JPET Miniseries: H3 Receptors 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 wildtype (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 corticostriato-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. Rat Models of Alcohol-Related Behaviors Several inbred and outbred rat lines with different alcohol preferences have been developed and reported (for a review, see Sinclair et al., 1989; Sommer et al., 2006). These include the high alcohol-preferring (HAP) and low alcohol-preferring (LAP) rats (Kitanaka et al., 2004), inbred alcohol-preferring and nonpreferring rats (McBride et al., 2010), and outbred alko alcohol (AA) and alko nonalcohol (ANA) rats (Sinclair et al., 1989; Sommer et al., 2006). A summary of rat and mouse models used in alcohol research is shown in Table 1. The AA and ANA 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, because the levels of 3-methoxy-4-hydroxy-phenylglycol are higher in AA rats (Sommer et al., 2006). However, there is no difference in the alcoholinduced release of dopamine between the lines, so 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 Our studies are supported by the Academy of Finland [Grants 126744, 118547], the Finnish Fund for Alcohol Research, and Magnus Ehrnrooth’s Foundation. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.110.170928. ABBREVIATIONS: HAP, high alcohol-preferring; LAP, low alcohol-preferring; AA, alko alcohol; ANA, alko nonalcohol; CPP, conditioned place preference; HDC, histidine decarboxylase; H1R, histamine H1 receptor; H3R, histamine H3 receptor; SD, Sprague-Dawley; WT, wild type; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2; [ H]Ro15-4513, [H]ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3carboxylate; BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride; ABT-239, 4-(2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}benzofuran-5-yl)benzonitrile; JNJ-10181457, 4-(3-(4-piperidin-1-ylbut-1-ynyl)benzyl)morpholine); VUF-5681, 4-[3-(1H-imidazol-4-yl)propyl]piperidine dihydrobromide. 0022-3565/11/3361-9–16$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 336, No. 1 Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics 170928/3645335 JPET 336:9–16, 2011 Printed in U.S.A. 9 at A PE T Jornals on July 8, 2017 jpet.asjournals.org D ow nladed from Eriksson, 1972), but metabolite levels are normal. Thus, there are differences in major catechol and indolamine neurotransmitter systems between the rat lines. Histamine levels in AA rats are 20 to 170% higher in different brain regions in AA than in ANA rat brain (Lintunen et al., 2001) (Table 2). It is noteworthy that 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 alcohol preference. Levels of tele-methylhistamine are generally 30 to 70% higher in AA TABLE 1 Examples of rat and mouse models and their suitability in the examination of alcohol-related studies For more information see Crabbe et al., 1994, 2005, 2010; Kiianmaa, 1990; Rhodes et al., 2007; Rustay et al., 2003; Tzschentke, 2007. 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 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 Lines selectively bred for high and low alcohol preference and consumption Breeding was initiated in 1970s in the United States; Wistar background, inbred sP and sNP Lines selectively bred for high and low alcohol preference and consumption Breeding started in 1981 in Sardinia; Wistar background AT and ANT 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 The Jackson Laboratory (Bar Harbor, ME) Multipurpose model; used in ethanol drinking studies because of the high ethanol consumption; EtOH-induced CPP and low stimulation DBA/2J Inbred strain from The Jackson Laboratory Multipurpose model; used 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 eight-way inbred strain cross, United States HDID-1, HDID-2 High drinking in the dark Derived from the HS/Npt 8-way inbred strain cross, United States