Saara Nuutinen

The histaminergic network in the brain: basic organization and role in disease

Histamine acts as a modulatory neurotransmitter in the mammalian brain. It has an important role in the maintenance of wakefulness, and dysfunction in the histaminergic system has been linked to narcolepsy. Recent evidence suggests that aberrant histamine signalling in the brain may also be a key factor in Gilles de la Tourette syndrome, Parkinsons disease and addictive behaviours. Furthermore, multiple sclerosis (MS) and experimental autoimmune encephalitis, which is an often-used model for MS, are associated with changes in the histaminergic system. This Review explores the possible roles of brain histamine in the mechanisms underlying these diseases.

Histamine in neurotransmission and brain diseases.

Apart from its central role in the mediation of allergic reactions, gastric acid secretion and inflammation in the periphery, histamine serves an important function as a neurotransitter in the central nervous system. The histaminergic neurons originate from the tuberomamillary nucleus of the posterior hypothalamus and send projections to most parts of the brain. The central histamine system is involved in many brain functions such as arousal, control of pituitary hormone secretion, suppression ofeating and cognitive functions. The effects of neuronal histamine are mediated via G-protein-coupled H1-H4 receptors. The prominent role of histamine as a wake-promoting substance has drawn interest to treat sleep-wake disorders, especially narcolepsy, via modulation of H3 receptor function. Post mortem studies have revealed alterations in histaminergic system in neurological and psychiatric diseases. Brain histamine levels are decreased in Alzheimers disease patients whereas abnormally high histamine concentrations are found in the brains of Parkinsons disease and schizophrenic patients. Low histamine levels are associated with convulsions and seizures. The release of histamine is altered in response to different types of brain injury: e.g. increased release of histamine in an ischemic brain trauma might have a role in the recovery from neuronal damage. Neuronal histamine is also involved in the pain perception. Drugs that increase brain and spinal histamine concentrations have antinociceptive properties. Histaminergic drugs, most importantly histamine H3 receptors ligands, have shown efficacy in many animal models of the above-mentioned disorders. Ongoing clinical trials will reveal the efficacy and safety of these drugs in the treatment of human patients.

Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice

RationaleNeuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.ObjectiveThe present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.Materials and methodsMale histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity.ResultsThe HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABAA receptor ligand [3H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward.ConclusionsHistaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.

Evidence for the role of histamine H3 receptor in alcohol consumption and alcohol reward in mice

Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a ‘drinking in the dark’ model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future.

Histamine and H3 Receptor in Alcohol-Related Behaviors

Data from rat models for alcohol preference and histidine decarboxylase knockout (HDC KO) mice suggest that brain histamine regulates alcohol-related behaviors. Histamine levels are higher in alcohol-preferring than in alcohol-nonpreferring rat brains, and expression of histamine H3 receptor (H3R) is different in key areas for addictive behavior. H3R inverse agonists decrease alcohol responding in one alcohol-preferring rat line. Conditioned place preference induced by alcohol is stronger in HDC KO mice than in control mice. The HDC KO mice display a weaker stimulatory response to acute alcohol than the wild-type (WT) mice. In male inbred C57BL/6 mice the H3R antagonist ciproxifan inhibits ethanol-evoked stimulation of locomotor activity. Ciproxifan also potentiates the ethanol reward, but does not alone result in the development of place preference. At least in one rat model developed to study alcohol sensitivity high histamine levels are characteristic of the alcohol-insensitive rat line, and lowering brain histamine with a HDC inhibitor increases alcohol sensitivity in the tilting plane test. However, the motor skills of HDC KO mice do not seem to differ from those of the WT mice. Current evidence suggests that the histaminergic system is involved in the regulation of place preference behavior triggered by alcohol, possibly through an interaction with the mesolimbic dopamine system. Histamine may also interact with dopamine in the regulation of the cortico-striato-pallido-thalamo-cortical motor pathway and cerebellar mechanisms, which may be important in different motor behaviors beyond alcohol-induced motor disturbances. H3R ligands may have significant effects on alcohol addiction.

Histamine is required for H3 receptor-mediated alcohol reward inhibition, but not for alcohol consumption or stimulation

Conflicting data have been published on whether histamine is inhibitory to the rewarding effects of abused drugs. The purpose of this study was to clarify the role of neuronal histamine and, in particular, H3 receptors in alcohol dependence‐related behaviours, which represent the addictive effects of alcohol.

Histamine h3 receptor: a novel therapeutic target in alcohol dependence?

The brain histaminergic system is one of the diffuse modulatory neurotransmitter systems which regulate neuronal activity in many brain areas. Studies on both rats and mice indicate that histamine H3 receptor antagonists decrease alcohol drinking in several models, like operant alcohol administration and drinking in the dark paradigm. Alcohol-induced place preference is also affected by these drugs. Moreover, mice lacking H3R do not drink alcohol like their wild type littermates, and they do not show alcohol-induced place preference. Although the mechanisms of these behaviors are still being investigated, we propose that H3R antagonists are promising candidates for use in human alcoholics, as these drugs are already tested for treatment of other disorders like narcolepsy and sleep disorders.

Histamine H3 Receptor Regulates Sensorimotor Gating and Dopaminergic Signaling in the Striatum

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor–mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor–mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.

DARPP-32 and Akt regulation in ethanol-preferring AA and ethanol-avoiding ANA rats.

Ethanol and other addictive drugs affect many intracellular phosphorylation and dephosphorylation cascades. These cascades are thought to be highly important in the regulation of neuronal activity. The present experiments characterized the regulation of three key signaling molecules, DARPP-32 (dopamine and cAMP regulated phosphoprotein, 32kDa), Akt kinase and ERK1/2 (extracellular signal-regulated kinase 1 and 2) in ethanol-preferring AA (Alko, alcohol) and ethanol-avoiding ANA (Alko, non-alcohol) rat lines. Radioactive in situ hybridization was used in drug naïve animals and Western blotting after acute ethanol administration in striatum, hippocampus and prefrontal cortex. The mRNA levels of DARPP-32 in striatal areas were higher in ANA rats than in AA rats. There was no difference in the striatal enriched phosphatase (STEP61), the downstream target of DARPP-32 expression between the rat lines. Ethanol (1.5g/kg) increased phosphorylation of DARPP-32 at threonine 34 in both AA and in ANA rats indicating that acute ethanol activates DARPP-32 similarly in these rat lines. The expression of Akt kinase was higher in the CA1 of hippocampus in ANA than in AA rats and acute ethanol activated Akt in hippocampus in ANA but not in AA rats. No significant alterations in the regulation of ERK1/2 were found in either rat line. Our findings suggest that DARPP-32 and Akt are regulated by ethanol and differences in the regulation of these molecules might contribute to the dramatically different ethanol drinking patterns seen in AA and ANA rats.

Interaction of Brain Histaminergic and Dopaminergic Systems

Brain neurons containing the neurotransmitter dopamine have two well-characterized functions: they are key regulators of movements, and they mediate reward and motivation induced by natural rewards such as food and sex but also by drugs of abuse including nicotine, alcohol, and illegal drugs [1]. Dopamine neurons from the midbrain and histamine neurons from the posterolateral hypothalamus both send their axons to a brain area called the striatum which is the center for the control of movements, reward, and motivation. The striatum is divided into two subregions: the dorsal striatum which is classically referred to as the motor control region and the ventral striatum, including the nucleus accumbens, which regulates reward and motivation. Recent evidence shows however that the classical division of striatal functions is not that clear and, e.g., dorsal striatal areas have been shown to be involved in the regulation of reward too. The midbrain areas where dopaminergic neuron somas are located, substantia nigra and ventral tegmental area, also receive histaminergic projections [2, 3]. Of importance, the striatum expresses a high density of histamine H1–H3 receptors [4–6] suggesting that histamine can directly affect striatal function and basal ganglia output. The expression of the histamine H3 receptor in the striatum is exceptionally high [5–7]. H3 receptors are G protein-coupled receptors that regulate the release of histamine but also other neurotransmitter release (e.g., GABA, noradrenaline, acetylcholine, and possibly dopamine) [8]. Importantly, majority of the H3 receptors in the striatum are located postsynaptically at GABAergic medium spiny neurons [5, 6, 9], and there is evidence of a direct interaction between H3 and dopamine receptors in co-expressing culture systems [10–12] and in vivo [13].