Methamphetamine-induced Hyperactivity In Mice Research Articles

Effects of cloperastine, a non-narcotic antitussive, on the expression of GIRK channels in the brain of methamphetamine-induced hyperactive mice

Objectives: Centrally-acting antitussives with inhibitory effects on G protein-coupled inwardly rectifying potassium (GIRK) channels have been shown to also inhibit methamphetamine-induced hyperactivity in mice. In this study, we examined if cloperastine, which is the most potent inhibitor of the GIRK channels among antitussives, is sensitive to the expression levels of GIRK channels in the brain of methamphetamine-treated mice. Materials and Methods: The brain tissues have been removed and the total RNA has been extracted from tissues. The mRNA levels were evaluated using semiquantitative reverse transcription-polymerase chain reaction. Results: The concentration levels of the mRNA of GIRK channels within the ventral midbrain of methamphetamine-treated mice increased as compared with that in control and cloperastine reduced an upregulation in GIRK2, one of the subunits of the GIRK channels, by the injection of methamphetamine. Conclusion: These findings suggest that cloperastine might ameliorate hyperactivity by inhibiting the GIRK channels in the brain.

Recombinant Adeno-Associated Virus-Mediated Expression of Methamphetamine Antibody Attenuates Methamphetamine-Induced Hyperactivity in Mice

Methamphetamine (Meth) is one of the most frequently abused drugs worldwide. Recent studies have indicated that antibodies with high affinity for Meth reduce its pharmacological effects. The purpose of this study was to develop a technique for virus-based passive immunization against Meth effects. We generated a recombinant adeno-associated virus serotype-8 vector (AAV-MethAb) carrying the gene for a Meth-specific monoclonal antibody (MethAb). Infection of 293 cells with AAV-MethAb resulted in the expression and secretion of antibodies which bind to Meth. The viral vector was then examined in adult ICR mice. Systemic administration of AAV-MethAb resulted in long-term expression of MethAb in the serum for up to 29 weeks. Serum collected from the animals receiving AAV-MethAb retained a high specificity for (+)-Meth. Animals were challenged with Meth five weeks after viral injection. Meth levels in the brain and serum were reduced while Meth-induced locomotor activity was significantly attenuated. In conclusion, AAV-MethAb administration effectively depletes Meth from brain and serum while reducing the behavioral response to Meth, and thus is a potential therapeutic approach for Meth abuse.

N-phenylpropyl-N′-substituted piperazines occupy sigma receptors and alter methamphetamine-induced hyperactivity in mice

This study examined the effect of the N-phenylpropyl-N′-substituted piperazine ligands SA4503 (3.4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [125I]E-IA-DM-PE-PIPZE and [125I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED50=0.2–0.6μmol/kg) with similar potency, but none occupied the transporter (ED50>10μmol/kg). At the highest dose tested (31.6μmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1–3.16μmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine's behavioral effects.

Centrally acting non-narcotic antitussives prevent hyperactivity in mice: Involvement of GIRK channels

We have previously reported that centrally acting non-narcotic antitussives inhibited G protein-coupled inwardly rectifying potassium (GIRK) channel-activated currents, and that the antitussives had multiple pharmacological actions on various models of intractable brain diseases in rodents. In this study, the question of whether these antitussives inhibit drug-induced hyperactivity in mice was investigated. Antitussives, such as cloperastine and tipepidine, at cough suppressant doses, inhibited an increase in ambulation of mice neonatally treated with 6-hydroxydopamine. In addition, all antitussives studied inhibited an increase in methamphetamine-induced hyperactivity in mice. Methylphenidate, which is used for treatment of ADHD, inhibited 6-hydroxydopamine-lesion-induced, but not methamphetamine-induced, hyperactivity in mice. By the rota-rod test, the drugs had little effect on motor coordination of the hyperactive mice. Significant correlation was found between the ameliorating effects of antitussives on methamphetamine-induced hyperactivity and their inhibitory actions on GIRK channel currents (coefficient factor, 0.998). Furthermore, tertiapin, a GIRK channel blocker, prevented an increase in methamphetamine-induced hyperactivity of mice. These results demonstrated that antitussive drugs (cloperastine, tipepidine and caramiphen) possessing inhibitory action on GIRK channels inhibit drug-induced hyperactivity in mice, suggesting that such antitussives may potentially be therapeutic for patients with ADHD.

Discovery of the first potent and orally available agonist of the orphan G-protein-coupled receptor 52.

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D2 receptor signaling and activates dopamine D1/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds 2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC50 = 7.53 ± 0.08) and good pharmacokinetic properties. Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function.

Pharmacological Properties and Procognitive Effects of ABT-288, a Potent and Selective Histamine H3Receptor Antagonist

Blockade of the histamine H(3) receptor (H(3)R) enhances central neurotransmitter release, making it an attractive target for the treatment of cognitive disorders. Here, we present in vitro and in vivo pharmacological profiles for the H(3)R antagonist 2-[4'-((3aR,6aR)-5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one (ABT-288). ABT-288 is a competitive antagonist with high affinity and selectivity for human and rat H(3)Rs (K(i) = 1.9 and 8.2 nM, respectively) that enhances the release of acetylcholine and dopamine in rat prefrontal cortex. In rat behavioral tests, ABT-288 improved acquisition of a five-trial inhibitory avoidance test in rat pups (0.001-0.03 mg/kg), social recognition memory in adult rats (0.03-0.1 mg/kg), and spatial learning and reference memory in a rat water maze test (0.1-1.0 mg/kg). ABT-288 attenuated methamphetamine-induced hyperactivity in mice. In vivo rat brain H(3)R occupancy of ABT-288 was assessed in relation to rodent doses and exposure levels in behavioral tests. ABT-288 demonstrated a number of other favorable attributes, including good pharmacokinetics and oral bioavailability of 37 to 66%, with a wide central nervous system and cardiovascular safety margin. Thus, ABT-288 is a selective H(3)R antagonist with broad procognitive efficacy in rodents and excellent drug-like properties that support its advancement to the clinical area.

Pharmacological Properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H3 Receptor Antagonist

Acute pharmacological blockade of central histamine H3 receptors (H3Rs) enhances arousal/attention in rodents. However, there is little information available for other behavioral domains or for repeated administration using selective compounds. ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] exemplifies such a selective, nonimidazole H3R antagonist with high affinity for rat (pK(i) = 8.9) and human (pK(i) = 9.5) H3Rs. Acute functional blockade of central H3Rs was demonstrated by blocking the dipsogenia response to the selective H3R agonist (R)-alpha-methylhistamine in mice. In cognition studies, acquisition of a five-trial, inhibitory avoidance test in rat pups was improved with ABT-239 (0.1-1.0 mg/kg), a 10- to 150-fold gain in potency, with similar efficacy, over previous antagonists such as thioperamide, ciproxifan, A-304121 [(4-(3-(4-((2R)-2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)(cyclopropyl) methanone], A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl) phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide], and A-349821 [(4'-(3-((R,R)2,5-dimethyl-pyrrolidin-1-yl)-propoxy)-biphenyl-4-yl)-morpholin-4-yl-methanone]. Efficacy in this model was maintained for 3 to 6 h and following repeated dosing with ABT-239. Social memory was also improved in adult (0.01-0.3 mg/kg) and aged (0.3-1.0 mg/kg) rats. In schizophrenia models, ABT-239 improved gating deficits in DBA/2 mice using prepulse inhibition of startle (1.0-3.0 mg/kg) and N40 (1.0-10.0 mg/kg). Furthermore, ABT-239 (1.0 mg/kg) attenuated methamphetamine-induced hyperactivity in mice. In freely moving rat microdialysis studies, ABT-239 enhanced acetylcholine release (0.1-3.0 mg/kg) in adult rat frontal cortex and hippocampus and enhanced dopamine release in frontal cortex (3.0 mg/kg), but not striatum. In summary, broad efficacy was observed with ABT-239 across animal models such that potential clinical efficacy may extend beyond disorders such as ADHD to include Alzheimer's disease and schizophrenia.

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.

Methamphetamineによるマウスの運動量増加に対するL-histidineの拮抗作用に関する研究

Methamphetamineによるマウスの運動量増加に対するL-histidineの拮抗作用に関する研究

選択的セロトニン取り込み阻害作用を有する新しい抗うつ薬Ｐａｒｏｘｅｔｉｎｅの行動薬理学的研究

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

A behavioral pharmacological study on CCK-8 related peptides in mice

The effects of CCK-8, ceruletide, their non-sulfated forms and CCK-4 on locomotor activity and rearing in mice were examined. CCK-8 and ceruletide, but not their non-sulfated forms and CCK-4, significantly inhibited the behavioral parameters dose-dependently. The inhibitory effects of CCK-8 and ceruletide were similar, but ceruletide acted more slowly and its inhibitory effect continued much longer than CCK-8, suggesting a difference in stability with the chemical structure. The antagonistic effects of ceruletide on behavioral changes induced by DA agonists were also examined. Peripherally injected ceruletide antagonized both methylphenidate- and methamphetamine-induced hyperactivity in mice dose-dependently, whereas it had no dose-related antagonistic effect on methylphenidate-induced stereo-typed behavior. Ceruletide also significantly inhibited apomorphine-induced hyperactivity when injected peripherally. However, no obvious dose-response relationship was observed in either intensity or duration of inhibitory action of ceruletide. These findings suggest that ceruletide does not interfere with dopaminergic transmission due to the blockade of postsynaptic DA receptors in the brain. In conclusion, peripheral injection of CCK-8 and ceruletide may affect directly or indirectly dopamine function producing behavioral changes that resemble those of neuroleptics in some respects.