Are Histamine H3 Antagonists the Definitive Treatment for Acute Methamphetamine Intoxication?

BACKGROUND: Methamphetamine (METH) is classified as a Schedule II stimulant drug under the United Nations Convention on Psychotropic Substances of 1971. METH and other amphetamine analogues (AMPHs) are powerful addictive drugs. Treatments are needed to treat the symptoms of METH addiction, chronic METH use, and acute METH overdose. No effective treatment for METH abuse has been established because alterations of brain functions under the excessive intake of abused drug intake are largely irreversible due in part to brain damage that occurs in the course of chronic METH use. OBJECTIVE: Modulation of brain histamine neurotransmission is involved in several neuropsychiatric disorders, including substance use disorders. This review discusses the possible mechanisms underlying the therapeutic effects of histamine H3 receptor antagonists on symptoms of methamphetamine abuse. CONCLUSION: Treatment of mice with centrally acting histamine H3 receptor antagonists increases hypothalamic histamine contents and reduces high-dose METH effects while potentiating lowdose effects via histamine H3 receptors that bind released histamine. On the basis of experimental evidence, it is hypothesized that histamine H3 receptors may be an effective target for the treatment METH use disorder or other adverse effects of chronic METH use.

Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice.

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.

Elevated H2 O2 levels in trinitrobenzene sulfate-induced colitis rats contributes to visceral hyperalgesia through interaction with the transient receptor potential ankyrin 1 cation channel.

BACKGROUND AND AIM: Inflammatory bowel disease is associated with chronic abdominal pain. Transient receptor potential ankyrin 1 (TRPA1) is a well-known pain sensor expressed in primary sensory neurons. Recent studies indicate that reactive oxygen species such as hydrogen peroxide (H2 O2 ) may activate TRPA1. METHODS: Colonic inflammation was induced by intra-colonic administration of trinitrobenzene sulfate (TNBS) in adult male Sprague-Dawley rats. Visceromotor response (VMR) to colorectal distention (CRD) was recorded to evaluate the visceral hyperalgesia. Rats were sacrificed 1 day after treatment with saline or TNBS; colonic tissues from the inflamed region were removed and then processed to assess the H2 O2 content. H2 O2 scavenger N-acetyl-l-cysteine or a TRPA1 antagonist, HC-030031, was intravenously administrated to the TNBS-treated rats or saline-treated rats. In a parallel experiment, intra-colonic H2 O2 -induced visceral hyperalgesia in naïve rats and the effect of intravenous HC-030031 were measured based on the VMR to CRD. RESULTS: Trinitrobenzene sulfate treatment resulted in significant increase in VMR to CRD at day 1. The H2 O2 content in the inflamed region of the colon in TNBS-treated rats was significantly higher than that of saline-treated rats. N-acetyl-l-cysteine or HC-030031 significantly suppressed the enhanced VMR in TNBS-treated rats while saline-treated rats remained unaffected. Moreover, blockade of TRPA1 activation by HC-030031 significantly reversed the exogenous H2 O2 -induced visceral hyperalgesia. CONCLUSION: These results suggest that H2 O2 content of the colonic tissue is increased in the early stage of TNBS-induced colitis. The increased H2 O2 content may contribute to the visceral hyperalgesia by activating TRPA1.

Memory impairment and reduced exploratory behavior in mice after administration of systemic morphine.

In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or ß-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by µ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety.

Agmatine attenuates methamphetamine-induced hyperlocomotion and stereotyped behavior in mice.

We investigated whether pretreatment with the neurotransmitter/neuromodulator agmatine (decarboxylated L-arginine) affected methamphetamine (METH)-induced hyperlocomotion and stereotypy in male ICR mice. Agmatine pretreatment alone had no effects on locomotion or stereotypy, but it produced a dose-dependent attenuation of locomotion and the total incidence of stereotyped behavior induced by a low dose of METH (5 mg/kg). The stereotypy induced by this dose was predominantly characterized by stereotyped sniffing. By contrast, agmatine did not affect the total incidence of stereotypy induced by a higher dose of METH (10 mg/kg). However, the nature of stereotypy induced by this dose of METH was substantially altered; agmatine pretreatment significantly reduced stereotyped biting but significantly increased stereotyped sniffing and persistent locomotion. Agmatine pretreatment therefore appears to produce a rightward shift in the dose-response curve for METH. Pretreatment of mice with piperazine-1-carboxamidine (a putative agmatinase inhibitor) had no effect on locomotion or stereotypy induced by a low dose of METH, suggesting that endogenous agmatine may not regulate the METH action.

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.

Straub tail reaction in mice treated with σ(1) receptor antagonist in combination with methamphetamine.

Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific σ receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative σ(1) receptor agonist) and partially by PB 28 (a putative σ(2) receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative σ(1) receptor antagonist), but not SM-21, a putative σ(2) receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective κ-agonist), suggesting that the STR may be mediated by activation of opioid receptor system.

Pretreatment with nomifensine or nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline augments methamphetamine-induced stereotypical behavior in mice.

Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10mg/kg, i.p.) and nomifensine (3mg/kg, i.p.) on METH (5 or 10mg/kg, i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice.

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.

Differential involvement of cell cycle reactivation between striatal and cortical neurons in cell death induced by 3-nitropropionic acid.

Recent evidence suggests that unscheduled cell cycle activity leads to neuronal cell death. 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces cell death in both striatum and cerebral cortex. Here we analyzed the involvement of aberrant cell cycle progression in 3-NP-induced cell death in these brain regions. 3-NP reduced the level of cyclin-dependent kinase inhibitor p27 in striatum but not in cerebral cortex. 3-NP also induced phosphorylation of retinoblastoma protein, a marker of cell cycle progression at late G(1) phase, only in striatum. Pharmacological experiments revealed that cyclin-dependent kinase activity and N-methyl-d-aspartate (NMDA) receptor were cooperatively involved in cell death by 3-NP in striatal neurons, whereas only NMDA receptor was involved in 3-NP-induced neurotoxicity in cortical neurons. Death of striatal neurons was preceded by elevation of somatic Ca(2+) and activation of calpain, a Ca(2+)-dependent protease. Both striatal p27 down-regulation and cell death provoked by 3-NP were dependent on calpain activity. Moreover, transfection of p27 small interfering RNA reduced striatal cell viability. In cortical neurons, however, there was no change in somatic Ca(2+) and calpain activity by 3-NP, and calpain inhibitors were not protective. These results suggest that 3-NP induces aberrant cell cycle progression and neuronal cell death via p27 down-regulation by calpain in striatum but not in the cerebral cortex. This is the first report for differential involvement of cell cycle reactivation in different brain regions and lightens the mechanism for region-selective vulnerability in human disease, including Huntington disease.

Ablation of p27 enhance kainate-induced seizure and hippocampal degeneration.

p27 is a cyclin-dependent kinase inhibitor which arrests cell cycle at G1-S phase. Using RNA interference method, we previously showed that reduction of endogenous p27 expression induces cell death through cell cycle progression in cultured cortical neurons. In this study, we investigated responses to kainate treatment using p27 knockout mice. Injection of kainic acid induced p27 downregulation and retinoblastoma protein phosphorylation in wild-type mouse hippocampus. No change was observed in hippocampal cell viability in untreated adult p27 heterozygous and homozygous mice compared with wild type (+/+). p27 homozygous mice, however, displayed enhanced seizure and hippocampal degeneration after kainic acid treatment. This study first suggests that ablation of p27 enhance kainate-induced seizure and hippocampal cell death in vivo.

Calpain activation is required for glutamate-induced p27 down-regulation in cultured cortical neurons.

Recent evidence suggests that cell cycle-related molecules play pivotal roles in multiple forms of cell death in post-mitotic neurons. Nevertheless, it remains unclear what molecular mechanisms are involved in the regulation of expression levels and activities of these molecules. We showed previously that treatment with extracellular glutamate decreases cyclin-dependent kinase inhibitor p27 before neuronal cell death. In this study, we demonstrate that reductions of both p27 and neuronal viability were dependent on activity of calpain, a Ca(2+)-dependent protease, but not on activity of caspase 3. Interestingly, the glutamate-induced reduction of p27 was not dependent on the ubiquitin-proteasome system. In fact, p27 was present only in the neuronal nucleus, whereas calpain 1, a ubiquitous calpain, was observed both in the neuronal nucleus and cytoplasm in control cultures. Glutamate treatment did not change the localization patterns of p27 and calpain 1. It reduced p27 expression level in the nucleus in a calpain-dependent manner. In vitro experiments using neuronal cell lysate and p27 recombinant protein revealed that p27 was degraded as a substrate of activated calpain 1. These results suggest that calpain(s), activated by glutamate treatment, degrade(s) p27 in the nucleus of neurons, which might promote aberrant cell cycle progression.

BDNF locally potentiates GABAergic presynaptic machineries: target-selective circuit inhibition.

Inhibitory neurotransmission is critical for neuronal circuit formation. To examine whether inhibitory neurotransmission receives target-selective modulation in the long term, we expressed the cDNA of brain-derived neurotrophic factor (BDNF), which has been shown to induce the augmentation of GABAergic synapses in vivo and in vitro, in a small population of cultured hippocampal neurons. At 48 h after transfection, the expression level of glutamic acid decarboxylase 65 (GAD65), a GABA synthetic enzyme that resides mainly in GABAergic terminals, was selectively enhanced around the BDNF-expressing neurons, in comparison with the neighboring control neurons interposed between the BDNF-expressing neurons and inhibitory neurons. Exogenous BDNF application for 48 h also increased the GAD level and enhanced the GABA release probability. These potentiating effects were attenuated in inhibitory synapses on neurons expressing a dominant negative form of the BDNF receptor (tTrkB). This suggests that postsynaptic BDNF-TrkB signaling contributes to the target-selective potentiation of inhibitory presynaptic machineries. Since BDNF is expressed in an activity-dependent manner in vivo, this selectivity may be one of the key mechanisms by which the independence of functional neuronal circuits is maintained.

Environmental control of the survival and differentiation of dentate granule neurons.

Dentate granule cells (DGCs) and their microcircuits have been implicated in hippocampus-dependent memory encoding and epileptogenesis. Little is known about how the proper maturation of DGCs is determined by their intrinsic programs or external factors during development. In order to explore this, we dispersed premature DGCs on living hippocampal slices. Here we report that the survival and network formation of DGCs are supported by local cues present in the dentate gyrus ex vivo. The density of surviving DGCs was almost uniform throughout the host slices 12 h after implantation but gradually became heterogenous across substrata, with the cells engrafted onto the stratum granulosum scoring the highest rate of survival. The mossy fiber axons arising from DGCs growing on this substratum were properly guided towards CA3, whereas other misplaced DGCs exhibited heterotopic axon projection. In particular, about half of the axons originating from the hilus were misguided into the molecular layer, which resembles the supragranular mossy fiber sprouting seen in epileptic disorders. These results suggest that local environmental factors influence the cell adhesion, neurite polarization and axon guidance of DGCs.

BDNF boosts spike fidelity in chaotic neural oscillations.

Oscillatory activity and its nonlinear dynamics are of fundamental importance for information processing in the central nervous system. Here we show that in aperiodic oscillations, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances the accuracy of action potentials in terms of spike reliability and temporal precision. Cultured hippocampal neurons displayed irregular oscillations of membrane potential in response to sinusoidal 20-Hz somatic current injection, yielding wobbly orbits in the phase space, i.e., a strange attractor. Brief application of BDNF suppressed this unpredictable dynamics and stabilized membrane potential fluctuations, leading to rhythmical firing. Even in complex oscillations induced by external stimuli of 40 Hz (gamma) on a 5-Hz (theta) carrier, BDNF-treated neurons generated more precisely timed spikes, i.e., phase-locked firing, coupled with theta-phase precession. These phenomena were sensitive to K252a, an inhibitor of tyrosine receptor kinases and appeared attributable to BDNF-evoked Na(+) current. The data are the first indication of pharmacological control of endogenous chaos. BDNF diminishes the ambiguity of spike time jitter and thereby might assure neural encoding, such as spike timing-dependent synaptic plasticity.

Developmental switch in axon guidance modes of hippocampal mossy fibers in vitro.

Hippocampal mossy fibers (MFs), axons of dentate granule cells, run through a narrow strip, called the stratum lucidum, and make synaptic contacts with CA3 pyramidal cells. This stereotyped pathfinding is assumed to require a tightly controlled guidance system, but the responsible mechanisms have not been proven directly. To clarify the cellular basis for the MF pathfinding, microslices of the dentate gyrus (DG) and Ammon's horn (AH) were topographically arranged in an organotypic explant coculture system. When collagen gels were interposed between DG and AH slices prepared from postnatal day 6 (P6) rats, the MFs passed across this intervening gap and reached CA3 stratum lucidum. Even when the recipient AH was chemically pre-fixed with paraformaldehyde, the axons were still capable of accessing their normal target area only if the DG and AH slices were directly juxtaposed without a collagen bridge. The data imply that diffusible and contact cues are both involved in MF guidance. To determine how these different cues contribute to MF pathfinding during development, a P6 DG slice was apposed simultaneously to two AH slices prepared from P0 and P13 rats. MFs projected normally to both the host slices, whereas they rarely invaded P0 AH when the two hosts were fixed. Early in development, therefore, the MFs are guided mainly by a chemoattractant gradient, and thereafter, they can find their trajectories by a contact factor, probably via fasciculation with pre-established MFs. The present study proposes a dynamic paradigm in CNS axon pathfinding, that is, developmental changes in axon guidance cues.

Beta-amyloid prevents excitotoxicity via recruitment of glial glutamate transporters.

Amyloid beta-protein (Abeta), a putative pathogenic endotoxin involved in Alzheimer's disease, induces redistribution of glutamate transporters in astrocytes and promotes their pump activity. Because the transporters are assumed to protect neurons against excitotoxicity by removing extracellular glutamate, we hypothesized that Abeta alters the vulnerability of neurons to glutamate. Cerebrocortical neuron-astroglial co-cultures were exposed to glutamate, the concentration of which was selected so that only 20% of the neurons exhibited degeneration. When cultures were pre-treated with Abeta, exposure to the same "mild" glutamate concentration failed to damage neurons. The Abeta-induced protection was abolished by a glial glutamate transporter inhibitor. Thus, Abeta can alleviate excitotoxicity through glutamate transporter activity. The present results may challenge prevailing concepts that Abeta-induced neuron loss causes Alzheimer's dementia and also provide practical insights into neuro-glial interactions in glutamate toxicity.