It seems obvious that histamine is a prime modulator in methamphetamine's catecholamine release. The nature of histamine "linked to hypoglycemia and to a variety of stressors" lead me to believe that it is a key target in tolerance prevention.
The effect of methamphetamine on histamine release in the rat hypothalamus.
www.ncbi.nlm.nih.gov/pubmed/9141145
In the present study, the effect of methamphetamine (MAP) on histamine (HA) release measured by in vivo brain microdialysis in the rat hypothalamus was investigated. Administration of MAP (3 mg/kg) significantly increase HA release from 40 to 160 min after the injection. This finding suggests that a moderate dose of MAP activates the hypothalamic HA neuron system, which may be related to effects of MAP on intrinsic biological rhythms.
Histamine level significantly increase post methamphetamine injection.
Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats.
www.ncbi.nlm.nih.gov/pubmed/15556146
Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.
Histamine H3 receptors
Expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, and serotonin.
H3-receptor antagonist
A classification of drugs used to block the action of histamine at the H3 receptor. Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause sedation if they are blocked in the brain, H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex.
Consequently unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.Examples of selective H3 antagonists include clobenpropit, ABT-239, ciproxifan, , Conessine, and A-349,821.
Conessine
Conessine is a steroid alkaloid found in a number of plant species from the Apocynaceae family, including Holarrhena floribunda, Holarrhena antidysenterica and Funtumia elastica, several of which are used in traditional herbal medicine as a treatment for amoebic dysentery. It acts as a histamine antagonist, selective for the H3 subtype.
Atypical antihistaminics
Catechin is a histidine decarboxylase inhibitor. It inhibits the conversion of histidine to histamine. It can be found in cocoa and teas.
Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice.
www.ncbi.nlm.nih.gov/pubmed/12421355
We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild-type mice. Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O-phosphoserine were decreased in the midbrain of the saline-treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild-type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.
Methamphetamine and brain histamine: a study using histamine-related gene knockout mice.
www.ncbi.nlm.nih.gov/pubmed/15542709
The central histamine (HA) neurons that originate from the posterior hypothalamus modulate a variety of physiological functions. In order to investigate the roles of brain histaminergic neuron system in the behavioral effects of methamphetamine (METH), we administrated METH repeatedly to L-histidine decarboxylase (HDC)-, histamine H1 receptor-, H2 receptor-gene knockout (KO) mice, H1/H2 receptor-gene double KO mice, and wild type (WT) mice corresponding to each of them, and we measured locomotor activities. We also measured the contents of monoamines and amino acids in the brain of HDC-gene KO and WT mice after a single administration of METH. METH-induced locomotor hyperactivity and the development of behavioral sensitization were facilitated more in the HDC-gene KO mice and H1/H2 gene double KO mice than the WT mice, suggesting that brain histamine has an inhibitory effect on the METH action through both H1 and H2 receptors. In addition, neurochemical study suggested the involvement of the GABAergic neuron system in the inhibitory effect of brain histamine.
Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release.
www.ncbi.nlm.nih.gov/pubmed/14735131
Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did not increase brain dopamine levels when given alone. These findings point to histamine H3 receptors as a new and important receptor system modulating the reinforcing, subjective, and neurochemical actions of methamphetamine.
The physiology of brain histamine.
Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep after hyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H3) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors.
Histamine activates four types of receptors.
H1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium-calcium exchanger.
H2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel.
H3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels.
Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.
The effect of methamphetamine on histamine release in the rat hypothalamus.
www.ncbi.nlm.nih.gov/pubmed/9141145
In the present study, the effect of methamphetamine (MAP) on histamine (HA) release measured by in vivo brain microdialysis in the rat hypothalamus was investigated. Administration of MAP (3 mg/kg) significantly increase HA release from 40 to 160 min after the injection. This finding suggests that a moderate dose of MAP activates the hypothalamic HA neuron system, which may be related to effects of MAP on intrinsic biological rhythms.
Histamine level significantly increase post methamphetamine injection.
Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats.
www.ncbi.nlm.nih.gov/pubmed/15556146
Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.
Histamine H3 receptors
Expressed in the central nervous system and to a lesser extent the peripheral nervous system, where they act as autoreceptors in presynaptic histaminergic neurons, and also control histamine turnover by feedback inhibition of histamine synthesis and release. The H3 receptor has also been shown to presynaptically inhibit the release of a number of other neurotransmitters (i.e. it acts as an inhibitory heteroreceptor) including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, and serotonin.
H3-receptor antagonist
A classification of drugs used to block the action of histamine at the H3 receptor. Unlike the H1 and H2 receptors which have primarily peripheral actions, but cause sedation if they are blocked in the brain, H3 receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine. Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex.
Consequently unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.Examples of selective H3 antagonists include clobenpropit, ABT-239, ciproxifan, , Conessine, and A-349,821.
Conessine
Conessine is a steroid alkaloid found in a number of plant species from the Apocynaceae family, including Holarrhena floribunda, Holarrhena antidysenterica and Funtumia elastica, several of which are used in traditional herbal medicine as a treatment for amoebic dysentery. It acts as a histamine antagonist, selective for the H3 subtype.
Atypical antihistaminics
Catechin is a histidine decarboxylase inhibitor. It inhibits the conversion of histidine to histamine. It can be found in cocoa and teas.
Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient mice.
www.ncbi.nlm.nih.gov/pubmed/12421355
We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild-type mice. Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O-phosphoserine were decreased in the midbrain of the saline-treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild-type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system.
Methamphetamine and brain histamine: a study using histamine-related gene knockout mice.
www.ncbi.nlm.nih.gov/pubmed/15542709
The central histamine (HA) neurons that originate from the posterior hypothalamus modulate a variety of physiological functions. In order to investigate the roles of brain histaminergic neuron system in the behavioral effects of methamphetamine (METH), we administrated METH repeatedly to L-histidine decarboxylase (HDC)-, histamine H1 receptor-, H2 receptor-gene knockout (KO) mice, H1/H2 receptor-gene double KO mice, and wild type (WT) mice corresponding to each of them, and we measured locomotor activities. We also measured the contents of monoamines and amino acids in the brain of HDC-gene KO and WT mice after a single administration of METH. METH-induced locomotor hyperactivity and the development of behavioral sensitization were facilitated more in the HDC-gene KO mice and H1/H2 gene double KO mice than the WT mice, suggesting that brain histamine has an inhibitory effect on the METH action through both H1 and H2 receptors. In addition, neurochemical study suggested the involvement of the GABAergic neuron system in the inhibitory effect of brain histamine.
Histamine h3 receptor antagonists potentiate methamphetamine self-administration and methamphetamine-induced accumbal dopamine release.
www.ncbi.nlm.nih.gov/pubmed/14735131
Methamphetamine administration increases brain levels of histamine and neuronal histamine attenuates several of methamphetamine's behavioral effects. The role of different subtypes of histamine receptors in this negative feedback, however, remains unclear. There is some evidence on possible involvement of histamine H3 receptors in these actions of methamphetamine. The aim of the present study was to evaluate the effects of two histamine H3 receptor antagonists, clobenpropit and thioperamide, on rewarding and neurochemical effects of methamphetamine utilizing three in vivo methodologies, drug self-administration, drug discrimination, and microdialysis in Sprague-Dawley rats. In rats self-administering methamphetamine intravenously under a fixed-ratio schedule, presession treatment with thioperamide (1.0-3.0 mg/kg, subcutaneous, s.c.) or clobenpropit (1.0-3.0 mg/kg, s.c.) potentiated the reinforcing effects of methamphetamine, as indicated by a dose-dependent increase in responding for a low 0.03 mg/kg dose of methamphetamine, that by itself failed to maintain responding above saline substitution levels, and a decrease in responding for a higher 0.06 mg/kg training dose of methamphetamine. In contrast, neither thioperamide nor clobenpropit treatment increased responding during saline substitution. In other rats trained to discriminate intraperitoneal (i.p.) injection of 1.0 mg/kg methamphetamine from i.p. injection of saline, both thioperamide and clobenpropit (0.3-3.0 mg/kg, s.c.) dose dependently increased methamphetamine-appropriate responding when administered with a low 0.3 mg/kg i.p. dose of methamphetamine, which by itself produced predominantly saline-appropriate responding. However, thioperamide and clobenpropit produced only saline-appropriate responding when administered with saline vehicle. Finally, thioperamide and clobenpropit potentiated methamphetamine-induced elevations in extracellular dopamine levels in the shell of the nucleus accumbens, but did not increase brain dopamine levels when given alone. These findings point to histamine H3 receptors as a new and important receptor system modulating the reinforcing, subjective, and neurochemical actions of methamphetamine.
The physiology of brain histamine.
Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep after hyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H3) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors.
Histamine activates four types of receptors.
H1 receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium-calcium exchanger.
H2 receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel.
H3 receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels.
Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.
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