Invited Symposium: Neuronal Histamine Systems and Behavior
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Introduction
Adminstration of histamine intracerebroventricularly induces biphasic changes in locomotor activity. The initial decrease is followed by an increase which can be blocked by H1 receptor antagonists. Depletion of endogenous brain neuronal histamine by alfa-fluoromethylhistidine decreases locomotor activity in both mice and rats. Administration of histamine may activate some or all of the three G-protein coupled histamine receptors, which renders it difficult to elucidate the transduction mechanisms or exact sites involved in the motor effects of histamine. Mutant mice lacking the H1 receptor develop normally, but display significantly reduced exploratory behavior of ambulation and rarings in new environment. This suggests that at least H1 receptor may be involved in the motor effects.
No systematic studies are available on the possible involvent of histaminergic
mechanisms in genetically determined conditions involving motor behaviour.
The ethanol-sensitive ANT (Alcohol Nontolerant) rats display significant
performance decrement on a tilting plane after adminstration of ethanol
(2 g/kg), whereas the ethanol-insensitive AT (Alcohol Tolerant) rats do
not display impairment. The line differences cannot be explained by blood
ethanol or drug concentrations. They may therefore provide a good experimental
model to study the potential differences in brain histaminergic system
in strains that differ in motor impairing effects of several anxiolytic,
anticonvulsant, muscle relaxant and sedative substances including ethanol,
barbiturates and benzodiazepines.
To see if the brain histaminergic system is associated with the difference
in motor impairment between the ANT and AT lines, we examined native rats
of both strains to see if they differ in histamine content in key areas
of the brain, expression of the histamine-synthesizing enzyme L-histidine
decarboxylase (HDC), H1 or H2 receptor gene expression.
Materials and Methods
Histamine was determined with a sensitive fluorimetric HPLC method as described earlier (Vanhala et al. 1994). In situ hybridization was carried out for histidine decarboxylase as described (Castren and Panula, 1990), and for H1 receptor (Lintunen et al. 1998) using oligoprobes. Expression of H2 receptor was studied using a cRNA probe and standard methodology. Quantitative analysis was carried out using an image analysis system and software (Lintunen et al. 1998). For histamine immunocytochemistry, the rats were perfused with 1-ethyl-3(3-dimethylaminopropyl) carbodiimide and processed as previously described (Panula et al. 1984, 1989).
Results
ANT (Alcohol Nontolerant), AT (Alcohol Tolerant).
(Fig.1) Histamine concentrations in the hypothalamus, cerberal
cortex, and septum of the AT rats were significantly higher than those
of ANT rats. The levels in Sprague-Dawley rats fell between these two lines.
(Fig. 2) The density of histamine-immunoreactive fibres was
also higher in the brains of AT rats than in ANT rats. There was no difference
in the distribution and number of mast cells between the AT and ANT rats.
Expression of L-histidine decarboxylase was in both lines limited to the
tuberomammillary nucleus of the posterior hypothalamus.
(Fig. 3) In situ hybridization of H1 receptor expression
in ANT and AT rat brains. Expression of the H1 receptor in both lines as
studied by in situ hybridization was grossly similar to that previously
observed for other rat lines. However, the signal was stronger i ANT brains.
(Fig. 4) In several brain areas, quantitative in
situ hybridization revealed significant differences in H1 receptor expression
between the lines.
(Fig. 5) In situ hybridization of H2 receptor expression
in ANT and AT rat brains.
(Fig. 6) H2 receptor mRNA expression was identical in AT and
ANT rat brains.
Discussion and Conclusion
The observations suggest that the neuronal histamine systems in AT and ANT rats display significant differences. Mast cells were found in limited areas, and there were no differences in their numbers and distribution. Despite the higher histamine levels in the AT rat brains the expression of HDC did not differ in these lines. This is in agreement with the concept that significant differences are not found in histamine synthesis. Even if the mRNA quantitation does not directly indicate enzyme activity, it shows that no HDC synthesis occurs outside the tuberomammillary nucleus on detectable level.
The higher histamine levels in AT rats brains were associated with lower expression of H1 receptor mRNA, whereas no difference was observed in expression of H2 receptor mRNA.
It is possible that the elevated histamine levels in AT rat brains are associated with a higher histamine turnover, although this has not yet been examined. In that case the H1 receptor expression may be downregulated by histamine in AT rats. H2 receptor does not seem to be subject to similar regulation.
Future studies will address the effect of specific histamine receptor agonists and antagonists on the motor impairment induced by alcohol in these rats.
References
- Castren, E. and Panula, P. (1990) Neurosci. Lett., 120, 113-116.
- Lintunen, M., Sallmén, T., Karlstedt, K. Fukui, H., Eriksson, K.S. and Panula, P. (1998) Eur. J. Neurosci., 10, 2287-2301.
- Panula, P., Yang, H.-Y.T. and Costa, E. (1984) Proc. Natl. Acad. Sci. U.S.A., 81, 2572-2576.
- Panula, P., Pirvola, U., Auvinen, S. and Airaksinen, M.S. (1989) Neuroscience, 28, 586-610.
- Vanhala, A.A., Yamatodani, A. and Panula, P. (1994) J. Comp. Neurol., 347, 101-114.
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