Ambulation-increasing Effect Of Methamphetamine Research Articles

Effects of Sulpiride and Nemonapride, Benzamide Derivatives Having Distinct Potencies of Antagonistic Action on Dopamine D2 Receptors, on Sensitization to Methamphetamine in Mice

The acute ambulatory stimulation by methamphetamine (2 mg kg-1 S.C.) was dose-dependently reduced by 3-h pretreatment or combined treatment with sulpiride (1-100 mg kg-1 S.C.), and combined treatment with nemonapride (0.003-0.03 mg kg-1 S.C.), benzamide derivatives having selective antagonistic action on dopamine D2 receptors. The repeated (5 times) administrations of methamphetamine at 3-day intervals induced a sensitization to its ambulation-increasing effect, and the sensitization was significantly inhibited by 3-h pretreatment with either sulpiride (10-100 mg kg-1), or combined treatment with either sulpiride (3 or 10 mg kg-1) or nemonapride (0.01 or 0.03 mg kg-1) at each methamphetamine administration. Although the ambulation-increasing effect of methamphetamine disappeared by 3 h after the administration, the 3-h post-treatment with sulpiride (3 mg kg-1) or nemonapride (0.03 mg kg-1) after each methamphetamine administration was effective for a significant inhibition of the induction of methamphetamine sensitization, whereas, the comparatively higher doses of sulpiride (30 and 100 mg kg-1 in the combined treatment, and 10-100 mg kg-1 in the post-treatment) did not inhibit the methamphetamine sensitization. On the other hand, the repeated administrations of sulpiride (30 and 100 mg kg-1) alone, but not any doses of nemonapride, at 3-day intervals elicited a significant increase in the sensitivity to methamphetamine. These results suggest that, although the potencies of the anti-methamphetamine effects of sulpiride and nemonapride differ by a factor of 3000, they inhibit the induction of sensitization to methamphetamine in the pretreatment, combined treatment and early post-treatment schedules. However, it is also suggested that the repeated treatment with comparatively higher doses of sulpiride may produce a denervation supersensitivity of dopamine D2 receptors, and resultant increase in the sensitivity to methamphetamine.

Effects of Tetrabenazine on Methamphetamine-Induced Hyperactivity in Mice are Dependent on Order and Time-Course of Administration

The ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg SC) in mice persisted for about 3 h. Tetrabenazine (TBZ: 4 mg/kg SC), a depleter of monoamines from the cytoplasmic pool did not increase ambulation on its own. Pretreatment with TBZ at 1.5 h before administration of MAP inhibited the stimulant effect of MAP. In contrast, combined administration of two drugs resulted in a transient but considerable enhancement of MAPs stimulant effect. Post-MAP treatment with TBZ at 0.5–2 h hardly modified MAPs behavioral effects. In contrast, 3–6 h post-MAP treatment with TBZ induced a transient increase in activity, although the stimulant effect of MAP had already disappeared. The maximum increase in ambulatory stimulation was produced by 4-h post-MAP treatment with TBZ. The inhibitory effect of TBZ pretreatment on MAP-induced hyperactivity, as well as the transient hyperactivity elicited by TBZ when administered along with MAP, or 4 h after MAP, was dose-dependent. Preliminary studies revealed that transient hyperactivity was never produced by combination of GBR-12909 (a selective dopamine reuptake inhibitor) with TBZ or MAP with oxypertine (a selective norepinephrine releaser/depleter), but produced by combination of nialamide (a monoamine oxidase inhibitor) with TBZ. Inhibition of MAPs effects by TBZ pretreatment suggests that enhancement of dopamine release from cytoplasmic pool, and inhibition of dopamine reuptake by MAP, are involved in MAPs acute behavioral effects. Further, the fact that neither TBZ administration following GBR-12909 pretreatment, nor oxypertine treatment following MAP pretreatment, elicited transient hyperactivity suggests that dopamine is involved in hyperactivity elicited by post-MAP treatment with TBZ. It is also suggested that inhibition of monoamine oxidase (MAO) by MAP and dopamine displacement by TBZ may be responsible for the transient stimulation produced by 3–6 h post-MAP treatment with TBZ. It is hypothesized that the MAO inhibitory action of MAP persists after cessation of its acute stimulant effect, possibly up to 6 h after administration.

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.

Circadian variation in R-THBP-induced enhancement of the ambulation-increasing effect of methamphetamine on mice.

6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP), a co-factor for tyrosine hydroxylase and tryptophan hydroxylase, induces the enhancement of ambulation-increasing effect of methamphetamine on mice. In this study, we investigated the circadian variation in the interaction between R-THBP and methamphetamine by changing the time-of-day of both methamphetamine administration and pretreatment with R-THBP. The mouse's ambulatory activity was measured by a tilting-type activity cage for 4 hr. In the daytime, but not in the nighttime, the ambulation-increasing effect of methamphetamine (1 and 2 mg/kg, s.c.) was significantly enhanced by the pretreatment with R-THBP (100 mg/kg, s.c., 2 or 6 hr before). These data indicate the possibility that peripherally administered R-THBP increases the biosynthesis of catecholamine especially in the daytime.

Behavioral evaluation of psycho-pharmacological and psychotoxic actions of methylxanthines by ambulatory activity and discrete avoidance in mice.

The behavioral effects of methylxanthines, caffeine, theophylline and theobromine, were compared by means of ambulatory activity and discrete lever-press avoidance response in mice. The single oral administration of 10-100 mg/kg of caffeine, 30-300 mg/kg of theophylline, and 10 mg/kg of theobromine significantly increased the mouse's ambulatory activity. However, 1000 mg/kg of theobromine decreased the activity. The ambulation-increasing effect of methamphetamine (2 mg/kg s.c.) was enhanced by coadministration with caffeine (3-100 mg/kg), theophylline (10-300 mg/kg), and theobromine (10-100 mg/kg). On the other hand, comparatively higher doses of caffeine (up to 30 mg/kg) slightly but significantly decreased the avoidance rate without eliciting any significant change in the response rate. Theobromine significantly decreased the response rate at higher than 300 mg/kg, and the avoidance rate at higher than 100 mg/kg. Furthermore, 1000 mg/kg of theobromine was much toxic for mice, i.e., half mice died within a few hr after the end of the 1-hr avoidance session. Theophylline did not produce any significant change in the avoidance response at the dose range of 3-300 mg/kg. These results may indicate the relative order of the centrally stimulant and/or behavioral toxic actions of methylxanthines in human.

Effects of YM-09151-2, a Potent and Selective Dopamine D2 Antagonist, on the Ambulation-Increasing Effect of Methamphetamine in Mice

The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was markedly reduced by YM-09151-2 at 0.01 mg/kg, s.c, in drug-naive mice. The development of reverse tolerance to the ambulation-increasing effect of methamphetamine was also inhibited almost completely when 0.01 mg/kg, s.c, of YM-09151-2 was administered concomitantly in each administration. However, YM-09151-2, at 0.01 mg/kg, was partially suppressed the effect of methamphetamine in mice that exhibited reverse tolerance to methamphetamine.

Effects of YM-09151-2, a potent and selective dopamine D2 antagonist, on the ambulation-increasing effect of methamphetamine in mice.

The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was markedly reduced by YM-09151-2 at 0.01 mg/kg, s.c., in drug-naive mice. The development of reverse tolerance to the ambulation-increasing effect of methamphetamine was also inhibited almost completely when 0.01 mg/kg, s.c., of YM-09151-2 was administered concomitantly in each administration. However, YM-09151-2, at 0.01 mg/kg, was partially suppressed the effect of methamphetamine in mice that exhibited reverse tolerance to methamphetamine.

Enhancement of Ambulation-lncreasing Effect of Methamphetamine by Peripherally-Administered 6R-L-Erythro-5,6,7,8-Tetrahydrobiopterin (R-THBP) in Mice

Behavioral effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP), a co-factor for tyrosine hydroxylase and tryptophan hydroxylase, were investigated by means of ambulatory activity in mice. Single administration of R-THBP (50 and 100 mg/kg, s.c.) showed no significant effect on the mouse’s ambulatory activity for 5 hr. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was dramatically enhanced and prolonged by the pretreatment with R-THBP (100 mg/kg, s.c.) 0, 2. 6, 12 and 24 hr before, but not 18 or 36 hr before, the methamphetamine administration. However, when combined administration of R-THBP (100 mg/kg, s.c, 2 hr before) with methamphetamine (2 mg/kg, s.c.) was repeated at intervals of 3-4 days, the enhancement by R-THBP of the methamphetamine effect was observed only in the 1st and 2nd administration, but not in the later administration. The pretreatment with R-THBP (100 mg/kg, s.c, 2 hr before) enhanced the ambulation-increasing effect of ephedrine (80 mg/kg, i.p.), but failed to modify those of cocaine (20 mg/kg, s.c), mazindol (2.5 mg/kg, s.c), bromocriptine (8 mg/kg, i.p.), morphine (20 mg/kg, s.c.) and scopolamine (0.5 mg/kg, s.c). It is noteworthy that R-THBP differentially modifies the ambulation-increasing effect of the above-mentioned drugs.

Effects of buflomedil on ambulatory activity and discrete avoidance responses in mice

Behavioral effects of buflomedil, 4-(1-pyrrolidinyl)-1-(2,4,6-trimethoxyphenyl)-1-butanone hydrochloride, a vasoactive drug, were investigated by means of ambulatory activity and the discrete lever-press and shuttle avoidance responses in mice. Single administration of buflomedil (1,3,10,30 and 100 mg/kg, p.o.) produced no marked change in the ambulatory activity and the discrete lever-press avoidance response. However, the ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was suppressed by 30 mg/kg of buflomedil. The avoidance-suppressing effect of chlorpromazine (1 mg/kg, s.c.) was enhanced by 3 approximately 100 mg/kg of buflomedil, but the avoidance-suppressing effect of physostigmine (0.2 mg/kg, s.c.) was not modified by the same doses of buflomedil. On the other hand, the acquisition of the discrete shuttle avoidance response was not affected markedly by buflomedil 3, 10 and 30 mg/kg, p.o.) when the drug was administered immediately before the start of training. The present results suggest that buflomedil shows a central suppressing effect, probably through catecholaminergic neuronal systems, and that the effect is detectable only by the combined administration with typical psychoactive drugs.

Strain differences in the reverse tolerance to methamphetamine and changes in catecholaminergic neurons in mice.

The effect of methamphetamine (MAP) on ambulatory activity and neurochemical changes in catecholaminergic neurons in the brain were investigated in dd and C57BL/6 strains of male mice. The mice were given repeatedly MAP at 2 mg/kg, s.c., 10 times at a fixed interval of 4 days. Single MAP markedly increased the ambulatory activity in both strains of mice. The ambulation-increasing effect was progressively enhanced without accompanying stereotyped behaviors when the drug was repeatedly given. The dd mice showed higher susceptibility not only to single MAP but also to the enhancing effect of the drug (reverse tolerance) that the C57BL/6 mice. On the other hand, non-treated dd mice exhibited lower maximum densities of 3H-spiperone binding sites in the striatum and 3H-WB4101 binding sites in the cortex and hippocampus than non-treated C57BL/6 mice. In contrast, the dd mice exhibited higher noradrenaline turnover than the C57BL/6 mice in the brain regions examined. The repeated administration of MAP produced decrease in the densities of both 3H-spiperone and 3H-WB4101 binding sites in the corresponding regions with increase in catecholamine turnover in dd mice. However, the similar changes were observed only in 3H-WB4101 binding sites and noradrenaline turnover in C57BL/6 mice. These results suggest that the ambulation-increasing effect of MAP is positively correlated with catecholamine turnover, while it was correlated negatively with the densities of catecholamine binding sites. Furthermore, the enhancing effect of MAP is supposed to have been partially elicited by changes in brain catecholaminergic systems, in particular an increase in catecholamine turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect alteration of methamphetamine by amino acids or their salts on ambulatory activity in mice.

Effect alterations of methamphetamine by pretreatment of amino acids or their salts on ambulatory activity in mice were investigated to confirm a fact that certain amino acids, particularly monosodium L-glutamate, are added to methamphetamine by the street users, and that the amino acids augment the effect of methamphetamine. The ambulatory activity of mouse was measured by a tilting-type round activity cage of 25 cm in diameter. The amino acids or their salts tested were monosodium L-glutamate, monosodium L-aspartate, gamma-amino-butyric acid, L-alanine, L-lysine hydrochloride and L-arginine hydrochloride. A single administration of each chemical at doses of 1 and 2 g/kg i.p. did not induce a marked change in the ambulatory activity in mice. Methamphetamine 2 mg/kg s.c. induced an increase in the ambulatory activity with a peak at 40 min after the administration, and the increased ambulatory activity persisted for 3 hr. The ambulation-increasing effect of methamphetamine was augmented by the pretreatment of monosodium L-glutamate and monosodium L-aspartate at 30 min before the methamphetamine administration, while attenuated by the pretreatment of L-lysine hydrochloride and L-arginine hydrochloride in a dose-dependent manner. Gamma-aminobutyric acid and L-alanine did not affect the effect of methamphetamine. Similar augmentation and attenuation in the ambulation-increasing effect of methamphetamine were induced by the pretreatment of sodium bicarbonate 0.9 g/kg i.p. (urinary alkalizer) and ammonium chloride 0.07 g/kg i.p. (urinary acidifier), respectively. The urinary pH level was elevated by the administration of monosodium L-glutamate, monosodium L-aspartate and sodium bicarbonate, and decreased by L-lysine hydrochloride, L-arginine hydrochloride and ammonium chloride. Gamma-aminobutyric acid and L-alanine did not elicit a marked change in the urinary pH level. The present experiment confirms the fact in human that monosodium L-glutamate augments the effect of methamphetamine. Moreover, the present results suggest that monosodium salts of acidic amino acids augment, and conversely monohydrochloric salts of basic amino acids attenuate the effect of methamphetamine. The alterations of the ambulation-increasing effect of methamphetamine may be due to the urinary excretion rates of the drug through changes in the urinary pH level after the administration of amino acids or their salts.