Blockade of brain histamine metabolism alters methamphetamine-induced expression pattern of stereotypy in mice via histamine H1 receptors

The administration of methamphetamine (METH, 10 mg/kg, i.p.) to male ICR mice induced stereotyped behavior consisting of nail and/or wood chip biting (86.0%), continuous sniffing (12.0%), head bobbing (1.1%), and circling (1.0%) during the observation period of 1 h. Pretreatment of the mice with metoprine (2, 10, and 20 mg/kg, i.p.), a selective inhibitor of histamine N-methyltransferase (HMT), which metabolizes histamine in the brain, significantly increased and decreased METH-induced continuous sniffing (20.5, 51.3, and 80.3%) and nail and/or wood chip biting (77.4, 45.3, and 14.2%), respectively, in a dose-dependent manner. The hypothalamic contents of histamine and its metabolite N(tau)-methylhistamine were significantly increased and decreased by metoprine (10 mg/kg, i.p.), respectively. The metoprine action on METH-induced behavior was completely abolished by pyrilamine (10 and 20 mg/kg) and ketotifen (10 mg/kg), selective, centrally acting histamine H(1) receptor antagonists, but not by fexofenadine (20 mg/kg), zolantidine (10 mg/kg) and thioperamide (10 mg/kg), a peripherally acting histamine H(1) receptor antagonist and a selective, brain-penetrating antagonist for histamine H(2) and H(3) receptors, respectively. The metoprine action was mimicked by SKF 91488 (100 microg/animal, i.c.v.), another HMT inhibitor, and the action of SKF 91488 was also blocked by pyrilamine. The frequency of the expression of METH-induced total stereotypic patterns was unchanged after metoprine pretreatment. Mice pretreated with metoprine displayed no anxiety-like behavior in the elevated plus maze test. These results suggest that brain histamine, increased by agents such as metoprine and SKF 91488, binds to histamine H(1) receptors in the brain, resulting in the modulation of dopaminergic transmission associated with stereotyped behavioral patterns induced by METH.     

Changes in histamine in the rat striatum following local injection of kainic acid

The influence of local administration of kainic acid on the metabolism of histamine in the striatum of the rat has been investigated. Intrastriatal injection of kainic acid (1 μg) resulted in a more than 100% increase of the striatal content of histamine, which persisted from two days after the lesion up to ten weeks. Using two independent methods this accumulation of histamine has been found to be associated with a neuronal compartment of the striatum: (a) the concentration of histamine in synaptosomes prepared from kainic acid lesioned striatum was higher than in synaptosomes derived from the untreated (contralateral) striatum; (b) electrolytic lesions of the medial forebrain bundle, in animals whose striatum had been lesioned with kainic acid, abolished the increase in histamine levels induced by the neurotoxin. Since the rate of disappearance of histamine from the tissue after inhibition of its synthesis by α-fluoromethylhistidine (20 mg/kg, i.p.) was reduced in the lesioned striatum, the kainic acid induced increase in striatal histamine level may be due to a decrease of histamine turnover.Specific binding of [³H]histamine and [³H]cimetidine was measured in the lesioned striatum, revealing a 40% and 20% decrease in binding sites, respectively, when compared with the untreated striatum; the affinity for either ligand was not changed in the lesioned tissue.The data demonstrate considerable neurochemical changes involving the neuronal histamine system in the striatum after destroying the interneurons and output neurons of this region with the convulsive neurotoxin kainic acid.     

Quantitative trait loci (QTL) for circadian rhythms of locomotor activity in mice

The loomotor activity of male mice (Mus musculus) was monitored by infrared photoelectric beams under three lighting regimens: LD (12 h of light and 12 h of dark), DD (constant dark), and LL (constant broad-spectrum light, 10 lux). Circadian period of locomotor activioty (τ) was compared among 3 inbred strains of mice, C57BL/6J (B6), BALB/c (C), and DBA/2J (D2), and 26 recombinant inbred strains B×D (B6×D2). the τ under both continuous low-intensity light and continuous darkenss varied significantly among strains. Under DD the mean τ was 23.8 h for B6, 23.7 h for D2, and 23.6 h for C. Under LL the mean τ was 25.1 for B6, 23.9 h for D2, and 25.5 h for C. Frequency histograms of the mean τ of 26B×D RI mouse strains (three to seven animals per strain) in either DD or LL and the difference between them, Δτ, had distributions which appeared unimodal, suggesting polygenic inheritances. The narrow-sense heritability determined using 26 strains of B×D RI mice was about 55% for τ and about 38% for both τ in LL and Δτ. An estimated four loci contribute to the variance of τ in constant darkness and five to the variance of τ in constant low-intensity light among the strains studied. Quantitative trait locus (QTL) analysis identified several potential genetic loci associated with τ in constant darkness, τ in constant low-intensity light, and Δτ. The associations of highest probability for each of these traits were theD1Nds4 locus (p<0.001) on mouse chromosome 1, theD5Ncvs52 locus (p<.05) on mouse chromosome 5, and thePmv12 locus (p<.01) at 70 cM on mouse chromosome 5, respectively. A QTL identified for τ was associated (p<.05) with theD2NDS1 marker at 45 cM on chromsome 2 near the Ea 6 marker at 46 cM associated (p<.05) with that reported for the period of wheel running activity in seven C×B RI strains (Schwartz, W. J., and Zimmerman, P.,J. Neurosci. 10:3685 1990).     

Hypothetical quantitative trait loci (QTL) for circadian period of locomotor activity in CXB recombinant inbred strains of mice

The locomotor activity of male mice (Mus musculus) of 13 CXB (BALB/cBy × C57BL/6J) recombinant inbred (RI) strains and their progenitor strains was monitored for 4 to 6 weeks by infrared photoelectric beams under constant dark. The circadian period (τ) of locomotor activity was calculated and used in quantitative trait locus (QTL) analysis of strains' means. Results were compared with potential QTL found in a previous study of the BXD RI series. The mean τ of 13 CXB RI mouse strains (three to six animals per strain) in constant dark had a unimodal distribution suggesting polygenic inheritance. A number of potential QTL were found for this trait. There were two associations atp<.001,H23 on chromosome 3 andPmv16 on chromosome 16. A region of chromosome 1 was associated with τ in both CXB and BXD RI series. There was also a conjunction with a locus determined from QTL analysis of the previously reported τ of wheel running activity in seven CXB RI strains (Schwartz and Zimmerman, 1990).     

Methamphetamine treatment causes delayed decrease in novelty-induced locomotor activity in mice

Methamphetamine (METH) is a psychostimulant that causes damage to dopamine (DA) axons and to non-monoaminergic neurons in the brain. The aim of the present study was to investigate short- and long-term effects of neurotoxic METH treatment on novelty-induced locomotor activity in mice. Male BALB/c mice, 12–14 weeks old, were injected with saline or METH (i.p., 7.5 mg/kg × 4 times, every 2 h). Behavior and neurotoxic effects were assessed at 10 days, 3 and 5 months following drug treatment. METH administration caused marked decreases in DA levels in the mouse striatum and cortex at 10 days post-drug. However, METH did not induce any changes in novelty-induced locomotor activity. At 3 and 5 months after treatment METH-exposed mice showed significant recovery of DA levels in the striatum and cortex. In contrast, these animals demonstrated significant decreases in locomotor activity at 5 months in comparison to aged-matched control mice. Further assessment of METH toxicity using TUNEL staining showed that the drug induced increased cell death in the striatum and cortex at 3 days after administration. Taken together, these data suggest that delayed deficits in novelty-induced locomotor activity observed in METH-exposed animals are not due to neurodegeneration of DA terminals but to combined effects of METH and age-dependent dysfunction of non-DA intrinsic striatal and/or corticostriatal neurons.     

Patterns of neural activity associated with differential acute locomotor stimulation to cocaine and methamphetamine in adolescent versus adult male C57BL/6J mice

Adolescence is a time period when major changes occur in the brain with long-term consequences for behavior. One ramification is altered responses to drugs of abuse, but the specific brain mechanisms and implications for mental health are poorly understood. Here, we used a mouse model in which adolescents display dramatically reduced sensitivity to the acute locomotor stimulating effects of cocaine and methamphetamine. The goal was to identify key brain regions or circuits involved in the differential behavior. Male adolescent (postnatal day (PN), 30–35) and young adult (PN, 69–74) C57BL/6J mice were administered an i.p. injection of cocaine (0, 15, 30 mg/kg) or methamphetamine (0, 2, 4 mg/kg) and euthanized 90 min later. Locomotor activity was monitored continuously in the home cage by video tracking. Immunohistochemical detection of Fos protein was used to quantify neuronal activation in 16 different brain regions. As expected, adolescents were less sensitive to the locomotor stimulating effects of cocaine and methamphetamine as indicated by a rightward shift in the dose response relationship. After a saline injection, adolescents showed similar levels of Fos as adults in all regions except the dorsal caudate (CPuD) and lateral caudate (CPuL) where levels were lower in adolescents. Cocaine and methamphetamine dose dependently increased Fos in all brain regions sampled in both adolescents and adults, but Fos levels were similar in both age groups for a majority of regions and doses. Locomotor activity was correlated with Fos in several brain areas within adolescent and adult groups, and adolescents had a significantly greater induction of Fos for a given amount of locomotor activity in key brain regions including the caudate where they showed reduced Fos under baseline conditions. Future research will identify the molecular and cellular events that are responsible for the differential psychostimulant-induced patterns of brain activation and behavior observed in adolescent versus adult mice.     

Characterization of histamine projections and their potential cellular targets in the mouse retina

The vertebrate retina receives histaminergic input from the brain via retinopetal axons that originate from perikarya in the posterior hypothalamus. In the nervous system, histamine acts on three G-protein-coupled receptors, histamine receptor (HR) 1, HR2 and HR3. In order to look for potential cellular targets of histamine in the mouse retina, we have examined the retina for the expression of histamine and the presence of these three receptors. Consistent with studies of retina from other vertebrates, histamine was only found in retinopetal axons, which coursed extensively through the ganglion cell and inner plexiform layers. mRNA for all three receptors was expressed in the mouse retina, and immunohistochemical studies further localized HR1 and HR2. HR1 immunoreactivity was observed on dopaminergic amacrine cells, calretinin-positive ganglion cells and axon bundles in the ganglion cell layer. Furthermore, a distinct group of processes in the inner plexiform layer was labeled, which most likely represents the processes of cholinergic amacrine cells. HR2 immunoreactivity was observed on the processes and cell bodies of the primary glial cells of the mammalian retina, the Müller cells. This distribution of histamine and its receptors is consistent with a brain-derived source of histamine acting on diverse populations of cells in the retina, including both neurons and glia.     

Reduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice

Ghrelin, an orexigenic hormone produced by the stomach, is secreted in anticipation of scheduled meals and in correlation with anticipatory locomotor activity. We hypothesized that ghrelin is directly implicated in stimulating locomotor activity in anticipation of scheduled meals. To test this hypothesis, we observed 24 h patterns of locomotor activity in mice with targeted mutations of the ghrelin receptor gene (GHSR KO) and wild-type littermates, all given access to food for 4 h daily for 14 days. While wild type (WT) and GHSR KO mice produced increases in anticipatory locomotor activity, anticipatory locomotor activity in GHSR KO mice was attenuated (P<0.05). These behavioral measures correlated with attenuated levels of Fos immunoreactivity in a number of hypothalamic nuclei from GHSR KO placed on the same restricted feeding schedule for 7 days and sacrificed at ZT4. Interestingly, seven daily i.p. ghrelin injections mimicked hypothalamic Fos expression patterns to those seen in mice under restricted feeding schedules. These data suggest that ghrelin acts in the hypothalamus to augment locomotor activity in anticipation of scheduled meals.     

新生小鼠胃内组胺免疫反应细胞的形态及分布

目的：观察出生后小鼠胃内组胺免疫反应细胞的个体发生、分布、形态及数量变化。方法：免疫组织化学技术。结果：小鼠出生后第5天,胃体部粘膜上皮中出现组胺阳性细胞,此后随着胃体部粘膜的发育,组胺阳性细胞数量明显增多,密集分布于胃体部粘膜下1/3处的上皮内。胃粘膜下层中也可见少量组胺弱阳性细胞。上皮内的组胺阳性细胞多为闭合型,胞体较小,常聚集、环抱壁细胞。结论：小鼠胃体部粘膜中组胺阳性细胞出现的时间较G细胞、D细胞、EC细胞晚,随着小鼠的生长发育,其数量呈显著性增加。位于胃粘膜下1/3处上二皮内的组胺阳性细胞可能为肠嗜铬样细胞（ECL细胞）,ECL细胞释放的组胺,有可能通过旁分泌的方式作用于壁细胞。     

Mu opioid receptor knockdown in the substantia nigra/ventral tegmental area by synthetic small interfering RNA blocks the rewarding and locomotor effects of heroin

Mu opioid receptors (MOP-r) play an important role in the rewarding and locomotor stimulatory effects of heroin. The aim of the current study was to determine whether infusion of small interfering RNAs (siRNA) targeting MOP-r into the midbrain could knock down MOP-r mRNA and affect heroin-induced locomotor activity or heroin-induced conditioned place preference. Ten-week-old male C57BL/6J mice were surgically implanted bilaterally with guide cannulae directed between the substantia nigra and ventral tegmental area. After 4 days' recovery, mice were infused bilaterally with siRNAs that target the MOP-r (2 mMx0.75 microl/side/day for 3 days) or control siRNA. Seven days after the last infusion, a procedure for conditioned place preference was begun with four heroin (3 mg/kg i.p.) administration sessions alternating with four saline sessions. While heroin induced an increase in locomotor activity in all groups, siRNAs targeting specific regions of MOP-r significantly attenuated this effect. Of particular interest, mice infused with specific siRNAs targeting the MOP-r failed to develop and express conditioned place preference to heroin, or showed a significantly attenuated preference. These alterations in reward-related behaviors are likely due to the reduction in MOP-r mRNA and protein, shown in separate studies by in situ hybridization and autoradiography using the same MOP-r- siRNA infusions. Taken together, these studies demonstrate the utility of siRNA in the neurobiological study of specific components of the reward system and should contribute to the study of other complex behaviors.     

Behavioral interaction of adenosine and trifluoperazine in mice

Mice were implanted with chronic indwelling cannulae in the lateral cerebral ventricle. A dose-response curve was established for the effect of i.p. injections of trifluoperazine (TFP) on spontaneous locomotor activity. In addition, the behavioral interaction of i.p. injections of TFP with intracerebroventricular (i.c.v.) injections of adenosine (ADO) was examined. TFP depressed locomotor activity in a dose-dependent manner. A dose of ADO, which had no effect on locomotor activity when given alone, enhanced the depressant effects of TFP at all doses. As a control for the specificity of this behavioral interaction, mice also were given i.p. injections of TFP in combination with i.c.v. injections of 5'-N-ethylcarboxamidoadenosine (NECA), an uptake-resistant adenosine analogue. TFP and NECA did not interact to produce a significantly more pronounced locomotor depression. These results substantiate the notion that the sedative actions of TFP involve the inhibition of adenosine uptake and thus potentiation of extracellular adenosine levels.     

Naloxone potentiates the depressant effect of chlordiazepoxide on spontaneous activity in mice

Recent reports suggest that at least some of the behavioural effects of benzodiazepines may involve interaction with endogenous opioid mechanisms. In the present study, chlordiazepoxide (CDP, 10-20 mg/kg, i.p.) induced dose-dependent reductions in spontaneous locomotor activity and rearing in mice. Although naloxone (1 mg/kg) was itself without effect, and did not alter behavioural changes induced by the lower dose of CDP, it enhanced the depressant effects of 20 mg/kg CDP on locomotor activity. Results are discussed in relation to previous studies in which opiate antagonists have been found to block or to have no effect upon behavioural actions of benzodiazepines.     

Abnormal response of melanin-concentrating hormone deficient mice to fasting: hyperactivity and rapid eye movement sleep suppression

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that has been implicated in energy homeostasis. Pharmacological studies with MCH and its receptor antagonists have suggested additional behavioral roles for the neuropeptide in the control of mood and vigilance states. These suggestions have been supported by a report of modified sleep in the MCH-1 receptor knockout mouse. Here we found that MCH knockout (MCH(-)(/)(-)) mice slept less during both the light and dark phases under baseline conditions. In response to fasting, MCH(-)(/)(-) mice exhibited marked hyperactivity, accelerated weight loss and an exaggerated decrease in rapid eye movement (REM) sleep. Following a 6-h period of sleep deprivation, however, the sleep rebound in MCH(-)(/)(-) mice was normal. Thus MCH(-)(/)(-) mice adapt poorly to fasting, and their loss of bodyweight under this condition is associated with behavioral hyperactivity and abnormal expression of REM sleep. These results support a role for MCH in vigilance state regulation in response to changes in energy homeostasis and may relate to a recent report of initial clinical trials with a novel MCH-1 receptor antagonist. When combined with caloric restriction, the treatment of healthy, obese subjects with this compound resulted in some subjects experiencing vivid dreams and sleep disturbances.     

A complex of histamine/mouse γ-globulin preferentially inhibits allergen-induced peritoneal accumulation of eosinophils, but not neutrophils, in mice

A complex of histamine/human γ-globulin (HhG) has been widely used in Japan for more than 25 years as a nonspecific hyposensitization drug in the treatment of allergic diseases. It has been reported that HhG decreases the number of eosinophils in the nasal secretions and peripheral blood of patients with allergy. In this study we used a mouse system to explore the possibility that HhG may actively inhibit the accumulation of eosinophils at inflammation sites. A complex of 0.15 μg of histamine dihydrochloride/12 mg of mouse γ-globulin (HmG) was incubated for 2 hours in saline solution in the normal fashion for HhG. HmG at 50 to 150 mg/kg/day inhibited the peritoneal accumulation of eosinophils induced by ragweed pollen in BALB/c mice in a dose-dependent fashion when the HmG was administered subcutaneously six times during a 20-day sensitization period. The inhibitory effect of HmG on this eosinophil accumulation was significant at 24 and 48 hours after challenge, but HmG had no effect on neutrophil accumulation. Complexes of serotonin/mouse γ-globulin (mγG), glutamine/mγG, and histamine dihydrochloride (His)/mouse albumin had no inhibitory effect when administered in the same way. The optimum combination ratio was between 0.15 μg of His/12 mg of mγG and 0.015 μg of His/12 mg of mγG for this eosinophil inhibition. Moreover, a 1- to 2-hour incubation period of His and mγG was needed to induce a plateau inhibition of the eosinophil accumulation. These results in mice suggest that HhG may actively inhibit allergen-induced eosinophil accumulation, which may be therapeutically useful in the treatment of allergic disease. (J Allergy Clin Immunol 1997;100:809-16.)     

A developmental genetic analysis of locomotor activity in mice: Maternal effects in the BALB/c and C57BL/6 strains and heredity in F1 hybrids

Continuous recording of locomotor activity of mice during 48 h in seminatural enclosures was performed at 21 and 75 days of age, on the same individuals. Four groups of inbred subjects were compared for amount of locomotor activity and its daily distribution: in both BALB/C ( = BALB) and C57BL/6 ( = C57) strains, pups were either fostered by a mother of their own strain or crossfostered to a mother of the other. In addition, two reciprocal F₁'s were compared to the parental strains. While no significant effect of crossfostering to a C57 dam appeared in BALB mice, 21-day-old C57 crossfostered to a BALB dam were more active and more nocturnal than those reared by a C57 dam. In C57 mice the change in activity level between 21 and 75 days was also affected by crossfostering. Reciprocal F₁ hybrids did not differ. A BALB pattern was dominant at 21 days for amount of activity and for change between 21 and 75 days. For daily distribution of activity, F₁ hybrids were BALB-like at weaning and C57-like (with heterosis) in adulthood.     

大鼠精神分裂症后自发性运动量及海马神经发生的改变

目的:探讨成年大鼠精神分裂症后自发性运动量和海马神经发生的改变。方法:通过连续2周腹腔注射环苯已哌啶(phencyclidine,PCP)建立大鼠精神分裂症模型,利用动物运动分析系统监测大鼠自发性运动量,5-溴-2-脱氧尿苷嘧啶(BrdU)标记新生的神经细胞,用免疫荧光标记法监测海马齿状回BrdU、NeuN、S-100β的表达,利用激光共聚焦显微镜观察海马神经细胞的增殖与分化情况。结果:精神分裂症模型大鼠比对照组大鼠自发性运动量高出2～3倍(P0.05);BrdU阳性细胞数约下降了24%(P0.05);两组BrdU阳性细胞的分化无明显差异性(P0.05),大多分化为神经元。结论:精神分裂症可导致成年大鼠自发性运动量增加,并引起海马神经发生的改变,降低神经细胞的增殖。     

Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization

Rationale

Mutant mice lacking the RIIβ subunit of protein kinase A (regulatory subunit II beta^−/−) show increased ethanol preference. Recent evidence suggests a relationship between heightened ethanol preference and susceptibility to ethanol-induced locomotor sensitization. It is currently unknown if protein kinase A signaling modulates the stimulant effects and/or behavioral sensitization caused by ethanol administration. To address this question, we examined the effects of repeated ethanol administration on locomotor activity RIIβ^−/− and littermate wild-type (RIIβ^+/+) mice on multiple genetic backgrounds.

Methods

Over three consecutive days, mice were given single i.p. saline injections and immediately placed in a locomotor activity apparatus to establish a composite baseline for locomotor activity. Next, mice maintained on a hybrid 129/SvEv×C57BL/6J or pure C57BL/6J genetic background were given 10 i.p. ethanol injections before being placed in the activity apparatus. Each ethanol injection was separated by 3–4 days. To determine if changes in behavior were specific to ethanol injection, naïve mice were tested following repeated daily saline injections. The effects of ethanol injection on locomotor behavior were also assessed using an alternate paradigm in which mice were given repeated ethanol injections in their home cage environment.

Results

Relative to RIIβ^+/+ mice, RIIβ^−/− mice, regardless of genetic background, consistently showed significantly greater ethanol-induced locomotor activation. RIIβ^−/− mice also showed increased sensitivity to ethanol-induced locomotor sensitization resulting from repeated administration, an effect that was dependent on genetic background and testing paradigm. Increased locomotor activity by RIIβ^−/− mice was specific to ethanol injections, and was not related to altered blood ethanol levels.

Conclusions

These data provide novel evidence implicating an influence of protein kinase A signaling on ethanol-induced locomotor activity and behavioral sensitization. The observation that RIIβ^−/− mice are more sensitive to the effects of repeated ethanol administration suggests that normal protein kinase A signaling limits, or is protective against, the stimulant effects of ethanol and the plastic alterations that underlie behavioral sensitization.     

Ontogenetic differences in adolescent and adult C57BL/6J and DBA/2J mice: anxiety-like, locomotor, and consummatory behaviors

Adolescence is a highly conserved period during which mammals undergo a number of hormonal, biological, and behavioral changes [Spear [2000] Neurosci. Biobehav. Rev. 24: 417-463]. Ethical constraints limit the research that can be done in human adolescents. Rodents provide a useful model of at least some of the features of adolescence, including increases in body growth, differences in sleep/wake, and eating patterns, as well as differences in risk-taking, novelty seeking, and exploratory behaviors. Much of the available developmental research has utilized rats; however, the use of inbred mouse strains provides a unique means to assess the genetic factors involved in behavioral differences during adolescence. We assessed differences between adults and adolescents in anxiety-like, locomotor, and consummatory behaviors using two commonly used inbred strains of mice, the DBA/2J and C57BL/6J strains. Age and genotype-dependent differences were found in all three behaviors measured, suggesting both factors are important determinants of behavior in mice.