Haloperidol-induced Catalepsy Research Articles

Metabotropic Glutamate 7 Receptor Subtype Modulates Motor Symptoms in Rodent Models of Parkinson's Disease

Metabotropic glutamate (mGlu) receptors modulate synaptic transmission in the central nervous system and represent promising therapeutic targets for symptomatic treatment of Parkinson's disease (PD). Among the eight mGlu receptor subtypes, mGlu7 receptor is prominently expressed in the basal ganglia, but its role in restoring motor function in animal models of PD is not known. The effects of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the first selective allosteric activator of mGlu7 receptors, were thus tested in different rodent models of PD. Here, we show that oral (5 mg/kg) or intrastriatal administration (0.1 and 0.5 nmol) of AMN082 reverses haloperidol-induced catalepsy in rats. AMN082 (2.5 and 5 mg/kg) reduces apomorphine-induced rotations in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. In a more complex task commonly used to evaluate major akinetic symptoms of PD patients, 5 mg/kg AMN082 reverses the increased reaction time to respond to a cue of bilateral 6-OHDA-lesioned rats. In addition, AMN082 reduces the duration of haloperidol-induced catalepsy in a mGlu7 receptor-dependent manner in wild-type but not mGlu7 receptor knockout mice. Higher doses of AMN082 (10 and 20 mg/kg p.o.) have no effect on the same models of PD. Overall these findings suggest that mGlu7 receptor activation can reverse motor dysfunction associated with reduced dopamine activity. Selective ligands of mGlu7 receptor subtypes may thus be considered as promising compounds for the development of antiparkinsonian therapeutic strategies.

Long-lasting resistance to haloperidol-induced catalepsy in male rats chronically treated with caffeine

Chronic caffeine consumption has been inversely associated with the risk of developing Parkinson's disease. Here we assessed whether chronic caffeine treatment increases the resistance of male Wistar rats to haloperidol (1 mg/kg, s.c.)-induced catalepsy, measured in the bar test at 15 min intervals during 3 h. Caffeine (5 mg/kg/day) was delivered for 6 months via drinking water. Control rats received only tap water. Treatments began when animals were 3–4 months old. In order to unveil long-lasting catalepsy refractoriness not attributable to the presence of caffeine in the brains of rats, they were evaluated from day 18 to day 27 after caffeine withdrawal, a time that is far in excess for the full excretion of a caffeine dose in this species. The average cataleptic immobility measured in caffeine-treated rats ( n = 23) was 1148 ± 140 s, a value 34 ± 8% lower than that recorded in control animals ( n = 20), whose mean immobility was 1736 ± 137 s ( P = 0.0026, t-test). The percentage of catalepsy reduction measured in caffeine-treated rats evaluated on days 18–20 after caffeine discontinuation (−32 ± 13%, n = 12, P < 0.05) was comparable to the catalepsy decrease recorded in those animals tested on days 21–27 (−36 ± 10%, n = 11, P < 0.02), a finding compatible with the notion that the effect was indeed mediated by enduring changes of brain functioning and not by the physical presence of caffeine or its metabolites. Caffeine-treated rats also had higher catalepsy latency scores compared with control rats ( P < 0.01, U-test). The present findings show that chronic consumption of caffeine produces perdurable resistance to catalepsy induced by dopamine receptor blockade, possibly through enhancement of dopamine transmission, giving further support to the epidemiological results indicating that prolonged caffeine consumption affords neuroprotection against Parkinson's disease.

Righting elicited by novel or familiar auditory or vestibular stimulation in the haloperidol-treated rat: Rat posturography as a model to study anticipatory motor control

External cues, including familiar music, can release Parkinson's disease patients from catalepsy but the neural basis of the effect is not well understood. In the present study, posturography, the study of posture and its allied reflexes, was used to develop an animal model that could be used to investigate the underlying neural mechanisms of this sound-induced behavioral activation. In the rat, akinetic catalepsy induced by a dopamine D2 receptor antagonist (haloperidol 5 mg/kg) can model human catalepsy. Using this model, two experiments examined whether novel versus familiar sound stimuli could interrupt haloperidol-induced catalepsy in the rat. Rats were placed on a variably inclined grid and novel or familiar auditory cues (single key jingle or multiple key jingles) were presented. The dependent variable was movement by the rats to regain equilibrium as assessed with a movement notation score. The sound cues enhanced movements used to regain postural stability and familiar sound stimuli were more effective than unfamiliar sound stimuli. The results are discussed in relation to the idea that nonlemniscal and lemniscal auditory pathways differentially contribute to behavioral activation versus tonotopic processing of sound.

Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism

Developing nondopaminergic palliative treatments for Parkinson's disease represents a major challenge to avoid the debilitating side effects produced by L-DOPA therapy. Increasing interest is addressed to the selective targeting of group III metabotropic glutamate (mGlu) receptors that inhibit transmitter release at presumably overactive synapses in the basal ganglia. Here we characterize the functional action of a new orthosteric group III mGlu agonist, LSP1-2111, with a preferential affinity for mGlu4 receptor. In mouse brain slices, LSP1-2111 inhibits striatopallidal GABAergic transmission by selectively activating the mGlu4 receptor but has no effect at a synapse modulated solely by the mGlu7 and mGlu8 receptors. Intrapallidal LSP1-2111 infusion reverses the akinesia produced by nigrostriatal dopamine depletion in a reaction time task, whereas an mGlu8-receptor agonist has no effect. Finally, systemic administration of LSP1-2111 counteracts haloperidol-induced catalepsy, opening promising perspectives for the development of antiparkinsonian therapeutic strategies focused on orthosteric mGlu4-receptor agonists.

Neuroprotective effect of naphtha[1,2-d]thiazol-2-amine in an animal model of Parkinson's disease

Increased oxidative stress has been implicated in the pathogenesis of dopaminergic neurodegeneration leading to the development of Parkinson's disease. In this study, we investigated whether naphtha[1,2-d]thiazol-2-amine (NTA) may ameliorate haloperidol-induced catalepsy and oxidative damage in mice brain. Haloperidol-induced catalepsy was measured with the standard bar test. The extent of oxidative stress has been evaluated by measuring levels of MDA, GSH and activities of antioxidant enzymes (SOD and GSH-Px) from brain homogenate. Haloperidol treatment significantly induced the catalepsy as observed from increased descent time measured in the bar test. Pretreatment with NTA significantly reduced the catalepsy induced by haloperidol in a dose-dependent manner. The elevated level of MDA in haloperidol-treated mice was significantly decreased by NTA pretreatment. The decreased level of GSH as well as SOD and GSH-Px activities in haloperidol-treated mice were significantly increased by NTA pretreatment. NTA reduces the oxidative stress allowing recovery of detoxifying enzyme activities and controlling free radical production, suggesting a potential role of the drug as an alternative/adjuvant drug in preventing and treating the neurodegenerative diseases, such as Parkinson's disease.

Neuropharmacological Evaluation of Hibiscus rosa sinensis Roots in Experimental Animals

Objective : To investigate the effect of the methanolic extract of Hibiscus rosa sinensis roots ( H. sinensis ) on the central nervous system in mice and rats. Materials and methods : The methanolic extract of H. sinensis was studied on pentobarbital-induced sleeping time, elevated plus maze, hole board test, foot shock-induced aggression, haloperidol-induced catalepsy, lithium-induced head twitches, locomotor activity, acetic acid-induced writhing and hot plate analgesiometer at various doses (50 - 200 mg/kg), intraperitoneally for sedative, anxiolytic, antipsychotic, muscle relaxant and analgesic activities. Results : The extract prolonged pentobarbital-induced sleeping time indicating sedative effect. The extract increased the time spent in open arms and the number of head dips in elevated plus maze and hole board test respectively demonstrating anxiolytic activity. H. sinensis decreased number of fights in foot shock-induced aggression and potentiated haloperidol-induced catalepsy in dose dependent manner showing antipsychotic effect. The extract significantly inhibited head twitches induced by lithium suggesting its inhibitory effect on serotonergic system. The H. sinensis significantly decreased the locomotor activity in dose dependent manner. The extract showed potential analgesic activity in acetic acid-induced writhing and hot plate analgesiometer. The H. sinensis attenuated the behavior mediated by the dopaminergic and serotonergic system and potentiated the GABAergic actions. Conclusion : The results suggest that the methanolic extract of Hibiscus rosa sinensis has potential neuropharmacological activities.

Caffeine withdrawal retains anticataleptic activity but Withania somnifera withdrawal potentiates haloperidol-induced catalepsy in mice

The previous study showed that chronic treatment with Withania somnifera extract (WS) inhibited haloperidol-induced catalepsy. It is suggested that caffeine and WS may be useful adjuvants in pharmacotherapy of Parkinson's disease. There are no studies on the effect of haloperidol on mice withdrawn from caffeine or W. somnifera. We therefore studied the effect of a single administration of standardised WS containing 5.1% total withanolides (WS, 30 or 100 mg kg−1 i.p.) and/or caffeine (3 mg kg−1 i.p.) and withdrawal from 6 days treatment with WS and/or caffeine, on haloperidol-induced catalepsy in albino mice. Single administration of both WS and caffeine, used either alone or in combination, significantly inhibited catalepsy. Mice withdrawn from caffeine significantly inhibited haloperidol-induced catalepsy, but mice withdrawn from WS showed increased catalepsy. The study indicated that withdrawal from WS does not retain anticataleptic activity, and caffeine but not WS may be a good adjuvant in pharmacotherapy of Parkinson's disease.

Deep brain stimulation of the posterior hypothalamic nucleus reverses akinesia in bilaterally 6-hydroxydopamine—lesioned rats

Deep brain stimulation (DBS) of the basal ganglia motor circuitry is a highly effective treatment for the debilitating motor symptoms of Parkinson's disease (PD). However, recent findings have indicated promising potential for PD therapy with DBS in brain structures outside the basal ganglia. For example, high frequency stimulation of the posterior hypothalamic nucleus (PH) can reverse haloperidol-induced akinesia in rats [Jackson J, Young CK, Hu B, Bland BH (2008) High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy. Exp Neurol 213:210–219]. In the current study, we used the bilateral 6-hydroxydopamine lesion model of Parkinsonian akinesia in male Long-Evans rats to further explore the efficacy of PH DBS. The application of PH DBS in lesioned animals reversed akinesia in an active avoidance paradigm with increased latency compared to pre-lesion performance. The dramatic reversal of akinesia in two models of rodent Parkinsonism by PH DBS warrants further exploration of its therapeutic potential.

A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol

Haloperidol, an antipsychotic agent, stimulates the release of gonadotropin-releasing hormone (GnRH), and this hormone is known to mimic some of the behavioral effects of haloperidol. Hence, the present study was carried out to find out the contribution of GnRH in the behavioral effects of haloperidol. The studies revealed that haloperidol (0.15, 0.25 and 0.5 mg/kg, i.p.) and leuprolide (GnRH agonist; 50, 100, 200 and 400 microg/kg, s.c.) dose-dependently inhibited conditioned avoidance response (CAR) in male Sprague-Dawley rats. In higher doses, haloperidol (0.5, 1 mg/kg, i.p.) and leuprolide (200, 400 microg/kg, s.c.) produced catalepsy in rats. Co-administration of sub-effective dose of leuprolide (50 or 100 microg/kg, s.c.) and haloperidol (0.15 or 0.5 mg/kg, i.p.) similarly inhibited CAR and induced catalepsy. Pre-treatment of rats with antide (GnRH antagonist; 10 microg/rat, s.c.), attenuated the inhibitory effect of both the agents on CAR; blocked leuprolide-induced catalepsy; and attenuated the intensity and reduced the duration of haloperidol-induced catalepsy. In conclusion, the studies suggest a possible role of GnRH in the neuroleptic and cataleptic effect of haloperidol.

Synthesis of some urea and thiourea derivatives of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5- d]pyrimidine and their antagonistic effects on haloperidol-induced catalepsy and oxidative stress in mice

A series of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5- d]pyrimidin-7-yl urea and thiourea derivatives were designed and synthesized. All the compounds have been evaluated for their antiparkinsonian activity in catalepsy induced by haloperidol in mice. A majority of the compounds exhibited significant antiparkinsonian activity after intraperitoneal administration. The most active compound carries methoxy group at 2-position of the phenyl ring. Some of the potent compounds were selected for biochemical estimations of malondialdehyde, glutathione, superoxide dismutase and glutathione peroxidase from brain homogenate to highlight the neuroprotective properties associated with them. The results obtained in the present study may lead to the development of a suitable approach to the treatment of Parkinson's disease and may be the starting point for the future drug design.

Effects of 5-HT in globus pallidus on haloperidol-induced catalepsy in rats

Histological, behavioral and electrophysiological studies have suggested that 5-HT may regulate motor function by affecting globus pallidus neurons activity. In this study, the effects of 5-HT in globus pallidus on haloperidol-induced catalepsy and its possible receptor mechanisms were examined in rats using bar tests. Bilateral microinjection of 5-HT (10 μM) into globus pallidus significantly attenuated haloperidol-induced catalepsy. This anticataleptic effect was completely counteracted by selective 5-HT 1B receptors antagonist SB-224289 (10 μM), while partly reversed by selective 5-HT 4 receptors antagonist GR-113808 (1 μM). In addition, the selective 5-HT 7 receptors antagonist SB-269970 (1 μM) partly reversed the anticataleptic effect of 5-HT only at the incipient period after the intrapallidal injection. In conclusion, 5-HT in globus pallidus could attenuate haloperidol-induced catalepsy via multiple receptor mechanisms.

Neurobehavioral Effects in Relation to Endocrine Alterations Caused by Exposure to Brominated Flame Retardants in Rats—Comparison to Polychlorinated Biphenyls

ABSTRACT The widespread use of brominated flame retardants (BFRs) has led to increasing concentrations in environmental samples. Previous reports suggested endocrine activity of these compounds. Because thyroid hormones and sex steroids are known to regulate the development of the nervous system, we examined neurobehavioral and endocrine effects of gestational exposure to 2,2′4,4′,5-pentabrominated diphenyl ether (PBDE99) and lifetime exposure to tetrabromobisphenol A (TBBPA) or hexabromocyclododecane (HBCD) in rats. Treatment with PBDE99 (0, 1, or 10 mg/kg bw) reduced serum testosterone and estradiol in male offspring and affected sexual development in both sexes. Exposed males exhibited increased sweet preference, indicating feminization of this sexually dimorphic behavior. In TBBPA and HBCD experiments, a benchmark design was used with dose ranges of 0-3000 mg/kg bw/day and 0–100 mg/kg bw/day, respectively. Because thyroid hormones are critical for auditory development, brainstem auditory evoked potentials (BAEPs) were recorded in young adult offspring. TBBPA exposure elevated BAEP thresholds in females and prolonged latencies in both sexes. Benchmark doses were comparable for auditory effects and decreased plasma T4. HBCD increased BAEP thresholds and delayed BAEP waves only in males, but the relation to thyroid hormones remains to be determined. HBCD also reduced latencies in haloperidol-induced catalepsy, suggesting effects on the dopaminergic system.

Effects of Tandospirone, a 5-HT1A Agonistic Anxiolytic Agent, on Haloperidol-Induced Catalepsy and Forebrain Fos Expression in Mice

We studied the effects of tandospirone, a 5-HT1A agonistic anxiolytic agent, on haloperidol-induced catalepsy and forebrain Fos expression in mice. Haloperidol (0.5 mg/kg, i.p.) markedly increased the catalepsy time and enhanced Fos expression in the shell (AcS) and core (AcC) regions of the nucleus accumbens, the dorsolateral striatum (dlST), and the lateral septal nucleus (LSN). Tandospirone (0.1 – 1 mg/kg, s.c.) significantly alleviated haloperidol-induced catalepsy in a dose-dependent manner, which was antagonized by WAY-100135 (a selective 5-HT1A antagonist). The anticataleptic dose of tandospirone (1 mg/kg, s.c.) significantly reduced haloperidol-induced Fos expression in the dlST. This inhibition by tandospirone was regionally specific, and it failed to affect haloperidol-induced Fos expression either in the AcS, AcC, or LSN. In addition, the reversal of haloperidol-induced striatal Fos expression by tandospirone was antagonized by WAY-100135. These results support the notion that stimulation of 5-HT1A receptors region-specifically counteracts the D2-blocking actions of haloperidol in the striatum, which may account for the ameliorative effects of 5-HT1A agonists on antipsychotic-associated extrapyramidal disorders.

N-Oleoyl-Dopamine Decreases Muscle Rigidity Induced by Reserpine in Rats

N-oleoyl-dopamine (OLDA), a product of condensation of oleic acid and dopamine (DA), is a bioactive compound that crosses the blood-brain barrier after systemic administration. The possibility arises that OLDA could have a potential role in treating DA-related disorders, such as Parkinsons disease (PD). In the present study we seek to determine whether OLDA would affect muscle tone and akinesia in two rat models of PD: the reserpine-evoked muscle rigidity and the reserpine- and haloperidol-induced catalepsy. We found that OLDA (20 mg/kg) significantly decreased muscle rigidity induced by reserpine (2.5 mg/kg), measured as an increased mechanical muscle resistance (MMG) in response to a passive extension and flexion of a rat hind limb at the ankle joint. Moreover, OLDA potently decreased the reserpine-enhanced tonic and reflex electromyographic (EMG) activities recorded before and during the movement, respectively. A lower dose of OLDA (10 mg/kg) failed to have appreciable effects. The reference compound L-DOPA (25 mg/kg) also attenuated the reserpine-increased MMG and EMG activities; the effects were, however, observed much later and were less prominent than those characteristic of OLDA. In contrast to the effects on muscle tone, OLDA (20 and 40 mg/kg) did not influence catalepsy induced by either reserpine (1.25 mg/kg) or haloperidol (0.5 mg/kg). In conclusion, the study demonstrates a novel biological action of N-oleoyl-dopamine consisting of lowering the reserpine-induced muscle rigidity. However, the lack of influence on akinesia suggests that the compound has myorelaxant rather than anti-Parkinsonian properties.

Antihistaminic effect of various extracts ofPunica granatumLinn. flower buds

Punica granatum Linn. (Punicaceae) s ower buds are used in the treatment of asthma traditionally, so the present work was undertaken to prove it scientiÞ cally using suitable animal models. Antihistaminic principles are useful in the treatment of asthma,;hence, in present work antihistaminic activity of various extracts of P. granatum s ower buds was checked using clonidine-induced catalepsy and haloperidol-induced catalepsy in Swiss albino mice at the dose of 50 and 100 mg/kg, p.o. The results showed that ethanol extracts (100 mg/kg, p.o.) are having signiÞ cant antihistaminic activity amongst other extracts. Thus, it can be concluded that tannins from the s ower buds of P. granatum may be responsible for antihistaminic activity and may have potential role in the treatment of asthma. Key words: Antihistaminic, catalepsy, clonidine, haloperidol, Punica granatum.

Neurobehavioral effects ofphoenix dactyliferain mice

The present study deals with the investigation of the neurobehavioral effects of the methanolic extract of Phoenix dactylifera (PD) fruits, studied on locomotor activity, exploratory behavior, motor coordination, hot-plate test, haloperidol-induced catalepsy, sodium nitrite–induced respiratory arrest, maximum electroshock–induced convulsions using mice. The results revealed that the extract in mice considerably reduced the exploration time in closed arms with an increased exploration in open arms, increased the time spent in mirrored chamber, increased the discrimination index, potentiated the haloperidol-induced catalepsy, reduced the onset of death in sodium nitrite–induced respiratory arrest. These results suggest that the methanolic extract of P. dactylifera fruits possess a wide range of CNS activities, which need further investigation. Key words: Anxiety, convulsions, locomotor activity, nootropic, Phoenix dactylifera.

Effects of the brominated flame retardant hexabromocyclododecane (HBCD) on dopamine-dependent behavior and brainstem auditory evoked potentials in a one-generation reproduction study in Wistar rats

Hexabromocyclododecane (HBCD) is a widely used brominated flame retardant which has been recently detected in many environmental matrices. Data from a subacute toxicity study indicated dose-related effects particularly on the pituitary thyroid-axis and retinoids in female rats. Brominated and chlorinated aromatic hydrocarbons are also reported to exert effects on the nervous system. Several investigations revealed a pronounced sensitivity of the dopaminergic system and auditory functions to polychlorinated biphenyls. Therefore, the present experiment should examine, whether or not HBCD affects these targets. Rats were exposed to 0, 0.1, 0.3, 1, 3, 10, 30 or 100 mg HBCD/kg body weight via the diet. Exposure started before mating and was continued during mating, gestation, lactation, and after weaning in offspring. Haloperidol-induced catalepsy and brainstem auditory evoked potentials (BAEPs) were used to assess dopamine-dependent behavior and hearing function in adult male and female offspring. On the catalepsy test, reduced latencies to movement onset were observed mainly in female offspring, indicating influences on dopamine-dependent behavior. The overall pattern of BAEP alterations, with increased thresholds and prolonged latencies of early waves, suggested a predominant cochlear effect. Effects were dose-dependent with lower bounds of benchmark doses (BMDL) between ≤1 and 10 mg/kg body weight for both catalepsy and BAEP thresholds. Tissue concentrations at the BMDL values obtained in this study were 3–4 orders of magnitude higher than current exposure levels in humans.

Potent and selective adenosine A 2A receptor antagonists: 1,2,4-Triazolo[1,5- c]pyrimidines

Antagonism of the adenosine A 2a receptor offers great promise in the treatment of Parkinson’s disease. In the course of exploring pyrazolo[4,3- e]-1,2,4-triazolo[1,5- c]pyrimidine A 2A antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5- c]pyrimidines with potent and selective (vs A 1) A 2a antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure–activity relationships and plasma levels are described for this series.

Synthesis of some urea and thiourea derivatives of naphtha[1,2-d]thiazol-2-amine as anti-Parkinsonian agents that cause neuroprotection against haloperidol-induced oxidative stress in mice

A series of N-(substituted phenyl)-N′-(naphtha[1,2-d]thiazol-2-yl)urea and thiourea derivatives were synthesized starting from N-naphthylthiourea. The structures were confirmed by spectral and elemental analyses. The newly synthesized compounds were found to possess anti-Parkinsonian and antioxidant activities. Anti-Parkinsonian activity was evaluated on haloperidol-induced catalepsy in mice by employing the standard bar test. All of the synthesized compounds ameliorated the catalepsy induced by haloperidol in mice. The most potent compounds (5, 6, 22, and 29) were selected for biochemical evaluation from the brain homogenate and were found to be effective in decreasing the elevated levels of malondialdehyde while restoring the cellular defense mechanisms such as glutathione content as well as glutathione peroxidase and superoxide dismutase activities in haloperidol-treated mice, suggesting the role of free radicals in the pathophysiology of haloperidol-induced catalepsy and possible antioxidant action of title compounds.

To breed or not to breed? Empirical evaluation of drug effects in adolescent rats

The recent upsurge of research on adolescent rats raises the issue of the extent to which different methods of rodent procurement might affect results. Here, we examined the effects of acute and repeated dosing with two antipsychotics, haloperidol and clozapine, and Δ9-tetrahydrocannabinol [Experiments 1 and 2, respectively] in adolescent rats of both sexes that differed in shipping status (i.e., shipped from a commercial breeder at weaning or bred in-house). In each experiment, test drugs produced effects that were characteristic for their respective classes in previous studies with adult rodents. Both haloperidol and clozapine produced catalepsy and haloperidol decreased locomotion in shipped and bred rats of both sexes, with sensitization to haloperidol-induced catalepsy developing with repeated dosing. The most prominent between-status difference in this experiment was greater sensitivity of the shipped rats to haloperidol-induced changes in locomotor activity over a wider dose range, an effect that was especially evident in females. In Experiment 2, vehicle levels of motor activity were decreased in bred rats (which did not occur in Experiment 1), resulting in flattening of the Δ9-tetrahydrocannabinol dose–effect curve for this measure in bred rats of each sex. Acutely, Δ9-tetrahydrocannabinol produced antinociception, hypothermia and catalepsy in both groups of rats, with tolerance developing after repeated dosing. Status-related differences were sex-dependent. Whereas bred female rats were more sensitive to Δ9-tetrahydrocannabinol's antinociceptive effects, shipped male rats were more sensitive to its antinociceptive effects as well as to its hypothermic and cataleptic effects. Together, the results of these descriptive experiments suggest that between-status differences tend to be quantitative rather than qualitative. Further, these results suggest that careful attention to issues related to rodent procurement during adolescence is warranted and may help to account for divergent findings in different labs.