Ambulatory Activity In Mice Research Articles

Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones

Substitutions to the phenethylamine structure give rise to numerous amphetamines and cathinones, contributing to an ever-growing number of abused novel psychoactive substances. Understanding how various substitutions affect the pharmacology of phenethylamines may help lawmakers and scientists predict the effects of newly emerging drugs. Here, we established structure-activity relationships for locomotor stimulant and monoamine transporter effects of 12 phenethylamines with combinations of para-chloro, β-keto, N-methyl, or N-ethyl additions. Automated photobeam analysis was used to evaluate effects of drugs on ambulatory activity in mice, whereas in vitro assays were used to determine activities at transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT) in rat brain synaptosomes. In mouse studies, all compounds stimulated locomotion, except for 4-chloro-N-ethylcathinone. Amphetamines were more potent stimulants than their β-keto counterparts, while para-chloro amphetamines tended to be more efficacious than unsubstituted amphetamines. Para-chloro compounds also produced lethality at doses on the ascending limbs of their locomotor dose-effect functions. The in vitro assays showed that all compounds inhibited uptake at DAT, NET, and SERT, with most compounds also acting as substrates (i.e., releasers) at these sites. Unsubstituted compounds displayed better potency at DAT and NET relative to SERT. Para-chloro substitution or increased N-alkyl chain length augmented relative potency at SERT, while combined para-chloro and N-ethyl substitutions reduced releasing effects at NET and DAT. These results demonstrate orderly SAR for locomotor stimulant effects, monoamine transporter activities, and lethality induced by phenethylamines. Importantly, 4-chloro compounds produce toxicity in mice that suggests serious risk to humans using these drugs in recreational contexts.

Expression of Concern: l-Menthol increases extracellular dopamine and c-Fos-like immunoreactivity in the dorsal striatum, and promotes ambulatory activity in mice.

Expression of Concern: l-Menthol increases extracellular dopamine and c-Fos-like immunoreactivity in the dorsal striatum, and promotes ambulatory activity in mice.

L-Menthol increases extracellular dopamine and c-Fos-like immunoreactivity in the dorsal striatum, and promotes ambulatory activity in mice.

Similar to psychostimulants, the peripheral administration of menthol promotes mouse motor activity, and the neurotransmitter dopamine has been suggested to be involved in this effect. The present study aimed to elucidate the effects of l-menthol on parts of the central nervous system that are involved in motor effects. The subcutaneous administration of l-menthol significantly increased the number of c-Fos-like immunoreactive nuclei in the dorsal striatum of the mice, and motor activity was promoted. It also increased the extracellular dopamine level in the dorsal striatum of the mice. These observations indicated that after subcutaneous administration, l-menthol enhances dopamine-mediated neurotransmission, and activates neuronal activity in the dorsal striatum, thereby promoting motor activity in mice.

Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability.

Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions as to what mechanism(s) of action should be targeted for developing pharmacotherapies. Atypical dopamine transporter (DAT) inhibitors, based on (±)modafinil, have shown therapeutic potential in preclinical models of psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1-3 have impeded further development. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT affinities and metabolic stability in rat liver microsomes. Aminopiperidines 7 (DAT Ki=50.6nM), 21b (DAT Ki=77.2nM) and 33 (DAT Ki=30.0nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.

Affinin and hexahydroaffinin: Chemistry and toxicological profile.

The present work aimed to determine the safety parameters of two new alkamides, affinin and hexahydroaffinin, with antinociceptive activity. To predict the preliminary acute toxicity, we used the acute and subchronic toxicity (50 mg/kg, orally [po]) in Swiss Webster mice. Genotoxicity assayed via analysis of cell micronuclei of the femoral bone marrow in mice; at the same time, metabolic parameters determined from peripheral blood samples. Furthermore, to discard the neuropharmacological effects, we assessed the ambulatory activity in mice to determine the possible effects in the central nervous system. Finally, we used capsaicin as a positive control of alkamides. According to our results, hexahydroaffinin (LD50 ≥ 5,000 mg/kg, po) is significantly less noxious than affinin (LD50 = 1,442.2 mg/kg, po) or capsaicin (LD50 = 489.9 mg/kg, po). In subchronic administration, we did not observe any changes in hematological or biochemical parameters in any compound analyzed from peripheral blood samples. Finally, the data from the genotoxicity assay showed micronuclei formation in 28%, 5%, and 3% of mice in the capsaicin, affinin, and hexahydroaffinin groups, respectively. With the results obtained in the present investigation, we suggest that affinin and hexahydroaffinin are not only useful candidates for possible new drugs but also safe compounds.

Chenopodium incisum Aerial Parts Extract Induces Anxiolytic-Like Effects in Mice

Chenopodium incisum Poir., Amaranthaceae, is employed as a remedy to alleviate susto, a culture-bound syndrome. This study evaluated the anxiolytic-like effect of a single oral dose of a hydroethanolic extract of C. incisum and two of its main constituents, pinostrobin and stigmasterol, in the elevated plus maze and hole-board test in mice. The nonspecific effects of the drugs on the ambulatory activity of mice were evaluated in the open field test. The acute toxicity of the extract was determined, and the extract composition was analyzed. The extract at 50, 100, and 200 mg/kg, as well as pinostrobin and stigmasterol (1 to 30 mg/kg), induced anxiolytic-like effects in both the elevated plus maze and in the hole-board tests, significantly increasing the exploratory behaviors. The anxiolytic actions of drugs were not associated with changes in the ambulatory activity of animals. No evidence of toxicity was observed in the animals treated with hydroethanolic extract of C. incisum. The mean lethal dose was higher than 2000 mg/kg. Chenopodium incisum elicited anxiolytic effects in mice. To the best of our knowledge, this is the first report regarding the anxiolytic effect of pinostrobin. Our results suggest that C. incisum is beneficial to patients with mood disorders.

The aversive, anxiolytic-like, and verapamil-sensitive psychostimulant effects of pulegone.

We investigated the psychostimulant, rewarding, and anxiolytic-like effects of pulegone. Possible interactions between pulegone and menthol concerning their psychostimulant effect were also analyzed. General mouse activity after pulegone treatment, and the interacitons between pulegone and menthol, were determined in the open field. The anxiolytic-like activity, motor coordination and strength force were evaluated using the elevated plus maze (EPM), rotarod test and grasping test, respectively. The motivational properties of pulegone were evaluated by pairing the drug effects on the mice with the least preferred compartment (previously determined) of a conditioned place preference (CPP) apparatus. Pulegone increased mouse locomotor activity and immobilization time. Verapamil, but not diltiazem, haloperidol or picrotoxin, decreased the psychostimulation induced by pulegone. Pulegone also decreased grooming and rearing behaviors and caused motor incoordination and weakness at high doses. Pulegone increased the time spent by mice in the open arms of the EPM, and flumazenil pre-treatment did not alter this effect. Pulegone either produced no CPP or induced conditioned place aversion. The changes in mouse ambulatory activity caused by the association of pulegone with menthol were either lower than those predicted by the theoretical curve or not different from the predicted values. Therefore, pulegone induces a verapamil-sensitive psychostimulant effect that appears to independ on the opening of L-type calcium channels. Pulegone has negative reinforcing properties and seems to possess anxiolytic-like actions unrelated to the benzodiazepine site of the γ-aminobutyric acid type A (GABAA) receptor. Finally, pulegone might act in an addictive or synergic way with menthol.

Evaluation of Central Nervous System Acting Effects of Plant-Derived Essential Oils Using Ambulatory Activity in Mice

Although plant-derived essential oils (EOs) have traditionally been used for treating various kinds of mental disorders, their Central Nervous System (CNS) acting effects have not yet been clarified well. The present study examined effects of 30 kinds of EOs on ambulatory activity, a kind of spontaneous motor activity, in ICR mice. Nineteen kinds of them did not produce any significant effects on the ambulatory activity of mice. Although effects of EOs of lavender, jasmine and neroli on the activity were statistically significant, their CNS acting properties remained unclear. EOs of peppermint, chamomile, thyme, tea tree, rosemary and basil significantly increased the ambulatory activity of mice as well as CNS stimulants, suggesting that they possess CNS stimulant-like effects. In contrast, an EO of myrtle significantly decreased the activity as well as CNS depressants, suggesting that it possesses a CNS depressant-like effect. An EO of palmarosa significantly increased the activity at a lower dose and decreased at a higher dose as well as some kinds of CNS depressants such as ethanol, suggesting that it also possesses a CNS depressant-like effect. These 8 kinds of EOs might be useful for treating some kinds of mental troubles and/or symptoms through their CNS acting effects.

Unusual Effects of Nicotine as a Psychostimulant on Ambulatory Activity in Mice

The present study examined the effect of nicotine, alone and in combination with various drugs that act on the CNS, on ambulatory activity, a behavioral index for locomotion, in ICR (CD-1) strain mice. Nicotine at 0.25–2 mg/kg acutely reduced ambulatory activity of ICR mice. The effect of nicotine was similar to that of haloperidol and fluphenazine but distinct from that of bupropion and methylphenidate. ICR mice developed tolerance against the inhibitory effect of nicotine on ambulatory activity when nicotine was repeatedly administered. This effect was also distinct from bupropion and methylphenidate as they produced augmentation of their ambulation-stimulating effects in ICR mice. Nicotine reduced the ambulation-stimulating effects of bupropion and methylphenidate as well as haloperidol and fluphenazine. Taken together, nicotine exhibited unusual effects as a psychostimulant on ambulatory activity in ICR mice.

Dopamine antagonists can inhibit methamphetamine sensitization, but not cocaine sensitization, when assessed by ambulatory activity in mice.

The repeated subcutaneous administration of methamphetamine (2 mg kg-1) and cocaine (10 mg kg-1) at 3-4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.003-0.03 mg kg-1) and YM-09151-2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide; 0.003-0.03 mg kg-1), the selective dopamine D1 and D2 antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151-2 in the repeated administration schedule. Although SCH 23390 (0.01-0.1 mg kg-1) and YM-09151-2 (0.01-0.1 mg kg-1) also reduced the ambulation-increasing effect of cocaine (10 mg kg-1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0.03 mg kg-1) or YM-09151-2 (0.03 and 0.1 mg kg-1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D1 and D2 antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.

Interactions of opioids with caffeine: evaluation by ambulatory activity in mice.

Morphine (up to 10 mg kg-1), buprenorphine (up to 0.1 mg kg-1), pentazocine (30 mg kg-1) and caffeine (up to 10 mg kg-1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D1- and D2-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0.1-3 mg kg-1) itself did not change mouse ambulation, at 3 mg kg-1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg-1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg-1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg-1) with buprenorphine (0.3 mg kg-1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg-1) by the repeated treatment with buprenorphine (0.3 mg kg-1) was inhibited by caffeine (10 mg kg-1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on mu- or sigma-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.

Ambulation-promoting effect of peppermint oil and identification of its active constituents

Various plant-derived essential oils (EOs) have traditionally been used in the treatment of mental disorders, despite a lack of scientific evidence. In a previous study, we demonstrated that certain EOs possess behavioral effects, a finding that supports our original hypotheses that EOs possess psychoactive actions. The present study was conducted in order to obtain further evidence to support our hypothesis. Peppermint oil, a type of EO, is believed to be effective for treating mental fatigue. When the oil was administered intraperitoneally to ICR mice, the ambulatory activity of mice increased dramatically. We identified α-pinene, β-pinene, ( R)-(+)-limonene, 1,8-cineol, isomenthone, menthone, menthol, ( R)-(+)-pulegone, menthyl acetate and caryophyllene as constituent elements of peppermint oil by GC–MS analysis. We then examined the effect of each constituent element of peppermint oil on ambulatory activity in mice. Intraperitoneal administration of 1,8-cineol, menthone, isomenthone, menthol, ( R)-(+)-pulegone, menthyl acetate and caryophyllene significantly increased ambulatory activity in mice, suggesting that these chemicals are the behaviorally active elements of peppermint oil. Intravenous administration of these substances to mice induced a significant increase in ambulatory activity at much lower doses. The present study provides further evidence demonstrating that EOs possess pharmacological actions on behavior. In addition, our finding revealed that the action of peppermint oil comes from its constituent elements.

O–306 - Behavioral pharmacology of plant-derived substances (3): Effects of peppermint oil on ambulatory activity in mice and identification of its effective components

O–306 - Behavioral pharmacology of plant-derived substances (3): Effects of peppermint oil on ambulatory activity in mice and identification of its effective components

Tris(2-chloroethyl)phosphate Increases Ambulatory Activity in Mice: Pharmacological Analyses of Its Neurochemical Mechanism

The present study was conducted to clarify the acute effect of tris(2-chloroethyl)phosphate (TRCP), an organophosphate flame-retardant, on spontaneous ambulatory activity (AA) in male ICR mice and to examine the neurochemical mechanism of this effect. Single dose administration of 200 mg/kg ip of TRCP increased AA in ICR mice. Neither the nicotinic cholinergic antagonist mecamylamine (MA) nor the muscarinic cholinergic antagonist scopolamine (SCP) affected the AA response to TRCP. On the other hand, the benzodiazepine agonist diazepam (DZ), the GABAAagonist muscimol (MUS) and the GABABagonistbaclofen (BAC) all attenuated the effect of TRCP. DZ and MUS blocked the increase of AA within the first 10 min after administration of TRCP. These drugs did not attenuate the AA-increasing effect of SCP, suggesting that the mechanism of TRCP action is distinct from that of SCP. MUS and BAC did, but DZ did not, inhibit the AA increasing effect of the dopaminergic agonist apomorphine (APO), suggesting that dopamine is involved in the control of AA, and that GABA can affect AA through interaction with dopaminergic neurons. These results suggest that TRCP acts as a GABA antagonist and not as a cholinergic agonist, and that TRCP increases AA in ICR mice through a GABAergic mechanism.

Characteristics of Behavioural Stimulant Effect of N‐Cyanomethylmethamphetamine, a Main Product of Smoking Methamphetamine Mixed with Tobacco: Evaluation by Ambulatory Activity in Mice

N-cyanomethylmethamphetamine is main product of smoking methamphetamine HCl (CAS code value: 537-46-2, molar mass: 185.70 g/mol) mixed with tobacco, and has a central stimulant action. The aims of this study were to assess in terms of ambulation in mice whether repeated administration of N-cyanomethylmethamphetamine HCl (molar mass: 211.70 g/mol) induced sensitization to its central stimulant effect, and whether there were cross-sensitization from N-cyanomethylmethamphetamine HCl to methamphetamine HCl, and from methamphetamine HCl to N-cyanomethylmethamphetamine HCl. N-cyanomethylmethamphetamine HCl 14.2 and 47.2 mumol/kg subcutaneously dose-dependently accelerated ambulation of mice. Five administrations at 3 day intervals caused sensitization, the activity counts in the fifth administration being approximately 2.6 and 1.6 times, higher respectively, than those in the first administration. Furthermore, the mice repeatedly given 14.2 and 47.2 mumol/kg N-cyanomethylmethamphetamine HCl exhibited cross-sensitization to methamphetamine HCl (10.8 mumol/kg subcutaneously). Whereas 1.4 and 4.7 mumol/kg N-cyanomethylmethamphetamine HCl did not induce significant acceleration of the ambulation throughout the 5 repeated administrations, nor cross-sensitization to methamphetamine HCl. On the other hand, the 5 repeated administrations of methamphetamine HCl (10.8 mumol/kg) also caused sensitization to its ambulation-increasing effect, and the activity count in the fifth administration attained approximately 2.0 times higher than that in the first administration. The mice given methamphetamine HCl demonstrated cross-sensitization to 1.42-14.2 mumol/kg N-cyanomethylmethamphetamine HCl. Haloperidol (CAS code value: 52-86-8, molar mass: 375.88 g/mol; 0.027-0.80 mumol/kg subcutaneously) dose-dependently reduced the ambulation-increasing effects of N-cyanomethylmethamphetamine HCl and methamphetamine HCl in the drug-naive, and N-cyanomethylmethamphetamine HCl- and methamphetamine HCl-sensitized mice. These dose-effect relationships were similar between groups. The present results suggest that N-cyanomethylmethamphetamine HCl has a behavioural stimulant effect almost similar to that of methamphetamine HCl.

Inhibition of Cocaine Sensitization by MK-801, a Noncompetitive N-Methyl-D-Aspartate (NMDA) Receptor Antagonist: Evaluation by Ambulatory Activity in Mice

Alterations of cocaine effects, which were induced by prior repeated 5-time administration of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (i.p.) alone or in combination with cocaine (s.c.) at 3- to 4-day intervals, were investigated by means of ambulatory activity in mice. The repeated administration of either cocaine (10 and 20 mg/kg) alone or MK-801 (0.3 mg/kg) alone progressively enhanced each drug’s effect. The enhanced effects of cocaine and MK-801 were estimated to be 1.8-2.2 times and about 1.4 times, respectively, as great as those at the 1st administration. Although the coadministration of MK-801 with cocaine produced a significant enhancement in the ambulation-increasing effect, the comparatively higher doses of MK-801 (0.3 and 1 mg/kg) acted not only to reduce cocaine sensitivity but also to inhibit the development of cocaine sensitization. Thus, the mice that had been given MK-801 (0.3 and 1 mg/kg) alone 5 times showed lower sensitivities to cocaine (20 mg/kg) than the mice given saline alone. The mice coadministered MK-801 (0.3 and 1 mg/kg) with cocaine (10 and 20 mg/kg) also exhibited lower sensitivities to cocaine (10 and 20 mg/kg) than those given cocaine alone. However, MK-801 could not ameliorate the established sensitization to cocaine. Similar interactions have been demonstrated between MK-801 at 1 mg/kg, but not 0.3 mg/kg, and methamphetamine. The present results indicate that MK-801 can inhibit the development of sensitization to cocaine at a lower dose than that required to inhibit methamphetamine sensitization.

Can posttreatment with the selective dopamine D 2 antagonist, YM-09151-2, inhibit induction of methamphetamine sensitization? Evaluation by ambulatory activity in mice

Effects of YM-09151-2; cis-N-(1-benzyl-2-methyl pyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide (YM), a potent and selective dopamine D 2 antagonist, on sensitization to methamphetamine (MAP) were investigated by means of ambulatory activity in mice. YM (0.003–0.03 mg/kg SC) reduced not only the acute ambulation-increasing effect of MAP (2 mg/kg SC) but also the induction of MAP sensitization when it was simultaneously administered with MAP in the repeated administration at 3/2-4 day intervals. Moreover, the post 3-h treatment with YM (0.01 and 0.03 mg/kg) following each MAP administration, at which time the acute ambulation-increasing effect of MAPalmost disappeared, significantly and dose dependently inhibited the induction of MAP sensitization. The post 24-h treatment with YM did not show such effect. The present results suggest that blockade of the dopamine D 2 receptors during postearly period following MAP administration is responsible for protecting the induction of MAP sensitization by means of ambulatory activity in mice.

Early post-treatment with haloperidol retards induction of methamphetamine sensitization in mice

The repeated administration of methamphetamine (2 mg/kg s.c.) at 3- to 4-day intervals induced sensitization to its ambulation-increasing effect in mice. When the simultaneous administration of methamphetamine with haloperidol (0.025, 0.1 and 0.4 mg/kg s.c.) was carried out, the acute ambulation-increasing effect as well as the development of sensitization were haloperidol-dose-dependently inhibited. Moreover, treatment with haloperidol (0.1 and 0.4 mg/kg) 3 h following each methamphetamine administration, which per se did not affect the acute ambulation increase caused by methamphetamine, could protect against the induction of methamphetamine sensitization in a dose-dependent manner, whereas treatment with haloperidol after 24 h did not show such protective action. The present results suggest that blockade of the dopamine receptors at an early period following each administration of methamphetamine may be responsible for the delay in development of methamphetamine sensitization as expressed by ambulatory activity of mice.

Effects of dopamine antagonism on methamphetamine sensitization: Evaluation by ambulatory activity in mice

SCH 23390 (SCH: 0.001–0.03 mg/kg SC) and YM: 0.001–0.03 mg/kg SC), the selective dopamine D 1 and D 2 antagonists, rspectively, reduced dose-dependently the ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg SC) in mice. The sensitization to MAP was inhibited when it was administered in combination with SCH (0.003–0.03 mg/kg) or YM (0.003–0.03 mg/kg) in the repeated administration regimen. The inhibitory action of YM on the MAP sensitization was more prominent than that of SCH. However, the repeated treatment with either SCH or YM could not ameliorate the established MAP sensitization Rather, the repeated treatment with the highest dose of YM (0.03 mg/kg) increased the MAP sensitivity in both the MAP-sensitized and drug-naive mice. SCH had no such action. The present results suggest that the dopamine D 2 receptors are more intimately involved than the dopamine D 1 receptors in the increased sensitivity to MAP induced by the repeated treatment with MAP itself, behavioral sensitization, or dopamine antagonists, denervation supersensitivity.

Effects of SUN 8399, a Potent and Selective 5-HT1A Agonist, on Conflict Behavior and Ambulatory Activity in Mice: Comparison with Those of Buspirone, Tandospirone and Diazepam

Behavioral effects of p.o. administration of SUN 8399, a selective 5-HT1A agonist, on the operant behavior under a MULT VI 1.5 min/FR 5-punishment schedule of food reinforcement and on the ambulatory activity were evaluated in mice, and the characteristics were compared with those of other 5-HT1A agonists, buspirone and tandospirone, and the benzodiazepine diazepam. Diazepam (3 and 10 mg/kg) significantly increased the punished response without eliciting any significant change in the non-punished response; i.e., showing anticonflict action. SUN 8399 (3-30 mg/kg) and buspirone (1-10 mg/kg) did not significantly change either the punished or non-punished responses. Tandospirone significantly increased the non-punished response at 10 mg/kg, but significantly decreased both the punished and non-punished responses at 30 mg/kg. The single administration of SUN 8399 (10 mg/kg), buspirone (3 and 30 mg/kg) and tandospirone (10 and 30 mg/kg) significantly increased the ambulatory activity, while diazepam tended to decrease it. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was reduced by buspirone (10 and 30 mg/kg) and tandospirone (10 and 30 mg/kg), but enhanced by diazepam (3 and 10 mg/kg). Buspirone (30 mg/kg), tandospirone (10 and 30 mg/kg) and diazepam (3 and 10 mg/kg) significantly reduced the ambulation-increasing effect of scopolamine (0.5 mg/kg, s.c.). SUN 8399 (3-100 mg/kg) did not modify the effects of either methamphetamine or scopolamine. The present results suggest that 5-HT1A agonists scarcely show anticonflict action on the Geller-type conflict behavior in mice. However, SUN 8399 possesses different behavioral characteristics from those of the other two 5-HT1A agonists in terms of interactions with methamphetamine and scopolamine.