histamine and h3 receptor in alcohol-related behaviors

JPET#170928 1

Histamine and H3 receptor in alcohol-related behaviors*

Pertti Panula and Saara Nuutinen

Neuroscience Center and Institute of Biomedicine/Anatomy (PP, SN), University of Helsinki,

Haartmaninkatu 8, 00290 Helsinki. Finland

JPET Fast Forward. Published on September 23, 2010 as DOI:10.1124/jpet.110.170928

Copyright 2010 by the American Society for Pharmacology and Experimental Therapeutics.

This article has not been copyedited and formatted. The final version may differ from this version.JPET Fast Forward. Published on September 23, 2010 as DOI: 10.1124/jpet.110.170928

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Running title: Histamine, H3 receptor and alcohol addiction

Corresponding author:

Pertti Panula

Neuroscience Center and Institute of Biomedicine/Anatomy

POB 63

00014 University of Helsinki

Finland

Tel: +358919125263

FAX: +358919125261

E-mail: [email protected]

The number of text pages: 24

The number of tables: 3

The number of figures: 3

The number of references: 76

The number of words in the Abstract: 249

The number of words in the Introduction: N/A

The number of words in the Discussion: N/A


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A list of nonstandard abbreviations used in the paper

AA Alko Alcohol

ANA Alko Non-Alcohol

CPP conditioned place preference

Ctx cortex

DARPP-32 dopamine, cAMP-regulated phosphoprotein of 32,000 kDa

DID Drinking in the dark

HAP high alcohol-preferring

HDC Histidine decarboxylase

H1R Histamine H1 receptor



Hypot hypothalamus

LAP low alcohol-preferring

MHPG 3-methoxy-4-hydroxy-phenylglycol

NAcc nucleus accumbens

PFC prefrontal cortex

SD Sprague-Dawley

Thal thalamus

VP ventral pallidum

WT wild type


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Abstract

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 alcohol non-preferring rat brains, and expression of histamine H3 receptor is different in

key areas for addictive behavior. Histamine H3 receptor inverse agonists decrease alcohol responding in

one alcohol-preferring rat line. Conditioned place preference induced by alcohol is stronger in HDC KO

mice than 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 H3 receptor antagonist ciproxifan inhibits the

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 appear to differ from those of the WT mice.

Current evidence suggests that the histaminergic system is involved in regulation of place preference

behavior triggered by alcohol, possibly through an interaction with the mesolimbic dopamine system.

Histamine may also interact with dopamine in 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. Histamine H3 receptor ligands may have significant effects

on alcohol addiction.


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Rat models of alcohol-related behaviors

Several inbred and outbred rat lines with different alcohol preference have been developed and reported

(for a review, see Sinclair et al., 1989;Sommer et al., 2006). These include the high (HAP) and low

(LAP) alcohol-preferring (Kitanaka et al., 2004;Kitanaka et al., 2004), inbred alcohol-preferring (iP) and

non-preferring (iNP)(McBride et al., 2010) and outbred Alko alcohol (AA) and Alko, non alcohol

(ANA) rats (Sommer et al., 2006;Sinclair et al., 1989). A summary of rat and mouse models used in

alcohol research is shown in Table 1.

The AA (Alko, alcohol) and ANA (Alko, non-alcohol) rat lines were among the first lines produced

using a bidirectional selection method (Eriksson, 1968) for alcohol preference, and these rats have now

been maintained beyond the 100th generation (Sommer et al., 2006). The AA rats have higher levels of

dopamine in several brain regions including striatum and limbic forebrain than the ANA rats (Ahtee and

Eriksson, 1975), and tyrosine hydroxylase activity is also 42% higher in AA than ANA rats (Pispa et al.,

1986). The levels of noradrenaline are also higher in AA rats than in ANA rats in the cortex and limbic

areas (Ahtee and Eriksson, 1975). Noradrenaline turnover also appears higher in AA rats, as the levels of

3-methoxy-4-hydroxy-phenylglycol (MHPG) are higher in AA rats (Sommer et al., 2006). However,

there is no difference in the alcohol-induced release of dopamine between the lines, so that the

sensitivity to ethanol is not the major difference between the lines (Sommer et al., 2006). Serotonin

levels are higher in AA rats than in ANA rats in all brain regions studied (Ahtee and Eriksson, 1972),

but the metabolite levels are normal. Thus, there are differences in major catechol- and indolamine

neurotransmitter systems between the lines.

Histamine levels in AA rats are 20-170% higher in different brain regions in AA than in ANA rat brain

(Lintunen et al., 2001), Interestingly, in almost all brain areas histamine levels in Sprague-Dawley (SD)

rats are between the values seen in AA and ANA rats, suggesting correlation of histamine levels to


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alcohol preference. Levels of tele-methylhistamine are generally 30-70% higher in AA than ANA rats,

with pons as the only exception where no difference is seen (Lintunen et al., 2001). Thus, there is a

distinct difference in histamine turnover between the rat lines. Significantly higher histamine and tele-

methylhistamine concentrations were found in several brain regions relevant for the alcohol preference,

including the frontal cortex, striatum, septum, hypothalamus and hippocampus. Immunohistochemical

analysis showed that this increased histamine resided in nerve fibers rather than mast cells. Higher

histamine-immunoreactive fiber densities in AA rats were found in e.g. medial and lateral septum,

nucleus accumbens and medial preoptic nucleus (Lintunen et al., 2001) (Fig. 1). Generally, histamine

levels in different rat strains are variable due to different numbers of mast cells found predominantly in

the thalamus and median eminence. In agreement with this concept, histamine levels in the thalamus of

SD rats were significantly higher than in either AA or ANA rats, whereas the levels in e.g.

hypothalamus, septum and hippocampus are about twice as high in AA as in ANA or SD rat brain

(Lintunen et al., 2001). Histamine H3 receptor regulates histamine synthesis and release (Arrang et al.,

1983), and in rat brain the different isoforms of this receptors are also differentially expressed (Drutel et

al., 2001). Due to its function, possible changes in H3R expression and/or receptor radiolingand binding

may be due to a primary difference in the histamine. On the other hand, primary changes in receptor

regulation may lie behind changes in histamine turnover. In AA rats, a distinct statistically significant

difference to ANA rats in H3R radioligand binding was found in motor cortex, nucleus accumbens and

CA1 area of the hippocampus, all areas which may be of relevance for the behavioral phenotype. H3R

radioligand binding was lower in AA rats than in ANA rats in only these areas, whereas there was no

difference in e.g. lateral septum or tuberomamillary nucleus (Lintunen et al., 2001). These differences

suggest no direct correlation between histamine levels and H3R radiolingand binding. Thus, the

observed differences in receptor binding are not merely due to higher histamine levels and release in

these areas, but may depend on other factors which are potentially important for the behavioral

differences. Interestingly, H1R expression was generally significantly lower or showed a tendency to


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lower values in AA rats in all brain areas (Lintunen et al., 2001). This can be interpreted as a

downregulation due to high histamine level and release. Behaviorally, histamine H1R antagonist

mepyramine did not affect ethanol self-administration in AA rats, whereas two H3R inverse agonists,

thioperamide and clobenpropit, significantly and in a dose-dependent manner reduced self-

administration of ethanol (Lintunen et al., 2001). These differences in histaminergic system function

have not been tested similarly in the other rat line models of high/low alcohol consumption. However,

the histamine-stimulated phosphoinositide hydrolysis in the cerebral cortex is significantly lower in high

alcohol preferring HAP than in LAP rats with low alcohol preference (Takemura et al., 2003). Although

the histamine levels were not significantly different in that study, the mean of histamine concentration in

the cortex was more than twice as high as in LAP rats, and the lack of significance may be due to the

low number of experimental animals (n=3) (Kitanaka et al., 2004). The μ-opioid receptor antagonist

CTOP injected into the amygdala, and δ-opioid receptor antagonist naltrindole administered into the

nucleus accumbens or basolateral amygdala also decrease ethanol responding in a two-lever operant

system in both AA and Wistar rats (Hyytia, 1993;Hyytia and Kiianmaa, 2001). AA rats also show lower

spontaneous release of beta-endorphin in the hypothalamus (de Waele et al., 1994;Nylander et al., 1994)

and lower levels of proenkephalin peptides in the nucleus accumbens and prodynorphin peptides in the

VTA than ANA rats. Differences in pro-opiomelanocortin expression have been reported in both AA

and ANA rats (Gianoulakis et al., 1992) and HAP/LAP rats (Kinoshita et al., 2004), although in

somewhat different brain regions, which suggest that the same mediators are at least common

phenotypic signs of the selectively bred animals.

Rat lines have also been developed to study sensitivity to a moderate dose (2 g/kg) of alcohol (Rusi et

al., 1977), and in these alcohol-sensitive (alcohol non-tolerant, ANT) and alcohol-insensitive (alcohol

tolerant, AT) rats distinct differences have been observed in histamine levels, H1R mRNA expression,

H3R radioligand binding and H3R agonist-induced G protein activation (Lintunen et al., 2002). The


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alcohol-sensitive rats have significantly reduced histamine levels in frontal cortex, septum,

hypothalamus and hippocampus, and increased H1R mRNA expression in several brain regions. In these

rats, brain histamine may be causally linked to the differences in alcohol sensitivity. Administration of

α-fluoromethylhistidine, a suicide inhibitor of HDC, induces a decline in both brain histamine levels and

motor coordination as measured on a tilting plane in alcohol-insensitive AT rats, which have high brain

histamine levels (Lintunen et al., 2002). Both histamine and immepip-evoked GTPγ[35S] binding is

higher in alcohol sensitive ANT rats in primary motor cortex, insula and caudate putamen (Lintunen et

al., 2002). These regions are important in motor disorders like Tourette’s syndrome, where functional

imaging has revealed abnormalities in a network involving e.g. prefrontal cortex, insula, caudate,

premotor and primary motor cortex (Stern et al., 2000). Tourette’s syndrome is also characterized by

increased dopamine release following amphetamine challenge both in striatal (Singer et al., 2002) and

extrastiatal (Steeves et al., 2010) sites. It is possible that histamine/dopamine interactions are widely

important in several motor disorders, as also in both Parkinson’s disease and experimental rat models the

H3R expression and radioligand binding are altered in substantia nigra and caudate putamen (Anichtchik

et al., 2000b;Anichtchik et al., 2000a;Anichtchik et al., 2001;Ryu et al., 1994). Thus, interactions of

histamine and dopamine are likely to span a wide range of disorders ranging from motor system to

addiction.

The alcohol-induced motor incoordination may also depend on cerebellar mechanisms. Indeed, the

diazepam-insensitive binding of the benzodiazepine [3H]Ro15-4513 is lacking in the granule cells of the

ANA rats, a phenomenon that is caused by a point mutation in the alpha6 subunit of the GABAA

receptor (Korpi et al., 1993). This mutation renders the alpha subunit benzodiazepine sensitive (Korpi et

al., 1993), suggesting that the altered GABAergic signaling may contribute to the behavior of the ANA

rats. The cerebellum receives a direct hypothalamocerebellar input from the histaminergic TMN neurons

both in rodents and humans (Panula et al., 1993;Panula et al., 1989), and fibers pass through the granule

cell layer and Purkinje cell layer perdendicularly, to then turn 90 degrees to make contact with Purkinje


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cell dendrites (Panula et al., 1993). Thus, both extensive systems (basal ganglia and cerebellum) which

control the upper motor neuron functions are modulated by the histaminergic system in a manner that

may contribute to alcohol dependent motor incoordination.

Mouse strain properties and differences, methods used to study, pros and cons

Alcohol has strong behavioral effects in mice of which most studied are the reinforcing and rewarding

effects and the stimulation of locomotor activity. In addition, the motor impairing effect of alcohol is

well-known and can be studied in mouse behavioral models. The reinforcing and rewarding properties of

alcohol are studied using self-administration paradigms or conditioned place preference. Even though

both of these methods are thought to measure reinforcement it is possible that they do not measure

exactly same aspects of alcohol reinforcement, and the brain areas involved can be different (Green and

Grahame, 2008). Thus, a combination of the two methods is advisable. Self-administration of alcohol

has been largely done using a two-bottle choice test where mice have a chance to choose between water

or alcohol solution. However, most mouse strains do not drink alcohol initially at concentrations that are

pharmacologically relevant (Sanchis-Segura and Spanagel, 2006). Thus, procedures to train mice to

drink have been developed, such as ascending concentrations of alcohol and addition of a sweet flavor

agent which can progressively fade out or not. The recently described Drinking in the dark –method

(DID) (Rhodes et al., 2005) offers a faster option to screen the effects of drugs on alcohol drinking. The

DID method is based on the high voluntary alcohol consumption of C57BL/6J mice during their active

period of day and has received a lot of interest among alcohol researches as model for binge drinking.

Conditioned place preference (CPP) is a form of Pavlovian conditioning where environmental cues

become associated with alcohol administration (Tzschentke, 2007). CPP is routinely used to measure the


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reinforcing and rewarding or aversive effects of drugs. The use of CPP in alcohol studies requires

careful planning of the study design since the alcohol dose, the length of the conditioning period and the

use of a biased vs. an unbiased protocol might lead to unexpected or misleading results (Cunningham et

al., 2006). The mice of the DBA/2J strain show strong alcohol CPP and are commonly used whereas

C57BL/6J mice do not develop alcohol-evoked CPP (Cunningham and Noble, 1992) or it is rather weak

(Gremel et al., 2006). Examples of different mouse strains used in alcohol studies are shown in Table 1.

Modifications of CPP and operant alcohol self-administration paradigms are used when other addictive

features beyond reinforcement, such as alcohol seeking and relapse are the focus of research.

The stimulatory effect of alcohol can be detected by measuring the horizontal locomotor activity in

response to alcohol administration. Typical to alcohol stimulation is that it occurs only with fairly low

doses and is rather short-lived. Sensitivity of different mice strains towards stimulatory effect of alcohol

vary to a great extent, the DBA/2 and FVB strains being most stimulated by alcohol and 129/Sv and

C57BL/6 strains showing moderate to complete loss of activation by alcohol (Crabbe et al., 1994)

(Crabbe et al. 1994; Crabbe et al. 2005). In a repeated alcohol administration some strains, but not all,

develop sensitization to the stimulatory effect of alcohol- a phenomenon that is commonly seen with

psychostimulants such as amphetamine and cocaine. The locomotor stimulation and the development of

psychomotor sensitization have been suggested to predict the addictive property of a drug (Wise and

Bozarth, 1987;Robinson and Berridge, 1993) respectively. However, these theories are vividly discussed

(Sanchis-Segura and Spanagel, 2006) and many studies including ours (Nuutinen et al., 2010) do not

support this view. Acute sedative effects of alcohol can be examined with various behavioral tests of

which rotating rod test is the most widely used. However, this test has been criticized to its lack of

sensitivity (Stanley et al., 2005). Different mouse strains differ in their sensitivity for ethanol also in

rotarod task (Rustay et al., 2003;Rustay et al., 2003). A more sensitive task to study alcohol-induced

ataxia and motor incoordination in mice is the balance beam walking test. However, finding the right


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combination of alcohol and size of the beam that shows marked but not too strong impairment by

alcohol can be rather challenging and it is important to measure not only time to cross the beam but

more importantly how many foot slips the mouse makes while walking on the beam. In addition to these,

sedation can be studied using a grid or a dovel test or ataxia can be observer-rated. Very high doses of

alcohol (e.g. 4 g/kg) induce the loss of the righting reflex (LORR) which can be also a marker for

alcohol sedation. However, due to the high dose LORR tests measure different aspects of sedation than

the other motor function tests mentioned above.

Histamine in mouse models of addiction

Histamine has been suggested to have an inhibitory role in reward and reinforcement. This is supported

by the findings that cocaine-induced CPP is attenuated by increasing brain histamine levels with L-

histidine whereas inhibition of histamine synthesis by alpha-fluoromethylhistamine potentiates CPP by

cocaine (Suzuki et al., 1996). In line with this, the CPP induced by ethanol (Nuutinen et al., 2010) and

morphine (Gong et al., 2010) is stronger in HDC KO mice. However, no difference for cocaine reward

in CPP model was found between HDC KO and WT mice (Brabant et al., 2007). This discrepancy could

be explained by the different CPP designs. The cocaine study was carried out using a “biased” CPP

paradigm wheras an “unbiased” design was used for ethanol and morphine. In a biased model animal is

placed in the initially unpreferrred side of the conditioning apparatus following drug administration

(Tzschentke, 2007). In an unbiased paradigm, conditioning apparatus is designed so that there is no

initial preference for one of the conditioning compartments. The advantage of unbiased conditioning is

that the possible anxiolytic or anxiogenic effects of the drugs or e.g. anxious phenotypes of mice do not

affect the outcome of the study. Thus, the unbiased design is a more accurate model for measuring

reward than a biased design. Although the CPP responses differ for ethanol and cocaine, the HDC KO

mice show decreased locomotor stimulation in response to ethanol (Nuutinen et al., 2010) and to


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cocaine (Brabant et al., 2007). These findings suggest that histamine is needed for the acute stimulation

by drugs of abuse whereas the reward and reinforcement might be inhibited by neuronal histamine.

Histamine’s inhibitory role in drug reward is further supported by the stronger methamphetamine-

induced CPP in H1 receptor knockout mice (Takino et al., 2009). Interestingly, histamine receptor triple

knockout mice (H1, H2, H3 KO) do not differ from wild type animals in place preference induced by

methamphetamine (Okuda et al., 2009).

Studies using histamine receptor ligands have resulted in variable findings concerning the behavioral

effects of abused drugs. Similar to what was shown in rat with first generation H1R antagonists (Suzuki

et al., 1996), diphenhydramine induces cocaine CPP with a cocaine dose that is not reinforcing alone

(Nguyen et al., 2010) in mice. However, this effect is probably due to the unspecific effect of

diphenhydramine on dopamine transporter (Tanda et al., 2008). Interestingly, a combination of

dihydrocodeine and the second generation antihistamine ebastine was found to evoke place preference

(Kamei et al., 2003) even though ebastine does not affect dopamine uptake (Fujisaki et al., 2002). Also

H2R antagonists can enhance reward in mice as was shown in the study by Suzuki et al. (Suzuki et al.,

1995) with zolantidine in combination with morphine.

Studies concerning the role of H3R in the effects of drugs of abuse are contradictory since

methamphetamine (Clapham and Kilpatrick, 1994;Morisset et al., 2002;Fox et al., 2005) and alcohol

stimulation are decreased by H3R antagonist but cocaine-induced hyperactivity is potentiated by H3R

inactivation (Brabant et al., 2006;Brabant et al., 2009). One reason for the different results can be the

ability of thioperamide to inhibit cocaine metabolism and increase plasma concentrations of cocaine

(Brabant et al., 2009). A CPP study using thioperamide showed that H3R inactivation resulted in

cocaine reward with a low dose of cocaine that is not rewarding alone (Brabant et al., 2006). In

agreement, we showed that ethanol-induced CPP was stronger in response to ciproxifan (H3R


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antagonist/inverse agonist) pretreatment (Nuutinen et al., 2010). In contrast, H3R KO mice are not

different from the wild type mice in the methamphetamine-induced reward although they are less

stimulated by methamphetamine than the control animals (Okuda et al., 2009). Altogether these findings

suggest a role for histamine receptors, especially for H3Rs in the regulation of behavioral effects of

drugs of abuse. The H3R has a multifunctional role which includes the control of not only histamine

release but also the release of several other neurotransmitters and the recently described interaction of

postsynaptic H3Rs with dopamine receptors (Ferrada et al., 2008;Ferrada et al., 2009). Thus, more

studies are needed to clarify the actual role of histamine in addictive behaviors and to what degree the

effects seen with the H3R ligands are due to modulation of e.g. dopamine neurotransmission and

signaling. In this respect, and in chemical nature and pharmacological properties the different H3R

ligands (Table 3) have significantly different properties.

The studies described above have used either CPP paradigm or measured activation of locomotion by

drugs of abuse. Thus, it would be important to get data from self-administration paradigms to better

understand the role of histamine in addiction. Also it is worth noticing that an acute hyperactive

response is not a direct measure of reinforcement and reward drug. Indeed, findings from our laboratory

using HDC KO mice (Nuutinen et al., 2010) and e.g. in DARPP-32, the key dopamine signaling

molecule, knockout mice (Risinger et al., 2001) suggest that alcohol CPP and stimulatory response are

dissociated. Thus a combination of many behavioral methods examining different aspect of

reinforcement and other addictive behaviors are needed.

Are the models relevant for human alcoholism?

The basic structure and organization of the histaminergic system with all neurons in the posterior

hypothalamic tuberomamillary nucleus in human brain is very similar to that of all other studied


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mammals (Airaksinen et al., 1991). Very little is known of the functions of brain histamine in human

alcoholics and other addicts. However, in one study on post-mortem brains of type 1 (late onset, often

females, low degree of association with violence) and type 2 (early onset, often males, high degree of

association with violence) alcoholics histamine levels were significantly higher in cortical grey matter of

type 1 alcoholics than normal control brains (Alakarppa et al., 2002). The levels of the first metabolite,

tele-methylhistamine, were significantly increased in type 2 alcoholics, indicating increased histamine

release and turnover (Alakarppa et al., 2002). This may mean that histamine synthesis and/or

metabolism are primarily altered in alcoholics, or that the possibly associated liver pathology lies behind

the abnormal findings. Indeed, histamine concentration is increased fourfold in the caudate-putamen and

significantly also in cortical regions of hepatic encephalopathy patients, and tele-methylhistamine levels

are also increased suggesting increased histamine turnover, whereas H3R radioligand binding is

decreased (Lozeva et al., 2003). A concomitant increase in densities (Bmax) of H1R in frontal cortex has

also been reported in patients with hepatic encephalopathy (Lozeva et al., 2001). Similar increases in

brain histamine have been reported in portocavally shunted rats (Fogel et al., 2002). Taken together,

changes in brain histamine, H1R and H3R are found in patients with hepatic failure, and these changes

coincide with sleep disturbances, abnormal circadian rhythm and other neuropsychiatric disturbances.

These findings, although they suggest that histaminergic drugs may be useful in treatment of alcohol-

related disorders associated with hepatic failure, do not imply that histamine alone would be necessary

or essential. Alterations in brain circuits containing multiple transmitters relevant for those in alcohol

addiction, including the hypothalamo-cortical or hypothalamo-striatal/accumbeal pathways may be

important.


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*Footnotes

The original studies have been financially supported by grants form the Academy of Finland [grant no

126744, 118547], Finnish Fund for Alcohol Research and Magnus Ehrnrooth’s Foundation


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Legends for Figures

Figure 1

HA-immunoreactive nerve fibers in ANA (a,c,e,g) and AA (b,d,f,h) rat brain regions show distinct

differences in the medial septum (a,b), lateral septum (c,d), nucleus accumbens (e.f) and medial preoptic

nucleus. 3V, third ventricle; Aca, commissural anterior; acb, nucleus accumbens; LSV, lateral septum,

ventral part; LV, lateral ventricle; MPO, medial preoptic nucleus; Pe, periventricular nucleus. Scale bar

= 100 µm. Reproduced with permission from (Lintunen et al., 2001).

Figure 2 Lack of histamine synthesis leads to alterations in responses to alcohol. A) Male histidine decarboxylase

knockout (HDC KO) mice are not stimulated by acute alcohol (1.5 g/kg, i.p.). Data represents

cumulative distance moved within 30 min. ***p<0.001 from the baseline of wild type control mice. B)

Alcohol-induced reward is stronger in HDC KO mice than wild type control animals. An unbiased,

counterbalanced conditioned place preference paradigm was used where each animal received four 5-

min conditioning trials with alcohol and saline on alternating days. Grid+ stands for the conditioning

subgroup where metal grid floor was paired with alcohol (2 g/kg, i.p.) administration. In the Grid-group

plastic floor material was paired with alcohol injection. Place preference was indexed by comparing the

Grid+ and Grid- groups. ***p<0.001 from the corresponding Grid+ group. Two-way ANOVA yielded a

significant conditioning subgroup x genotype interaction indicating that the alcohol preference in HDC

KO mice was stronger that in control animals.

Figure 3


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Distribution of the histaminergic neurons in the tuberomamillary nucleus of adult human posterior

hypothalamus in a frontal (A) and horizontal (B) sections. The schematic figures are based on camera

lucida drawings of two individuals (Airaksinen et al. 1991). Each dot represents a cell in a 30-40 um

thick section stained with an antibody against histamine. 3V, third ventricle; LH, lateral hypothalamic

area; Arc, arcuate nucleus, VMH, ventromedial hypothalamic nucleus, MM, medial mamillary nucleus;

f, fornix


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Table 1 Examples of rat and mouse models and their suitability in the examination of alcohol-related

studies

Animal strain or line Description Characteristics

Rats

Sprague-Dawley Outbred line General multipurpose model , albino Wistar Outbred line General multipurpose model, albino AA and ANA rats Lines selectively bred for

high and low alcohol preference and consumption

Breeding program started in Finland in 1960s. Derived from Wistar and Sprague-Dawley background, Lewis and Brown Norwegian genotype was introduced later.

P and NP rats “ Breeding was initiated in 1970s in USA. Wistar background, inbred

sP and sNP rats “ Breeding started in 1981 in Sardinia, Wistar background AT and ANT rats Rats with genetic tolerance

or hypersensitivity towards alcohol-induced ataxia

Breeding started in 1970s in Finland. Several background lines.

Mice C57BL/6J Inbred strain, J refers to the

substrain from Jackson Laboratory

Multipurpose model. Used in ethanol drinking studies due to the high ethanol consumption. EtOH-induced CPP and stimulation low.

DBA/2J Inbred strain from Jackson Laboratory

Multipurpose model. Used e.g. in place preference studies. Do not drink ethanol voluntarily.

129/Sv Inbred strain, typically the background strain when generating knockout mice

Moderate to low responses to alcohol, high alcohol CPP, low spontaneous activity.

HAP/LAP High/low alcohol consumption

Derived from the HS/Igb 8-way inbred strain cross, USA

HDID-1, HDiD-2 High Drinking in the Dark Derived from the HS/Npt 8-way inbred strain cross, USA

For more information see: Crabbe et al., 1994, 2005, 2010; Kiianmaa 1990; Rhodes et al., 2007; Rustay et al., 2003; Tzschentke, 2007


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Table 2 Summary of the findings concerning brain histaminergic system in relation to alcohol-related behaviors

Animals Line/Strain

Description Result Method Reference

Alcohol preferrring vs. alcohol avoiding rats

AA/ANA Histamine ↑ HPLC (Lintunen et al., 2001)

Histamine fibers ↑ Immunoreactivity ”

Histidine

decarboxylase activity increased Enzyme assay Unpublished

H1R ↓ HIP, CTX Receptor binding (Lintunen et al.,

2001)

H2R ns Receptor binding ”

H3R ↓ NACC, CTX, PFC, HIP Receptor binding ”

Alcohol intake

↓ by H3R antagonists thioperamide and clobenpropit Self-

administration “

”

↑ by H3R agonist R-α-methylhistamine “ “

Alcohol tolerant vs. alcohol non-tolerant rats

AT/ANT Histamine ↑ CTX, Hypot, HIP, Septum Thal.

HPLC (Lintunen et al., 2002)

Histamine fibers ↑ Hypot., Motor CTX Immunoreactivity “

H1R ↓ HIP, Hypot., MPA

In situ hybridization

(mRNA)

“

“ ↓ HIP Receptor binding “

H3R ↓ MPA, VP Receptor binding “

Alcohol-evoked motor impairment

↓ by inhibition of histamine synthesis by α-fluoro-

methylhistidine

Tilting plane test “

Histidine decarboxylase knockout vs. wildtype mice

HDC KO Alcohol-induced place preference

(reward)

↑ Conditioned place preference

(Nuutinen et al., 2010)

Alcohol

stimulation ↓ Locomotor

activity “

Wildtype mice 129/Sv Alcohol-induced

place preference ↑ by H3R antagonist ciproxifan Conditioned place

preference (Nuutinen et al.,

2010)

C57BL/6Sc

a Alcohol

stimulation ↓ by H3R antagonist ciproxifan Locomotor

activity “

CTX, cortex; HIP, hippocampus; Hypot, hypothalamus; MPA, medial preoptic area; NAcc, nucleus accumbens; ns, not significant; PFC, prefrontal cortex; Thal, thalamus; VP, ventral pallidum


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Table 3 Examples of brain penetrating histamine H3 receptor ligands

pKi=-logKi , the greater the pKi value → the higher the affinity towards H3Rs

Mechanism of action Human Rat Reference Agonists

Imetit agonist pKi= 9.2-9.7 pKi=9.4 (Ireland-Denny et al., 2001; Schnell et al., 2010)

Immepip partial agonist pKi=9.6 pKi=9.0 (Ireland-Denny et al., 2001) R-α-methylhistamine agonist pKi=8.9-9.2 pKi=8.6-8.7 (Ireland-Denny et al., 2001;

Schnell et al., 2010) Antagonists Imidazole-based

Ciproxifan Inverse agonist pKi=7.0 pKi=8.9-9.2 (Ireland-Denny et al., 2001; Schnell et al., 2010)

Thioperamide Inverse agonist pKi= 7.1-7.3 pKi= 7.9-8.1 ”

Clobenpropit Inverse agonist pKi=9.1-9.3 pKi=9.1-9.4 ”

Non-imidazole compounds

Pitolisant (BF2.649) Inverse agonist IC50=5.3 nM Ki=17 nM (Ligneau et al., 2007)

ABT-239 Inverse agonist pKi=9.4 pKi=8.9 (Cowart et al., 2004; Esbenshade et al., 2005)

JNJ-10181457 Neutral antagonist pKi=8.9 pKi=8.2 (Bonaventure et al., 2007)

VUF-5681 Neutral antagonist pKi=8.4 (Kitbunnadaj et al., 2003)


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