect of flunitrazepam on free recall (P>0.3) and the subjects' rating of attention (P>0.7), and these effects had nearly equal time courses during the treatment period. This may indicate that the amnesic effect of benzodiazepines is at least partially mediated through the effects on attention or general arousal. Two of the subjects in the active drug group reported adverse reactions or incidents of discomfort during the 1st week following the treatment period, whereas none in the placebo group reported such reactions.     

Cannabinol and cannabidiol exert opposing effects on rat feeding patterns

Rationale

Increased food consumption following ?⁹-tetrahydrocannabinol-induced cannabinoid type 1 receptor agonism is well documented. However, possible non-?⁹-tetrahydrocannabinol phytocannabinoid-induced feeding effects have yet to be fully investigated. Therefore, we have assessed the effects of the individual phytocannabinoids, cannabigerol, cannabidiol and cannabinol, upon feeding behaviors.

Methods

Adult male rats were treated (p.o.) with cannabigerol, cannabidiol, cannabinol or cannabinol plus the CB₁R antagonist, SR141716A. Prior to treatment, rats were satiated and food intake recorded following drug administration. Data were analyzed for hourly intake and meal microstructure.

Results

Cannabinol induced a CB₁R-mediated increase in appetitive behaviors via significant reductions in the latency to feed and increases in consummatory behaviors via increases in meal 1 size and duration. Cannabinol also significantly increased the intake during hour 1 and total chow consumed during the test. Conversely, cannabidiol significantly reduced total chow consumption over the test period. Cannabigerol administration induced no changes to feeding behavior.

Conclusion

This is the first time cannabinol has been shown to increase feeding. Therefore, cannabinol could, in the future, provide an alternative to the currently used and psychotropic ?⁹-tetrahydrocannabinol-based medicines since cannabinol is currently considered to be non-psychotropic. Furthermore, cannabidiol reduced food intake in line with some existing reports, supporting the need for further mechanistic and behavioral work examining possible anti-obesity effects of cannabidiol.     

Amphetamine pretreatment facilitates appetitive sexual behaviors in the female rat

Rationale

Intermittent treatment of rats with psychomotor stimulants induces behavioral sensitization to their motor-stimulating effects. This sensitization involves an increase in mesolimbic and nigrostriatal dopamine release, and in male rats, facilitates sexual behavior.

Objectives

The aim of this study is to investigate the effect of repeated injections of d-amphetamine on appetitive and consummatory sexual behaviors in female rats.

Materials and methods

Sexually experienced or naïve females were injected with either d-amphetamine (1 mg/kg, i.p.) or saline every other day for three injections each. After each amphetamine injection, females were placed either in a bilevel testing chamber or in their home cages. After saline injections, females were placed in bilevel chambers. Following a 3-week washout period, females were tested for sexual behavior in bilevel chambers in a drug-free state.

Results

Amphetamine pre-exposure facilitated the display of solicitations, hops and darts, and female–male mounting (FMM), regardless of whether the drug was paired with the testing environment.

Conclusion

Intermittent amphetamine pretreatment that induces behavioral sensitization facilitates appetitive sexual behaviors in female rats, as has been shown previously in male rats. This suggests that the physiological substrates that modulate sensitized responses to psychomotor stimulants also mediate sensitized appetitive responses to sexual cues, including solicitation, hops and darts, and FMM. As in male rats, this facilitation was a direct consequence of amphetamine sensitization and not due to conditioned associations between drug and test environment.

     

Nonparametric tests of conditional treatment effects with an application to single‐sex schooling on academic achievements

We develop a general class of nonparametric tests for treatment effects conditional on covariates. We consider a wide spectrum of null hypotheses regarding conditional treatment effects, including the following: (a) the null hypothesis of the conditional stochastic dominance between treatment and control groups; (b) the null hypothesis that the conditional average treatment effect is nonpositive for each value of covariates; (c) the null hypothesis of no distributional (or average) treatment effect conditional on covariates. The test statistics are based on L₁‐type functionals of uniformly consistent nonparametric kernel estimators of conditional expectations that characterize the null hypotheses. We show that our tests using the standard normal critical values have asymptotically correct size. We also show that the proposed nonparametric tests are consistent against general fixed alternatives and have non‐negligible powers against some local alternatives to the null hypothesis with inequality constraints and local alternatives to the null hypothesis with equality constraints, where h is a bandwidth, n is the sample size and d is the dimension of continuous covariates. We illustrate the usefulness of our tests by applying them to the effect of single‐sex schooling on academic achievements using Korean data.     

CSF 5-HIAA and aggression in female macaque monkeys: species and interindividual differences

Rationale: While the relationship among CSF 5-HIAA, impulsivity, and aggression is well characterized in males, its investigation in females is limited, and no studies have assessed its generalizability across primates by making simultaneous comparisons between and within closely-related species. Objectives: We tested three hypotheses. First, that female rhesus macaques would have lower CSF 5-HIAA concentrations and be more aggressive than would female pigtailed macaques. Second, that females of both macaque species would exhibit an inverse relationship between interindividual differences in CSF 5-HIAA concentrations and rates of severe aggression. Third, that subjects with high CSF 5-HIAA concentrations would be higher in social dominance within their respective groups than would subjects with low CSF 5-HIAA concentrations. Methods: We obtained CSF samples from 61 individually housed female primates of two closely related species: rhesus macaques (Macaca mulatta) and pigtailed macaques (Macaca nemestrina). We later placed subjects in unisex social groups, and correlated interindividual differences in CSF 5-HIAA with aggression, wounding, and acquisition of social dominance rank. Results: Between-species analyses indicated higher CSF 5-HIAA concentrations in pigtailed macaques, and higher rates of high-intensity aggression, escalated aggression, and wounds requiring medical treatment in rhesus macaques. Within-species analyses indicated that interindividual differences in CSF 5-HIAA concentrations were inversely correlated with escalated aggression and positively correlated with social dominance rank. Conclusions: These findings show that agonistic and social differences between closely-related species are correlated with CNS serotonin activity, as species that show relatively high rates of severe aggression also tend to have low concentrations of CSF 5-HIAA. We conclude that serotonergic functioning plays an important role in controlling impulses that regulate severe aggression and social dominance relationships in both male and female primates, and that between-species differences in agonistic temperament can be predicted by species typical CNS serotonin functioning. Received: 30 December 1998 / Final version: 3 June 1999