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

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     

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.     

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.     

Further studies of the aggressive behavior induced by Δ 9-Tetrahydrocannabinol in REM sleep-deprived rats

The aggressive behavior induced by ⁹-tetrahydrocannabinol in pairs of REM sleep-deprived rats was studied in five experiments by measuring dominant and submissive behavioral patterns. When 2 REM-deprived rats received ⁹-THC, one of the animals displayed very aggressive postures, while its partner assumed incomplete defensive postures. The intensity of these behavioral postures was dosedependent. In pairs composed of one REM-deprived rat injected with ⁹-THC and one normal or one REM-deprived partner injected with control solution the deprived/drugged rat showed an aggressive posture and catatonia, or a strikingly bizarre behavior, while the control partner displayed typical defensive postures. The behavioral alterations induced in REM-deprived rats by amphetamine, LSD-25, and pentobarbital failed to provoke defensive postures in the normal rats paired with them; however, apomorphine partially mimicked the ⁹-THC effects.It is concluded that in REM-deprived rats ⁹-THC not only provokes aggressive behavior but also impairs the defensive-submissive behavioral patterns.     

Influence of hashish extract on the social behaviour of encountering male baboons (Papio c. anubis)

The effects of hashish extract (2 mg Δ⁹-THC/kg)on the social behaviour of encountering male baboons were tested by ethological methods. In the “approaching” male the drug reduced “approach” and the aggressive elements “hit-ground”, “brows-back” and “attack” but increased the frequency of “retreat”. Social interactions were generally diminished. In the “retreating” male friendly social interactions as “lipsmack” and “touch-back/handle-genitals” were suppressed but thethreatening elements “open-mouth” and “tooth-grind” were stimulated. “Retreat” was additionally more frequent. Non-social activities and locomotion were not affected in either of the males. Treating both subjects with hashish resulted in a reduction of “lipsmack”, “approach”, “fight” and “chase” in the approaching and “lipsmack”, “touch-back/handle-genitals”, “chase”, “retreat” and “flee” in the retreating male. Social activities were generally reduced in both animals. Comparing the behavioural effects of hashish in male baboons to those described in other non-human primates, in rodents but also in man revealed analogous effects in all species. The drug generally impaired social interactions, induced social withdrawal and led to social isolation of the drugged subject.     

Anxiolytic and antidepressant-like effects of Melissa officinalis (lemon balm) extract in rats: Influence of administration and gender

Objective:

To analyse the behavioral effects of Melissa officinalis extract in rats following acute or subacute treatment.

Materials and Methods:

The behavioral effects of an acute or subacute (10-day course) orally administered M. officinalis (MO; 0, 30, 100 or 300 mg/kg) ethanol extract were evaluated in male and female Wistar rats in elevated plus-maze (EPM), forced swimming (FS) and open field (OF) tests. The effects of diazepam (DZP; 1 mg/kg) and fluoxetine (FXT; 10 mg/kg) were also assessed.

Results:

In the EPM test, the percentage of open arm entries and open arm times of both males and females given the subacute M. officinalis ethanol extract were significantly higher than those of the vehicle-treated animals but were at levels similar to those observed in the DZP group, regardless of the treatment length. In the FS test, immobility duration was significantly lower in both males and females treated with the plant extract when compared to vehicle-treated counterparts. A 10-day treatment with FXT induced the same antidepressant response, regardless of gender, and was more effective than the M. officinalis extract. Male and female rats demonstrated distinct gender profiles, and treatment × gender interactions were observed. Locomotion in the EPM and OF tests was not significantly altered by treatments.

Conclusion:

The potential psychoactive properties of M. officinalis may provide a unique pharmacological alternative for certain psychiatric disorders; however, the efficacy appears to be dependent on both gender and administration length.KEY WORDS: Anxiety, depression, gender, locomotion, Melissa officinalis     

An ethopharmacological assessment of the effects of zuclopenthixol on agonistic interactions in male mice

Zuclopenthixol is a thioxanthene derivative which acts as a mixed dopamine D1/D2 receptor antagonist. Although the antiaggressive action of neuroleptic drugs is well known, the effects of zuclopenthixol on agonistic interactions have not been explored and there are no studies comparing acute and subchronic effects of this compound on aggression in rodents. In this work, we examined the action of zuclopenthixol (0.025-0.4 mg/kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after the drug administration, and encounters were videotaped and evaluated using an ethologically based analysis. After acute treatment, zuclopenthixol (0.2 and 0.4 mg/kg)-treated animals exhibited ethopharmacological profiles characterized by a decrease in offensive behaviors without impairment of motor activity (0.2 mg/kg). In contrast, the antiaggressive action of the highest dose used (0.4 mg/kg) was accompanied by a marked increase of immobility. After subchronic treatment, no tolerance to zuclopenthixol antiaggressive or motor activity was observed. Overall, this behavioral profile is similar to that observed with other typical neuroleptics.     

Alcohol and “bursts” of aggressive behavior: ethological analysis of individual differences in rats

A quantitative ethological analysis of rodent aggression was performed in order to characterize the aggression-heightening effects of alcohol in certain individuals. In dyadic confrontations, a resident rat pursues, threatens and attacks an intruder, who reacts with defensive, flight and submissive behaviors. The behavioral data from five series of experiments conducted from 1984 through 1989 were subjected to a lag sequential analysis that identified highly predictable sequences of aggressive behavior, and to interval analysis that delineated a burst pattern of aggressive behavior. These analyses revealed a distinct behavioral sequence of pursuit sideways threat attack bite aggressive posture that occurs in bursts with an inter-event interval of less than 6.6 s. In the total population, alcohol heightened attack behavior at low acute doses (0.1, 0.3, 1.0 g/kg) in 47% of the animals (n=44), suppressed reliably attack behavior in another 25% (0.1–3.0 g/kg;n=23) and had unreliable effects in the remaining 28% (n=24). The peak enhancement of aggressive behavior was seen over more than a log cycle of alcohol doses (0.1, 0.3 or 1.0 g/kg) in different individuals. In an additional group of rats (n=20), individuals were identified according to whether or not acute low alcohol doses enhanced or suppressed the frequency of attack bites. In the subgroup of five rats who doubled their attack frequency upon acute alcohol challenge, this aggression-heightening effect was confirmed on repeated occasions. The aggression-heightening effects of alcohol were seen during the high-rate interactions in the initial phase of the confrontation and particularly during the lower level of fighting later on. Regardless of alcohol dose and subgroup, the highly predictable sequence of pursuit sideways threat attack bite aggressive posture remained intact as long as the individual was able to fight. The present analysis identifies those individuals in whom low alcohol doses increase the frequency of attack behavior, the number of aggressive elements in bursts and particularly the time in burst. Alcohol produces these changes without altering the latency to initiate aggressive behavior, the rate of aggressive behavior within a burst or the number of bursts in an encounter. Alcohol may lengthen aggressive bursts by preventing termination of longer aggressive sequences rather than by altering the initiation of this behavior.We dedicate this paper to our friend Dr. Milos Krsiak, Professor of Pharmacology, Charles University, Prague, Czechoslovakia     

Opposite effects of pentylenetetrazol on self-defensive and submissive postures in the rat

In a previous work, using the resident-intruder situation, we have shown that a benzodiazepine inverse agonist could exert a fear-promoting effect, in decreasing self-defensive behaviours while increasing submissive postures. To further test this hypothesis, the effects of pentylenetetrazol on different forms of defensive behaviour were examined in male intruder rats confronted with offensive residents. Administration of pentylenetetrazol (10 and 20 mg/kg, IP) increased submissive postures such as immobility and on-the-back, but reduced self-defensive postures. Other active behaviours were not reduced, thus excluding a non-specific behavioural suppression. These results suggest that self-defensive and submissive behaviours can be dissociated and that anxiogenic compounds are more likely to increase submissive behaviours than self-defensive ones.     

Relationship between behavioral and nociceptive changes in attacked mice: effects of opiate antagonists

The relationship between analgesia and behavior during and after an aggressive encounter was investigated in saline- and opiate antagonist-treated DBA mice. A low number of bites induced an analgesia that was reversed by -chlornaltrexamine but not by naloxone, and that correlated positively with increased displays of defensive upright and immobility upon contact with the opponent. Extended attacks induced a naloxone-sensitive analgesia that was linked to a delayed occurrence of panic escape behavior. In the post-conflict phase, the degree of immobility and analgesia correlated positively in attacked mice. Naltrexone prevented this analgesia and lowered immobility. Endogenous opioids released during social conflict may induce analgesia and immobility in DBA mice.     

Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice

Aim:

Aripiprazole is an antipsychotic agent to treat schizophrenia, which acts through dopamine D₂ partial agonism, serotonin 5-HT_1A partial agonism and 5-HT_2A antagonism. This study was designed to evaluate the neurobehavioral effects and genotoxic/mutagenic activities of the agent, as well as its effects on lipoperoxidation.

Methods:

Open field and inhibitory avoidance tasks were used. Thirty min before performing the behavioral tasks, adult male CF-1 mice were administered aripiprazole (1, 3 or 10 mg/kg, ip) once for the acute treatment, or the same doses for 5 d for the subchronic treatment. Genotoxic effects were assessed using comet assay in the blood and brain tissues. Mutagenic effects were evaluated using bone marrow micronucleus test. Lipoperoxidation was assessed with thiobarbituric acid reactive substances (TBARS).

Results:

Acute and subchronic treatments significantly decreased the number of crossing and rearing in the open field task. Acute treatment significantly increased the step-down latency for both the short- and long-term memory in the inhibitory avoidance task. Subchronic treatments with aripiprazole (3 and 10 mg/kg) caused significant DNA strain-break damage in peripheral blood but not in the brain. Mutagenic effect was not detected in the acute and subchronic treatments. Nor TBARS levels in the liver were affected.

Conclusion:

Aripiprazole improved memory, but could impair motor activities in mice. The drug increased DNA damage in blood, but did not show mutagenic effects, suggesting that it might affect long-term genomic stability.     

Learnt tolerance to sedative effects of chlordiazepoxide on self-stimulation performance,but no tolerance to facilitatory effects after 80 days

Sedative and facilitatory effects on variable-interval hypothalamic self-stimulation were monitored during chronic treatment with chlordiazepoxide (CDP; 7.5 mg/kg IP), given at 48-h intervals in two groups of rats. Group 1 was injected immediately before each of 40 1-h self-stimulation sessions (drugged responding); Group 2 was injected after self-stimulation for the first 20 sessions (undrugged responding), and before self-stimulation for a further 20 sessions (drugged responding). Significant sedation occurred in both groups in initial sessions of drugged responding, even though Group 2 had already received 20 injections of CDP (after undrugged sessions). Sedative effects showed very rapid tolerance, and disappeared after 1–3 sessions, but only in rats which had been responding while drugged (and which thus had had opportunities to develop coping strategies against the sedative effects). After further sessions of drugged responding, sedation was replaced by apparently stimulant effects. Stimulant effects showed no tolerance at all in either group even after 40 injections, thus differing from anti-conflict (and other) effects of BZDs, which generally show gradual tolerance. These results show that coping strategies acquired by instrumental learning can account for rapid and selective tolerance to sedative effects. Coping strategies do not account for the differing rates of tolerance to stimulant and to other effects of BZDs; these differences may indicate pharmacologically distinct brain systems downstream from the BZD receptor.     

Simultaneous analyses of the neurochemical and behavioral effects of the norepinephrine reuptake inhibitor reboxetine in a rat model of antidepressant action

Abstract Rationale. The forced swimming test (FST) is a rodent behavioral assay widely used to predict clinical efficacy of putative antidepressants. Few studies have examined the effects of the FST on neurotransmitter levels and how antidepressant drug treatment may alter neurotransmitter levels and behavior simultaneously during the performance of a stressful task. Objectives. The present study examined the role of norepinephrine in mediating active behaviors in the FST after treatment with reboxetine, a selective norepinephrine reuptake inhibitor. Methods. High-pressure liquid chromatography was used to analyze microdialysis samples collected from awake, freely moving rats before, during and after exposure to the FST. Reboxetine (10 mg/kg) was given three times over a 24-h period prior to the test swim. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test on day 1 and day 2. Results. The first exposure to swim stress elicited a 65% increase in extracellular norepinephrine (NE). A second exposure on day 2 elicited a 52% increase of NE and a behavioral profile characterized by increased immobility and a reduction of active behaviors. A subchronic course (three injections over 24 h) of treatment with reboxetine between the two swim exposures resulted in antidepressant-like activity, i.e., decreased immobility and increased climbing behavior on day 2. A significantly greater increase in extracellular NE (112%) was observed in the group of animals that received reboxetine injections. Conclusions. Treatment with reboxetine in a schedule commonly used in the FST resulted in a potentiated noradrenergic response to the swim challenge concomitant with behavioral alterations consistent with antidepressant-like activity. Electronic Publication     

Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice

Rationale Knockout and transgenic mice provide a tool for assessing the mechanisms of action of antidepressants. The effectiveness of oral administration of the tricyclic antidepressant amitriptyline (AMI) was assessed in C57BL/6J (B6) mice, a common genetic background on which knockout and transgenic mice are maintained.Objectives We determined whether oral AMI would have antidepressant-like effects in B6 mice and whether these effects varied according to sex, duration of treatment, and the depression model utilized.Methods Male and female B6 mice were administered AMI (200 g/ml) in the drinking water as the sole source of fluid, along with 2% saccharin to increase palatability. Control mice were administered 2% saccharin alone. Mice were assessed for responsiveness to AMI in the tail suspension test (TST), the forced swim test (FST), and the learned helplessness (LH) paradigm.Results In the TST, AMI decreased immobility time regardless of sex or duration of treatment. AMI also decreased immobility time in the FST, but chronic treatment was necessary for full efficacy in both sexes. In the LH paradigm, both subchronic and chronic AMI treatment decreased escape latencies in female mice, but AMI was effective only after chronic treatment in males. The antidepressant-like effects of AMI could not be explained by differences in locomotor activity because activity levels were not altered by antidepressant treatment.Conclusions Overall, oral AMI administration provides a valid model for behavioral assessment of antidepressant-like effects in knockout and transgenic mice maintained on a B6 background, but the effectiveness of oral AMI varies depending on sex, duration of treatment, and the depression model used.     

Sex differences in the burying behavior test in middle-aged rats: effects of diazepam

The full behavioral profile displayed during the burying behavior test was studied in middle aged (11-14 months) males, females with irregular estrous cycles, and females in persistent diestrus, with and without diazepam (0.5-2.0 mg/kg). Ambulation and motor coordination were also tested to discern behavioral changes from general motor alterations. Without diazepam treatment, middle-aged males showed longer burying behavior latencies, more prod explorations and less freezing than both groups of females. Untreated middle aged males also showed less cumulative burying and more immobility compared to females with irregular cycles. None of the parameters showed any difference between the female groups. Diazepam (0.5 and 1.0 mg/kg) increased burying behavior latency in females, but had no effect on any parameter in middle aged males. However, a higher dose (2.0 mg/kg) of diazepam increased immobility, freezing and the number of prod shocks and decreased prod explorations and groomings, but impaired motor coordination in males. In contrast with young males and females, diazepam at any dose reduced cumulative burying. Data are discussed on the bases of (1) sex and age differences in burying behavior and on (2) the anxiolytic-like action of diazepam and its side effects.     

Diazepam attenuates the antagonism of haloperidol against apomorphine-induced stereotypic behavior after subchronic but not acute treatment in rats

Summary Apomorphine-induced stereotypic behavior was investigated in rats treated with diazepam or haloperidol and with the combination of both drugs in a one day trial or subchronically. The drugs were administered via the drinking water.Diazepam dose-dependently reduced apomorphine stereotypies after the subchronic (6 days) but not after the acute treatment. Haloperidol suppressed apomorphine-induced stereotypic behavior dose-dependently after acute as well as after subchronic administration apparently without the development of tolerance. This discrepancy to other studies may be explained by the concomitant increase in maximum number of D₂-receptors in the striatum.The apomorphine antagonistic effect of haloperidol was attenuated when the neuroleptic was administered subchronically in combination with the benzodiazepine. This finding was unexpected since both drugs reduced apomorphine-induced stereotypic behavior when administered alone. The further increase in maximum number of D₂-receptors due to combined treatment with low doses of diazepam, suggesting a sort of over adaptation, possibly explains the haloperidol-antagonistic action of diazepam in the behavioral experiments.Binding studies on dopamine (D₁), 5-hydroxytryptamine (5-HT₂) and benzodiazepine receptors revealed that modification of the apomorphine-induced stereotypies by the combined treatment with haloperidol and diazepam cannot be explained by interactions of the drugs at the level of the D₁, 5-HT₂ or benzodiazepine-receptors.     

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

Rationale

Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated alcohol and drug use.

Objectives

The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal.

Methods

Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST), and air-puff-induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to 8 weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration, and 22-kHz USV production, as well as performance in the elevated plus maze (EPM).

Results

During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility, and 22-kHz USV production but did not show any behavioral change in the EPM unless the duration of alcohol exposure was extended to 4 weeks. Following 8 weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration, and increased 22-kHz USVs.

Conclusions

These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff-induced 22-kHz USVs could provide an ethologically valid alternative to the FST.     

Social model of depression in mice of C57BL/6J strain

Long experience of defeat in daily social intermale confrontations and permanent living with aggressive males under sensory contact conditions [Kudryavtseva (8)] has been shown to produce changes in the patterns of submissive behavior of male mice of C57BL/6J strain. The submissive males after 20 defeats demonstrated passive defense postures instead of active defense and withdrawal which they had displayed in first encounters. Moreover, new immobile postures appeared, which were very rare in the first confrontations. Submissive animals displayed a decrease of ambulation in the open-field test and increase the immobility time in the Porsolt's test. Chronic treatment with imipramine prevented the increase of "depressiveness" estimated by means of the Porsolt's test. There was a loss of weight and some disturbances in gastrointestinal functions. The data are discussed in terms of the development of depression in submissive male C57BL/6J mice as a result of chronic unavoidable social stress.     

Sex differences in novelty- and psychostimulant-induced behaviors of C57BL/6 mice

Rationale

Women are more sensitive than men to psychostimulants and progress from initial use to drug addiction more quickly. The mouse has been an under-utilized model to study sex differences in psychostimulant action. Mice could serve as an ideal genetically tractable model for mechanistic studies into sex and hormone effects on psychostimulant behavior.

Objectives

The objective of this study was to characterize psychostimulant effects in male and female mice with a combination of automated data collection and behavioral observation.

Methods

Male and female C57BL/6 mice (Charles River) were given a single dose or sequential ascending binge doses of d-amphetamine (AMPH) or cocaine (COC). Behavior was assessed in open field chambers using both automated photobeam interruptions and behavioral observations. Brain psychostimulant concentrations were determined at the time of maximum behavioral stimulation.

Results

Psychostimulants induced behavioral activation in mice including both increased locomotion as detected with an automated system and a sequence of behaviors progressing from stereotyped sniffing at low doses to patterned locomotion and rearing at high doses. Females exhibited more patterned locomotion and a shift towards higher behavior scores after either psychostimulant despite having lower AMPH and equivalent COC brain levels as males.

Conclusions

Female C57BL/6 mice exhibit enhanced psychostimulant-induced behavior compared to males, similar to reports in rats. The combination of automated behavioral measures and behavioral observation was essential for verifying the existence of these differences. These results indicate the importance of testing both sexes when characterizing genetically manipulated mice to control for potential sex-specific effects.