The selective µ opioid receptor antagonist ß-funaltrexamine attenuates methamphetamine-induced stereotypical biting in mice.

We investigated whether pretreatment with opioid receptor antagonists affected methamphetamine (METH)-induced stereotypy in mice. Pretreatment of male ICR mice with naloxone, a relatively non-selective opioid receptor antagonist, significantly attenuated the total incidence of METH-induced stereotypical behavior compared with saline vehicle-pretreated subjects. Furthermore, the distribution of METH-induced stereotypical behavior was affected by naloxone administration. Thus, METH-induced stereotypical sniffing and persistent locomotion were significantly increased by naloxone treatment while stereotypical biting was reduced. One way to interpret this pattern of effects is that pretreatment with naloxone appeared to produce a shift in the dose-response curve for METH. Thus, while the more intense forms of oral-facial stereotypies were reduced, increased persistent locomotion was observed in mice given naloxone followed by METH. The selective µ opioid receptor antagonist ß-funaltrexamine, but not nor-binaltorphimine (a κ-selective antagonist) nor naltrindole (a δ-selective antagonist), mimicked the effect of naloxone. These observations suggest that opioid receptor antagonists may attenuate METH-induced stereotypical biting in mice via µ opioid receptors, and suggest that antagonism of this system may be a potential therapeutic approach to reducing some deleterious effects of METH use and perhaps in the treatment of some forms of self-injurious behavior.

A single administration of methamphetamine to mice early in the light period decreases running wheel activity observed during the dark period.

Repeated intermittent administration of amphetamines acutely increases appetitive and consummatory aspects of motivated behaviors as well as general activity and exploratory behavior, including voluntary running wheel activity. Subsequently, if the drug is withdrawn, the frequency of these behaviors decreases, which is thought to be indicative of dysphoric symptoms associated with amphetamine withdrawal. Such decreases may be observed after chronic treatment or even after single drug administrations. In the present study, the effect of acute methamphetamine (METH) on running wheel activity, horizontal locomotion, appetitive behavior (food access), and consummatory behavior (food and water intake) was investigated in mice. A multi-configuration behavior apparatus designed to monitor the five behaviors was developed, where combined measures were recorded simultaneously. In the first experiment, naïve male ICR mice showed gradually increasing running wheel activity over three consecutive days after exposure to a running wheel, while mice without a running wheel showed gradually decreasing horizontal locomotion, consistent with running wheel activity being a positively motivated form of natural motor activity. In experiment 2, increased horizontal locomotion and food access, and decreased food intake, were observed for the initial 3h after acute METH challenge. Subsequently, during the dark phase period decreased running wheel activity and horizontal locomotion were observed. The reductions in running wheel activity and horizontal locomotion may be indicative of reduced dopaminergic function, although it remains to be seen if these changes may be more pronounced after more prolonged METH treatments.

Histamine H3 receptor agonists decrease hypothalamic histamine levels and increase stereotypical biting in mice challenged with methamphetamine.

The effects of the histamine H(3) receptor agonists (R)-α-methylhistamine, imetit and immepip on methamphetamine (METH)-induced stereotypical behavior were examined in mice. The administration of METH (10 mg/kg, i.p.) to male ddY mice induced behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing (1.9%), circling (1.7%), sniffing (14.3%), and biting (82.1%). Pretreatment with (R)-α-methylhistamine (3 and 10 mg/kg, i.p.) significantly decreased stereotypical sniffing, but increased stereotypical biting induced by METH, in a dose-dependent manner. This effect of (R)-α-methylhistamine on behavior was mimicked by imetit or immepip (brain-penetrating selective histamine H(3) receptor agonists; 10 mg/kg, i.p. for each drug). Hypothalamic histamine levels 1 h after METH challenge were significantly increased in mice pretreated with saline. These increases in histamine levels were significantly decreased by pretreatment with histamine H(3) receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting.

Withdrawal from fixed-dose injection of methamphetamine decreases cerebral levels of 3-methoxy-4-hydroxyphenylglycol and induces the expression of anxiety-related behavior in mice.

A variety of drug treatment regimens have been proposed to model the dysphoric state observed during methamphetamine (METH) withdrawal in rats, but little has been established in experiments using mice. In male ICR mice, a fixed-dose injection regimen of METH (1.0 or 2.5 mg/kg, i.p., twice daily for 10 consecutive days) induced a significant decrease in the time spent in open arms in an elevated plus maze after 5 days of drug abstinence. Under an escalating-dose injection regimen (0.2-2.0 mg/kg, i.p., 3 times daily for 4 days, total: 15 mg/kg/animal) or continuous subcutaneous administration with osmotic mini-pumps (15 or 76 mg/kg of METH for 2 weeks), no significant behavioral change was observed after 5 days of drug abstinence, compared with control animals. Reduced gains in body weight were observed during repeated treatment with METH in the fixed-dose injection and mini-pump treatment regimens, but not the escalating-dose injection regimen. HPLC analysis revealed significant decreases in the level of cerebral 3-methoxy-4-hydroxyphenylglycol, a norepinephrine metabolite, and norepinephrine turnover, which may be attributed to the expression of anxiety-related behavior in the elevated plus maze. These observations suggest that the mice treated with a fixed-dose of METH may model the anxiety-related behavior observed in the dysphoric state induced by METH withdrawal in humans.

Pretreatment with l-histidine produces a shift from methamphetamine-induced stereotypical biting to persistent locomotion in mice.

The administration of methamphetamine (METH; 10mg/kg, i.p.) to male ICR mice induced bizarre behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing, circling, sniffing, and biting. Pretreatment with l-histidine (750 mg/kg, i.p.) significantly decreased the stereotypical biting induced by METH and significantly increased persistent locomotion. This effect of l-histidine on behavior was completely abolished by simultaneous administration of pyrilamine or ketotifen (brain-penetrating histamine H(1) receptor antagonists; 10mg/kg each, i.p.), but not by the administration of fexofenadine (a non-sedating histamine H(1) receptor antagonist that does not cross the blood-brain barrier; 20mg/kg), zolantidine (a brain-penetrating histamine H(2) receptor antagonist; 10mg/kg), thioperamide, or clobenpropit (brain-penetrating histamine H(3) receptor antagonists; 10mg/kg each). The histamine content of the hypothalamus was significantly increased by l-histidine treatment. These data suggest that l-histidine modifies the effects of METH through central histamine H(1) receptors.

Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal.

Neuronal adaptations have been found to occur in multiple brain regions after chronic intake of abused drugs, and are therefore thought to underlie drug dependence, tolerance, and withdrawal. Pathophysiological changes in drug responsiveness as well as behavioral sequelae of chronic drug exposure are thought to depend largely upon the altered state of heterotrimeric GTP binding protein (G protein)-coupled receptor (GPCR)-G protein interactions. Responsiveness of GPCR-related intracellular signaling systems to drugs of abuse is heterogeneous, depending on the types of intracellular effectors to which the specific Galpha protein subtypes are coupled and GPCR-G protein coupling efficiency, factors influenced by the class of drug, expression levels of G protein subunits, and drug treatment regimens. To enhance understanding of the molecular mechanisms that underlie the development of pathophysiological states resulting from chronic intake of abused drugs, this review focuses on alterations in the expression levels of G protein subunits induced by various drugs of abuse. Changes in these mechanisms appear to be specific to particular drugs of abuse, and specific conditions of drug treatment.

Lack of effect of anticonvulsant topiramate on methamphetamine-induced stereotypy and rewarding property in mice.

The effects of topiramate, a structurally novel anticonvulsant, on the methamphetamine (METH)-induced expression of stereotypy and conditioned place preference (CPP) in male ICR mice were investigated. After a single administration of METH (10 mg/kg, i.p.), mice showed stereotyped behaviors with a plateau level 25 min after drug challenge. Pretreatment with topiramate (1, 10, and 100 mg/kg, i.p.) 30 min prior to METH challenge had no effect on the expression frequency of stereotypy, compared with saline challenge. No differential effects of topiramate on METH-induced stereotyped behavior (that is, head-bobbing, circling, continuous sniffing, nail and/or wood-chip biting, and vigorous and compulsive grooming) were observed. In saline-challenged groups, the doses of topiramate examined did not induce any stereotyped behaviors. Although mice showed a significant CPP for METH (0.5 mg/kg, i.p.), pretreatment with subchronic topiramate did not affect the magnitude of CPP. Locomotor activity was not affected by the doses of topiramate tested. Conditioned rewarding or aversive effects of topiramate were not observed as indexed by the place preference procedure. These results suggested the lack of effect of topiramate on METH-induced stereotypy and rewarding property in mice.

Lobeline attenuates methamphetamine-induced stereotypy in adolescent mice.

In this study, we investigated the effects of lobeline, an alkaloid constituent of Indian tobacco, on methamphetamine (METH)-induced stereotypy in male ICR mice (41-50 days old), an animal model for amphetamine psychosis. After a single administration of METH (10 mg/kg, i.p.), mice showed an initial short-lasting hyperlocomotion and subsequent stereotyped behaviors with a plateau level 25 min after drug challenge. Pretreatment with lobeline (3.0-30 mg/kg, i.p.) 15 min prior to the drug challenge significantly decreased the intensity of stereotypy and increased its latency to onset in a dose-dependent manner, especially 20 min after the drug challenge. In saline challenge groups, the doses of lobeline examined did not affect spontaneous locomotion nor induced any stereotyped behaviors. High-performance liquid chromatography analysis revealed that the range of lobeline doses examined except 30 mg/kg did not affect apparent monoamine turnover in the cerebral cortex, the region of the striatum and nucleus accumbens, and the region of the thalamus and hypothalamus of the mice 20 and 60 min after the drug challenge. These results suggested that the inhibitory effect of lobeline (3.0-10 mg/kg) on METH-induced stereotypy was not attributed to the change in the apparent monoamine turnover.

Methamphetamine reward in mice as assessed by conditioned place preference test with Supermex sensors: effect of subchronic clorgyline pretreatment.

Recent studies in our laboratory have shown that methamphetamine (METH)-induced hyperlocomotion and behavioral sensitization in mice were inhibited by clorgyline, an irreversible monoamine oxidase inhibitor. In this study, the effect of clorgyline pretreatment on METH-induced rewarding effect was assessed by a conditioned place preference (CPP) test, using an apparatus developed with Supermex sensors (infrared pyroelectric sensors). Although intact male ICR mice showed significant CPP for METH (0.5 mg/kg, i.p.), pretreatment with subchronic clorgyline (0.1 and 10 mg/kg, s.c.) did not affect the magnitude of CPP. At a dose of 1 mg/kg, pretreatment of the mice with clorgyline showed a similar CPP index in both saline/saline and METH/saline pairing groups. During the conditioning session, the mice did not express behavioral sensitization to METH. Pretreatment with clorgyline (0.1, 1, and 10 mg/kg) decreased striatal apparent monoamine turnover in a dose-dependent manner. These results indicated that clorgyline pretreatment (0.1 and 10 mg/kg) did not influence the METH-induced rewarding effect in mice, although pretreatment of the mice with clorgyline at a dose of 1 mg/kg appeared to influence the CPP for METH.

Effects of monoamine oxidase inhibitors on methamphetamine-induced stereotypy in mice and rats.

In male ICR mice, a single intraperitoneal administration of methamphetamine (METH) (10 mg/kg) induced stereotyped behavior such as continuous sniffing, circling, and nail biting, reaching a plateau level 20 min after the injection. Subcutaneous pretreatment with clorgyline, a monoamine oxidase (MAO)-A inhibitor, at a dose of 0.1 mg/kg 2 h prior to the drug challenge significantly decreased the initial (first 20 min) intensity of stereotypies and increased the latency to onset. The effect was not observed with either higher doses of clorgyline (1 and 10 mg/kg) or l-deprenyl, a MAO-B inhibitor, at doses of 0.1-10 mg/kg. In male Wistar rats, the inhibitory effect of clorgyline on METH-induced stereotypy was not observed. Pretreatment of the mice with clorgyline (0.1 mg/kg) had no effect on apparent serotonin and dopamine turnover in the striatum, although the higher doses of clorgyline (1 and 10 mg/kg) significantly decreased the turnover. These results suggest that a low dose of clorgyline tends to increase the latency and decrease the intensity of stereotypies induced by METH in a dopamine metabolism-independent manner in mice.

2-Phenylethylamine in combination with l-deprenyl lowers the striatal level of dopamine and prolongs the duration of the stereotypy in mice.

2-Phenylethylamine (PEA)-induced stereotypy in rodents is suggested to model psychotic symptoms of schizophrenia. It is reported that PEA induces dopamine release in the striatum in vivo and in vitro. The present study analyzed the PEA-induced stereotypy and possible associated brain dopamine metabolism in mice. Using male ICR mice treated with a combination of PEA (100 mg/kg, i.p.) and increasing doses of l-deprenyl (0-10 mg/kg, s.c.), we examined (1) the behavioral profile of stereotypy (rating the scores), and (2) the tissue levels of dopamine and its metabolites by high-performance liquid chromatography. The stereotypic scores reached a plateau level at 10 min which lasted until 30 min after a single administration of 100 mg/kg PEA. The stereotyped behavior completely disappeared 45 min after PEA administration. Pretreatment with l-deprenyl (0.1, 1, and 10 mg/kg, s.c.) dose-dependently prolonged the duration of PEA-induced stereotypy. Notably, pretreatment with l-deprenyl dose-dependently increased the continuous sniffing. Treatment with PEA in combination of l-deprenyl (1 and 10 mg/kg) significantly reduced the level of dopamine in the region of the striatum and nucleus accumbens, compared with control animals. These results suggest that PEA in combination with l-deprenyl prolonged the duration of the stereotypy (particularly, continuous sniffing) while reducing the striatal level of dopamine.