Effects of methylphenidate on food and water consumption at different body weights.

The effects of intraperitoneally administered methylphenidate at 0, 1.5, 3.0, 6.0, and 12.0 mg/kg were studied in two experiments. Experiment 1 determined the effects of methylphenidate on 0.5, 1.0, 2.0, and 24 hr post injection food and water consumption in rats at ad lib feeding body weights. Experiment 2 determined the post injection effects of methylphenidate on 0.5, 1.0 and 2.0 hr food and water and 24 hr water consumption in rats maintained at 80% ad lib feeding body weight due to partial food deprivation. The results of Experiment 1 indicate that when animals are feeding ad lib at normal body weight food and water consumption is decreased for 2 hr following the administration of the lowest 1.5 mg/kg dose of methylphenidate. Methylphenidate in doses as high as 12.0 mg/kg has no effect on 24 hr food and water consumption under these conditions. The results of Experiment 2 indicate that when animals are maintained at reduced body weight due to partial food deprivation, food consumption for 2 hr is significantly decreased by the highest, 12.0 mg/kg, dose of methylphenidate. These effects are observed within the first 30 min post injection when methylphenidate decreases food consumption in a dose dependent manner. Methylphenidate has no effect on water consumption under these conditions. The effects of methylphenidate on ingestive behavior are discussed in terms of previous experiments and the possible differential effects on motor activity at different body weights under different stimulus conditions.     

Differential effects of the new antipsychotic risperidone on large and small motor movements in rats: a comparison with haloperidol

Risperidone, a new antipsychotic agent, was studied for its effects on spontaneous motor activity in rats in comparison with haloperidol. Motor activity was recorded via the optical scanning technique (horizontal and vertical activity) and via a recently developed technique based on the piezo-electric principle which, in contrast to optical scanning, is very sensitive to small, stationary movements (piezo activity). Risperidone and haloperidol at low doses depressed both vertical activity (ED₅₀s: 0.062 and 0.038 mg/kg, respectively) and horizontal activity (0.18 and 0.060 mg/kg, respectively). With increase of dose, motor activity decline was significantly faster with haloperidol than with risperidone. Moreover, haloperidol also rapidly depressed piezo activity (ED₅₀: 0.085 mg/kg) whereas risperidone depressed this component of motor behaviour at much higher doses only (ED₅₀: 2.80 mg/kg). Visual inspection did not reveal abnormal behavioural movements following the test compounds. Risperidone, therefore, preserves normal small movements over a much larger dose interval than haloperidol; this effect may be related to its relatively low cataleptogenic activity and potentially also to a reduced EPS liability. The present results further confirm that the piezo technique may complement the optical scanning method, and thereby enhance the information on the extent that test compounds modify behaviour.     

Effects of chronic treatments with amineptine and despiramine on motor responses involving dopaminergic systems

The acute effects of increasing doses of the antidepressant drugs amineptine (5–40 mg/kg, IP) and desipramine (5–20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87–30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1–1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25–20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1–0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement. These data indicate that, as in chronic treatment with typical antidepressant drugs like desipramine, chronic treatment with amineptine alters selectively the sedative effects induced by stimulation of D-2 DA autoreceptors in the mesolimbic dopaminergic area involved in the horizontal (locomotor) activity.     

Comparison of the effects of NMDA and AMPA antagonists on the locomotor activity induced by selective D1 and D2 dopamine agonists in reserpine-treated mice

This study examined the interaction between various glutamate antagonists and selective D₁ (SKF 38393) and D₂ (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1–1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25–8 mg/kg) and CPP (0.2–20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4–10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2–25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D₁ and D₂ motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants tol-dopa in antiparkinson therapy.     

Psychopharmacological effects of Artemisia copa aqueous extract in mice

Objective: To evaluate the aqueous extract from aerial parts of Artemisia copa Phil. (Asteraceae) administered orallyfor its psychopharmacological activities in several experimental models

Methods: The extract was administered p.o. in Swiss albino mice and tested on pentobarbital-induced hypnosis, locomotor activity, exploration in the hole-board, anxiolytic like profile evaluated in the marble-burying test and anticonvulsant activity on convulsions induced by pentylenetetrazol.

Results: Artemisia copa at doses up to 1.5?g/kg produced a dose-dependent sleep induction and potentiation of sub-hypnotic and hypnotic doses of pentobarbital. The extract also produced a dose-dependent increase and decrease in the spontaneous motor activity (0.5–1.5?g/kg, respectively), no disruption or a decrease on exploratory (hole-board) behavioral profiles (0.5–1.5?g/kg respectively) and a dose-related anxiolytic-like activity as indicated by increases in the percentage of marbles they left uncovered in the marble-burying test at doses (0.5?g/kg) that do not disrupt the motor activity. In addition, the extract (1.5?g/kg) produced a significant increase in the latency time and a decrease in the duration of seizures and mortality induced by PTZ 75?mg/kg in mice.

Conclusion: These results suggest that the aqueous extract of Artemisia copa may contain sedative principles with potential anxiolytic and anticonvulsant activities.     

Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice

The effects of the radioprotector S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on locomotor activity were evaluated in CD2F1 male mice. Separate groups of animals (N = 10/group) received an IP injection of vehicle, 25, 50, 100, 200, or 400 mg/kg of WR-2721 immediately before testing. Horizontal and vertical activity were measured using a Digiscan automated animal activity monitor. The latency to onset and duration of action of each dose of the radioprotector were recorded. For both behavioral measures, a significant reduction was observed in activity at doses of 200 and 400 mg/kg. A dose of 200 mg/kg had a 12- to 14-min latency to onset and significantly reduced behavioral activity for 3 hr. Mice injected with 400 mg/kg exhibited locomotor deficits within 8-10 min and were affected for up to 9 hr. The ED50 for horizontal and vertical activities at 1 hr postinjection were determined to be 271 and 105 mg/kg, respectively. The results demonstrate that significant reductions in locomotor activity are exhibited at doses of 200 mg/kg or more and that vertical activity was more sensitive to the disruptive effects of WR-2721 than was horizontal activity.     

A new system for the measurement and analysis of motor activity in mice: effect of several central stimulants

To estimate the spontaneous motor activity in mice, a new system with highly stable sensitivity and good reproducibility was made, and the effects of five central stimulants were investigated. The apparatus consists of a doughnut-shaped cage with detectors for measuring spontaneous motor activity; i.e., the number of movements, vertical activity, total distance, etc., for every five min. Methamphetamine (0.5, 1 and 2 mg/kg, s.c.) produced an increase in the number of movement and markedly increased total distance. Cocaine (20, 50 and 75 mg/kg, s.c.) caused a marked increase in movement and total distance. Mice injected with 50 mg/kg of cocaine showed long-lasting locomotion with few stops throughout the observation period. Caffeine (10, 30 and 100 mg/kg, s.c.) produced a long-lasting and moderate excitation. Morphine (5, 10 and 20 mg/kg, s.c.) caused a marked increase in continuous locomotion dose-dependently. Apomorphine produced a transient increase in rearing and locomotion at a dose of 1 mg/kg, s.c.; and it produced long-lasting rearing and moderate locomotor activity at 3 mg/kg. These results suggest that this apparatus is able to detect characteristic changes in spontaneous motor activity produced by central stimulants and may be useful for analyzing drug-induced motor activity in mice in more detail.     

Effects of dopamine D3 receptor antagonists on spontaneous and agonist-reduced motor activity in NMRI mice and Wistar rats: comparative study with nafadotride, U 99194A and SB 277011

Studies investigating the role of the dopamine D3 receptor in the regulation of motor activity of rodents have used several ligands; however, there have been few comparative studies using agonist-antagonist interactions. In the present study, we compared the effects of dopamine D3 antagonists with different levels of selectivity over D2 receptors (nafadotride, U 99194A and SB 277011) on motor activity as well as on agonist-induced hypoactivity, in mice and rats. Horizontal and vertical movements were measured in photocell activity cages. 7-Hydroxy-2-(di-n-propylamino)tetralin (7-OH-DPAT) and PD 128907 were used as dopaminergic agonists. Both dose-dependently inhibited motor activity in mice and vertical activity in rats, while decreasing horizontal activity of rats at doses of 0.01 and 0.1 mg/kg s.c., with no effect (7-OH-DPAT) or stimulation (PD 128907) at the 1 mg/kg dose. In mice habituated to the activity cage, nafadotride (0.1-3 mg/kg i.p.) caused a dose-dependent decrease in motor activity but did not affect the hypomotility evoked by either 7-OH-DPAT (0.1 mg/kg) or PD 128907 (0.1 mg/kg). In habituated rats it had no significant effect on motor activity and was not able to antagonize the hypoactivity caused by PD 128907 (0.1 mg/kg s.c.). U 99194A (5, 10 and 20 mg/kg s.c.) dose-dependently and significantly increased motor activity in mice and inhibited the effects of both agonists. In rats, nafadotride produced considerable motor stimulation and significantly inhibited the PD 128907-induced decrease in horizontal, but not in vertical, activity. SB 277011 (15-45 mg/kg p.o.) significantly increased motor activity in mice and partially blocked the action of 7-OH-DPAT on vertical, but not on horizontal, activity while against PD 128907, its significant inhibitory effect was restricted to a single dose (20 mg/kg). In habituated rats, SB 277011 (13.5, 20 and 30 mg/kg p.o.) exerted no significant effects on motor activity and did not antagonize the hypoactivity caused by PD 128907. Considerable species differences and movement-type differences (horizontal versus vertical) were observed between the effects of the tested dopamine D2/D3 ligands on motor activity in rodents. The antagonists also differed markedly in the robustness of their action. The poorly D3 selective antagonist, nafadotride, had little effect on motor behaviour. The moderately selective U 99194A exerted marked stimulatory effects on motility, and potently inhibited the actions of agonists. SB 277011, a highly selective dopamine D3 receptor antagonist, showed limited ability to influence the motor activity of rodents.     

Differential effects of dopamine D1 and D2 agonists and antagonists on velocity of movement, rearing and grooming in the mouse. Implications for the roles of D1 and D2 receptors

A system combining visual recording of rearing and grooming, with automatic measurement of slow and fast components of locomotion, was examined for its suitability as a means of studying the effects on behaviour of conventional and novel dopaminergic drugs in the mouse. Amphetamine (0.1-10 mg/kg) selectively stimulated fast movements and affected rearing bimodally. Apomorphine (0.01-5 mg/kg) influenced locomotion polyphasically, depressing fast movements and enhancing slow ones, and producing parallel changes in rearing. Both drugs reduced grooming monotonically. A dose of apomorphine (25 micrograms/kg) which is considered to act presynaptically produced haloperidol-resistant sedation, while a larger dose (0.5 mg/kg; with postsynaptic actions) evoked head-down sniffing and ponderous walking that were partially prevented by pretreatment with 0.05 mg/kg haloperidol (D2 blocker), but not 0.01 mg/kg SCH 23390 (D1 blocker). The behavioural effects of haloperidol (0.2-0.4 mg/kg) and SCH 23390 (0.05 mg/kg) were indistinguishable; both drugs caused sedation and inhibited all forms of motor activity. Small doses of SCH 23390 (2-10 micrograms/kg) and large doses of the D1 agonist SKF 38393 (3-10 mg/kg) evoked excessive grooming. The drug SKF 38393 (1-30 mg/kg) had no other effects on motor behaviour, whereas the whole spectrum of pre- and postsynaptic motor responses produced by apomorphine could be duplicated with the D2 agonist RU 24213 (0.05-15 mg/kg). The differential sensitivity of fast and slow components of locomotion to treatment with drug suggests these are qualitatively distinct responses. The results implicate D2 receptors in the mechanisms of locomotion and rearing, and D1 receptors in the expression of grooming.     

SCH 58261 and ZM 241385 differentially prevent the motor effects of CGS 21680 in mice: evidence for a functional 'atypical' adenosine A(2A) receptor

The acute motor effects elicited by drugs acting upon adenosine A(2A) receptors, namely the highly selective agonist CGS 21680 or the antagonists SCH 58261 and ZM 241385, were investigated in mice. CGS 21680 dose-dependently (0.1-2.5 mg/kg i.p.) decreased horizontal and vertical motor activities. The depressant effect of CGS 21680 (0. 5 mg/kg i.p.) was maintained in mice pretreated by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (10-30 mg/kg i.p. ), which poorly penetrates the blood-brain barrier, but was completely lost in adenosine A(2A) receptor knockout mice. Thus, the adenosine A(2A) receptor is critically involved in motor activity. SCH 58261 (1-10 mg/kg i.p.) increased locomotion and rearing with a quick onset, but for a shorter period in mice habituated to the environment than in mice unfamiliar to it. ZM 241385 (7.5-60 mg/kg i. p.) stimulated horizontal and vertical activities with a slow onset at the two highest tested doses, similarly in naive and in habituated mice. The increase in locomotion elicited by ZM 241385 (15-30 mg/kg i.p. and 10-20 nM i.c.v.) was retained in mice treated by CGS 21680 (0.5 mg/kg i.p.) but that elicited by SCH 58261 (1-3-10 mg/kg i.p. and 10-20 nM i.c.v.) partially subsided. In conclusion, both 'striatal-like'/'SCH 58261-sensitive' adenosine A(2A) receptors and 'ZM 241385-sensitive'/'atypical' CGS 21680 binding sites may mediate CGS 21680-induced motor effects. Moreover, our results suggest that 'atypical' CGS 21680 binding sites could be adenosine A(2A) receptors with a peculiar pharmacological profile.     

Sensitization and tolerance with episodic (weekly) nicotine on motor activity in rats

Nicotine's effects on motor activity have been studied extensively. Sensitization or tolerance can develop to nicotine's acute effects with daily exposure. Limited data indicate that sensitization can also develop when nicotine is given less frequently than daily. The present experiments were designed to extend this finding and to more fully characterize the effects of nicotine on motor activity when given at weekly intervals. In both experiments, the horizontal and vertical activity of adult female Long-Evans (LE) rats was recorded in photocell chambers. In Experiment 1, either saline or nicotine hydrogen tartrate (0.3, 0.6, 1.2 or 1.8 mg of salt/kg BW, s.c.) was administered once each week to rats that were tested daily (M-F). Acute nicotine administration produced no significant effect on horizontal activity at lower doses, while the highest dose produced a decrease (ca. 30%). Substantial and significant dose-related decreases in vertical activity were also obtained initially. Weekly dosing produced tolerance to nicotine's decreasing effects on vertical activity and increases (i.e., sensitization) in horizontal activity at all doses, and these effects persisted for at least 3 weeks. Experiment 2 partially replicated the results of Experiment 1 and indicated further that small sequential dose variations generally had little influence on nicotine tolerance and sensitization. The present results on horizontal activity extend prior findings of sensitization to weekly nicotine to include a broad range of doses. Results also showed that tolerance, but not sensitization, occurred to nicotine's effects on vertical activity over a comparable dose range. Further research is warranted on the importance of episodic, or recurring intermittent exposures in determining nicotine's effects, and those of other nicotinic agents, on behavior.     

Inhibition of morphine-induced analgesia and locomotor activity in strains of mice: a comparison of long-acting opiate antagonists

The long-acting opiate antagonistic potency of naloxazone (NXZ), beta-chlornaltrexamine (beta-CNA) and beta-funaltrexamine (beta-FNA) was compared using three inbred strains of mice, in which morphine induces either analgesia (DBA/2), locomotion (C57BL/6), or both responses (C3H/He). The antagonists were applied SC 24-120 hr before morphine (10 or 20 mg/kg, IP), followed by the tests after 30 min. The minimal dose which completely antagonized morphine-induced analgesia in DBA and locomotion in C57 mice during 24 hr were: for NXZ 50 and 100 mg/kg, for beta-CNA 0.8 and 6.2 mg/kg, for beta-FNA 1.6 and 12.5 mg/kg, respectively. beta-FNA and beta-CNA more potently blocked morphine-induced analgesia in DBA mice than the activity response in the C57 strain. In contrast, beta-FNA prevented morphine-induced locomotion at a lower dose (6.2 mg/kg) than analgesia (greater than 50 mg/kg) in C3H mice, while beta-CNA was equipotent (1.6 mg/kg). In general, beta-CNA turned out to be the most reactive compound, antagonizing morphine effects in low doses up to 120 hr. beta-FNA selectively antagonized either morphine-induced analgesia or locomotion, depending on the strain used. This suggests that a given morphine response might be caused by a genetically determined multiplicity of opiate receptor types and their mutual interactions.     

Scopolamine produces environment-specific conditioned activity that is not blocked by pimozide in rats

A classical conditioning paradigm was employed to determine if the stimulant effects of the anticholinergic scopolamine could show conditioning. In experiment 1 rats had 12 60-min pairings of scopolamine (1.0 or 8.0 mg/kg, IP) with a distinctive environment that monitored horizontal and vertical activity. Experimental (paired) groups received the drug 30 min prior to each session, whereas control (unpaired) groups received saline. Following each session the Paired groups were injected with saline, and the Unpaired groups received the same doses of scopolamine. After every fourth pairing a test session assessed conditioning by comparing activity of paired und unpaired groups in response to saline. Scopolamine enhanced horizontal activity, although conditioning was seen only with 8.0 mg/kg. The low dose increased vertical activity, whereas an initial decrease was observed with 8.0 mg/kg. However, conditioned vertical activity was seen with both doses. Experiment 2 assessed the possible role of dopamine in conditioning with 8.0 mg/kg scopolamine. Rats treated as in experiment 1 were additionally given 0.4 mg/kg pimozide 4 h prior to each pairing session. Pimozide did not block scopolamine's stimulant effect. Conditioned horizontal and vertical activity were also observed, suggesting that this effect may be mediated by direct changes within cholinergic systems.     

Effect of 5-HT1A agonists on stress-induced deficit in open field locomotor activity of rats: evidence that this model identifies anxiolytic-like activity

Deficits in locomotion and exploratory behaviour in an open field were induced in rats by restraint for 2 hr, 23 hr before testing. Diazepam, 0.62 and 1.25 mg/kg, intraperitoneally (i.p.), 15 min before testing, reversed the stress-induced reduction in locomotion; 1.25 mg/kg also attenuated the effect of stress on exploration (rearing and object exploring). Diazepam did not affect the activity of controls. A putative anxiogenic compound, pyrazoloquinoline (CGS 8216, 10 mg/kg administered 30 min before testing), also markedly reduced locomotion and exploration and the effect was reversed by 2.5 mg/kg diazepam, 15 min before testing. Buspirone, 0.1 mg/kg subcutaneously (s.c.) 15 min before testing, significantly attenuated the effect of stress on locomotion and exploration but had no effect in controls. Larger doses (0.5 and 1.0 mg/kg) markedly reduced the behavioural measures in controls and did not modify or enhance the effect of stress. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 0.25 and 0.5 mg/kg (s.c.), 1 hr before testing, significantly attenuated the reduction in locomotion without affecting rearing and object-exploring in stressed rats. At doses from 0.125 to 0.5 mg/kg, 8-OH-DPAT reduced exploration in control rats. Two hr after restraint (corresponding to 21 hr before testing in the open field) 8-OH-DPAT, 0.125 to 2 mg/kg (s.c.), did not modify the open field deficits, caused by stress. In these treatment conditions, 0.5 and 2 mg/kg 8-OH-DPAT reduced locomotion and exploration in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of arsenic trioxide on brain monoamine metabolism and locomotor activity of mice

The arsenic trioxide (AsT) content, and monoamine levels in the cerebral cortex, hippocampus, hypothalamus and corpus striatum were determined in mice administered AsT (3 and 10 mg/kg) for 14 days. The vertical and horizontal motor activity was also examined. The AsT content in discrete brain areas differed but was clearly dose-dependent. Metabolites of norepinephrine and dopamine increased in the cerebral cortex, hippocampus and hypothalamus and decreased in the corpus striatum in AsT-treated mice. Metabolites of 5-hydroxytryptamine increased in all the discrete brain areas. The vertical and horizontal motor activity was increased by AsT at 3 mg/kg and decreased by AsT at 10 mg/kg. These results show that AsT modifies CNS metabolism and function at low doses. AsT penetrates the blood-brain barrier to cause these effects.     

Stimulation of rat spontaneous locomotion by low doses of haloperidol and (−)-sulpiride: Importance of animal selection and measurement technique

Rats showed differential hyperactivity responses to the dopamine agonist (−)-N-n-propylnorapomorphine ((−)-NPA, 0.0125–0.1 mg/kg s.c.) which allowed their selection as non-responders, low (LA), moderate (MA) or high (HA) activity responders (maximum response to 0.05 mg/kg s.c. (−)-NPA being respectively zero, 10–25, 30–55, 60–85 counts/5 min as measured in photocell cages). This subdivision could be confirmed using treadwheels but not by using Automex activity meters. A second dopamine agonist, (+)-amphetamine, could not differentiate the subgroups as defined by (−)-NPA whether using photocells, treadwheels or Automex activity meters. Non-selected rats and those categorised as non-responders, LA, MA or HA responders to (−)-NPA were subject to low and high doses of the neuroleptic agents (−)-sulpiride and haloperidol. The treadwheels showed non-selected rats to exhibit hyperactivity to low doses of (−)-sulpiride (2.5–10 mg/kg i.p.) and, less markedly, to haloperidol (0.04–0.16 mg/kg i.p). The ability of a low dose of (−)-sulpiride (10 mg/kg i.p.) to stimulate spontaneous locomotion was shown to be highly selective for animals categorised as LA responders to (−)-NPA; low dose haloperidol (0.04 mg/kg i.p.) was less specific, stimulating the locomotion of both LA and MA rats: low dose (−)-sulpiride but not haloperidol depressed the spontaneous locomotion of HA rats. These effects revealed by treadwheel measure were not detected by the use of photocell cages or Automex activity meters. Higher doses of both neuroleptics depressed the locomotor activity of all animals using all measurement techniques. It is concluded that the ability of dopamine antagonists to stimulate or depress the spontaneous locomotor activity of the rat is critically dependent on three factors, dose of drug methodology of locomotor assessment and the basal locomotor responsiveness of the animal to the dopamine agonist (−)-NPA.     

A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats

Although most commonly associated with actions at cannabinoid CB1 receptors on the extracellular surface of the plasma membrane, the endocannabinoid anandamide (AEA) is also transported into the cell, by the putative anandamide membrane transporter (AMT), and activates the vanilloid receptor 1 (TRPV1) at an intracellular site. AEA is then inactivated by fatty acid amide hydrolase (FAAH). As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH. Motor activity was assessed in normal, in reserpine-treated, and in reserpine-treated rats treated with L-DOPA. In normal rats, the TRPV1 agonist capsaicin (1 mg/kg) or the FAAH inhibitor URB597 (10 mg/kg) caused a significant reduction in movement in both the horizontal (locomotion) and vertical (rearing) planes (-45% and -53% respectively with capsaicin; -33% and -37% for URB597). Capsaicin-induced hypolocomotion was attenuated by the TRPV1 antagonist, capsazepine. There was no effect of capsaicin, URB597 or the AMT inhibitor OMDM-2 on motor activity in reserpine-treated rats. L-DOPA treatment of reserpine-treated rats elicited high levels of motor activity in both the horizontal and vertical planes. Horizontal activity was attenuated by capsaicin (1 mg/kg, -60%), but not by URB597 (10 mg/kg) or OMDM-2 (5 mg/kg). Vertical activity was attenuated by capsaicin (1 mg/kg, -61%) and by URB597 (10 mg/kg, -54%), but not by OMDM-2. These data suggest that activation of the TRPV1 system can suppress spontaneous locomotion in normal animals and modulates several L-DOPA-induced behaviours in reserpine-treated rats.     

Long-term effects of prenatal phenytoin exposure on offspring behavior in rats

Pregnant Sprague-Dawley CD rats were administered phenytoin by gavage on days 7-18 of gestation in doses of 0 or 200 mg/kg. The offspring were tested at various ages to determine the duration of postnatal dysfunction and its replicability and generality compared to previous experiments. Phenytoin offspring had increased newborn (5.2%) and preweaning (16.7%) mortality compared to controls (0% and 3.1%, respectively), and an 8.5% reduction in average body weight at 28-70 days. No weight differences were significant at other ages. Phenytoin offspring showed increased activity on multiple tests, swam slower in a straight channel, committed more errors and took more time in the Cincinnati water maze, startled less, and had longer latencies on the Morris hidden platform test. Among phenytoin offspring 42.3% exhibited the abnormal circling defect previously described (14,17). Consequently, data were reanalyzed in terms of circlers, noncirclers, and controls to determine the contribution of this effect to the dysfunctions observed. Circlers accounted for the differences in open-field activity, figure-8 ambulation, hole-board horizontal locomotion, straight channel swimming time, water maze retention errors, tactile prepulse startle inhibition, and some trials of the Morris test. Circlers and noncirclers differed from one another and from controls on measures of figure-8 rearing, water maze errors and times, and some trials of the Morris test, with circlers more affected than noncirclers. Circlers and noncirclers did not differ from one another, but both differed from controls, on measures of early locomotion, hole-board vertical activity, and unmodified startle amplitude. Circling was hypothesized to reflect an underlying vestibular defect, however, the data also support the view that phenytoin has effects beyond those accounted for by possible vestibular effects.     

Effects of methamphetamine and morphine on the vertical and horizontal motor activities in mice

The effects of methamphetamine and morphine on the vertical (VMA) and the horizontal motor activities (HMA) in male ddY mice (six weeks of age) was investigated between 9:00 and 13:00, using an apparatus which can differentiate spontaneous motor activity into VMA and HMA, measuring their activities simultaneously. VMA and HMA were evaluated by counting the number of times that an infrared ray was blocked by the mouse in the activity cage. Nine infrared photo-couplers were used to measure the VMA and one to measure the HMA. All measurements were taken at 10 min intervals during the 180 min period after subcutaneous injection of methamphetamine (0.1, 1 and 10 mg/kg) or morphine (2, 10 and 50 mg/kg). A small dose of methamphetamine (0.1 mg/kg) did not exert influence on the counts of the VMA and the HMA, whereas a large dose enhanced both activities, especially at 10 mg/kg, where each activity showed qualitatively different biphasic patterns. On the other hand, three doses of morphine significantly inhibited the VMA for 20 min after administration, while morphine at 2 mg/kg depressed the HMA for 10 min after administration and at 10 mg/kg or more markedly enhanced it during the 180 min observation period. These results show that different doses of methamphetamine and morphine exert different effects on the VMA and the HMA in mice.     

Effects of chlormethiazole (Heminevrin®) on drug discrimination and open-field behavior in gerbils

Chlormethiazole (CMZ, 80 mg/kg) was used as a discriminative stimulus in gerbils; i.e., the presence or absence of certain effects of the drug controlled the choice behavior (left or right turn) of the animals trained to escape electric shocks in a T-maze. Substitution tests with pentobarbital (5–25 mg/kg) and ethanol (0.5–2.5 g/kg) indicated at least a partial similarity in the stimulus effects of CMZ and the two other drugs. The CMZ stimulus was attenuated by 30 mg/kg of the analeptic bemegride (BMG). In Experiment II, gerbils were trained to discriminate CMZ (80 mg/kg) from either of two doses of ethanol (1.5 or 2.0 g/kg). The acquisition rates for the latter groups appeared some-what slower than that noted for the gerbils in Experiment I, although only one measure significantly differentiated the groups. A qualitative difference is proposed as the basis for the discrimination between CMZ and ethanol. Open-field (O-F) tests 5 min after injections of CMZ (80 mg/kg) depressed both horizontal (ambulation) and vertical (rearing) activity, effects found to be counteracted by BMG (30 mg/kg) during the initial segment of the O-F testing. However, a second O-F test carried out 60 min after injections showed that the behaviors of the gerbils treated with the combination of CMZ and BMG were now markedly depressed. The effects of the drug combination on colonic temperature of the gerbils showed similar changes over time; i.e., the mixture of BMG and CMZ resulted in a normal colonic temperature response 5 min postinjection (p.i.), after which a marked drop of temperature followed at the recordings 60 min p.i.