Invited Symposium: Neuronal Histamine Systems and Behavior
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Locomotion and Rhythmic Release
Using the microdialysis technique it has been shown that, in the rat hypothalamus, the release of histamine is not constant but varies according to a circadian rhythm. Enhanced histamine release appears in the night and coincides with increased rat motility suggesting that hypothalamic histamine is involved in arousal phenomena and in locomotion (Mochizuki et al., 1992). Using the push-pull superfusion technique (Philippu et al., 1996) a similar circadian rhythm, with maximum histamine release rates at about 1 a.m., has been found in the posterior hypothalamus of the conscious rat (Prast et al., 1992). Push-pull superfusion experiments revealed that, in the hypothalamus of anaesthetized cats and rabbits, histamine is released according to a more frequent, ultradian rhythm, with a frequency of 1 cycle per 60-80 min (Philippu et al.,1982). Additional to the circadian rhythm, a similar, slow ultradian rhythm with a frequency of 1 cycle per 83 min has been found in the posterior hypothalamus of the conscious rat (Prast et al., 1992). In the above mentioned push-pull superfusion experiments, the superfusate was continuously collected in time periods of 20 min. Collection in short-time periods of 2.5 min revealed in the mamillary body and the medial amygdaloid nucleus the existence of an additional, fast ultradian rhythm, with a frequency of 1 cycle per 19 min. This fast ultradian rhythm reflects periodical changes in the activity of histaminergic neurons (Prast et al., 1988).
EEG Spectral Power
In the rat hippocampus (Sei et al., 1991), the intensity of EEG spectral power fluctuates. Similarly, in the hypothalamus of anaesthetized rats, the EEG spectral power of the delta and theta frequency bands fluctuates with a frequency of 1 cycle per 100 min (Grass et al., 1995). Interestingly, intracerebroventricular injection of the H1-receptor antagonist mepyramine prolongs the cycle duration of the EEG spectral power in the delta and theta frequency bands. The H2-receptor antagonist famotidine shortens the cycle duration, while the H2-agonist amthamine and the H3-agonist immepip exert the opposite effect (Prast et al., 1996). Many H1- and H2-receptor antagonists are used in pharmacotherapy. It is not known, whether changes in the frequency of the EEG spectral power fluctuations have consequences for patients treated with these drugs. The similarity between the frequency of the EEG fluctuations on the one hand and the frequency of the slow ultradian fluctuations (1 cyle per 83 min) of the histamine release on the other (Prast et al., 1992) prompted us to investigate, whether a relationship exists between them. Combination of the push-pull cannula with a tungsten microelectrode inserted into the outer needle of the cannula made it possible to simultaneously monitor EEG spectral power and release of histamine. Analysis by Sperman’s test revealed, in the delta and theta frequency bands, a negative correlation between the ultradian rhythm of the histamine release rate and the ultradian rhythm of the EEG spectral power. It is assumed that fluctuations in EEG spectral power and histamine release rate are implicated in processing signals that modulate the hypothalamic function (Prast et al., 1997).
Memory
Several lines of evidence point to the importance of histaminergic neurons in memory processes. It has been shown that an intimate relation exists between response latency in the active avoidance response and the decrease in the brain histamine level (Kamei et al., 1993). Intracerebroventricular injection of histamine seems also to facilitate memory in adult (De Almeida and Izquierdo, 1988) and old rats (Kamei and Tasaka, 1993). Using the olfactory, social memory test (Carr et al., 1976) we have shown that endogenous histamine facilitates short-term memory. The olfactory, social memory test is based on the recognition of a juvenile rat by a male adult, sexually-experienced rat (Carr et al., 1976; Sawyer et al., 1984; Thor et al., 1982). Intracerebroventricular injection of histamine, its precursor histidine or thioperamide reduce recognition time thus improving short-term memory. On the other hand, treatment with a-fluoromethylhistidine (FMH), that inhibits neuronal synthesis of histamine, prolongs recognition time. Similarly, recognition time is prolonged by central administration of the H3-receptor agonist immepip that inhibits histamine release via stimulation of presynaptically located H3-autoreceptors. Since short-term memory is improved by thioperamide, histaminergic neurons of the brain seem to facilitate memory processes (Prast et al., 1996). The novel histamine H3-receptor antagonist 3-(4-chlorophenyl)propyl-3-(1H-imidazol-4-yl)propyl ether (FUB 181) also ameliorates scopolamine-induced learning deficit in the elevated plus-maze test (Onodera et al., 1998). These findings suggest that the development of new H3-receptor antagonists may open new horizons in the treatment of brain disorders associated with memory deficit.
References
Carr WJ, Yee L, Gable D, Marasco E (1976) Olfactory recognition of conspecifics by domestic norway rats. J Comp Physiol Psychol, 90:821-828.
De Almeida MAMR, Izquierdo I (1988) Intracerebroventricular histamine, but not 48/80, causes posttraining memory facilitation in the rat. Arch int Pharmacodyn, 291:202-207.
Grass K, Prast H, Philippu A (1995) Ultradian rhythm in the delta and theta frequency bands of the EEG in the posterior hypothalamus of the rat. Neurosci Lett, 191:161-164.
Kamei C, Tasaka K (1993) Effect of histamine on memory retrieval in old rats. Biol Pharm Bull, 16:128-132.
Kamei C, Okumura Y, Tasaka K (1993) Influence of histamine depletion on learning and memory recollection in rats. Psychopharmacology, 111:376-383.
Mochizuki T, Yamatodani A, Okakura K, Horii A, Inagaki N, Wada H (1992) Circadian rhythm of histamine release from the hypothalamus of freely moving rats. Physiol Behav, 51:391-394.
Onodera K, Miyazaki S, Imaizumi M, Stark H, Schunack W (1998) Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice. Naunyn-Schmiedeberg’s Arch Pharmacol, 357:508-513.
Philippu A, Hanesch U, Hagen R, Robinson RL (1982) Release of endogenous histamine in the hypothalamus of anaesthetized cats and conscious, freely moving rabbits. Naunyn-Schmiedeberg’s Arch Pharmacol, 321:282-286.
Philippu A, Prast H, Singewald N (1996) Identification and dynamics of neuronal modulation and function in brain structures and nuclei by continuous determination of transmitter release rates using the push-pull superfusion technique: a compelling approach to in vivo brain research. Sci Pharm, 64:609-618.
Prast H, Saxer A, Philippu A (1988) Pattern of in vivo release of endogenous histamine in the mamillary body and the amygdala. Naunyn-Schmiedeberg’s Arch Pharmacol, 337:53-57.
Prast H, Dietl H, Philippu A (1992) Pulsatile release of histamine in the hypothalamus of conscious rats. J Auton Nerv Syst, 39:105-110.
Prast H, Argyriou A, Philippu A (1996) Histaminergic neurons facilitate social memory in rats. Brain Res, 734:316-318.
Prast H, Grass K, Philippu A (1997) The ultradian EEG rhythm coincides temporally with the ultradian rhythm of histamine release in the posterior hypothalamus. Naunyn-Schmiedeberg’s Arch Pharmacol, 356:526-528.
Sawyer TF, Hengehold AK, Perez WA (1984) Chemosensory and hormonal mediation of social memory in male rats. Behav Neurosci, 98:908-913.
Sei H, Azekawa T, Morita Y (1991) Ultradian rhythm of 100 min in the dark phase EEG of the rat. Physiol Behav, 49:207-210.
Thor DH, Holloway WR (1982) Social memory of the male laboratory rat. J Comp Physiol Psychol, 96: 1000-1006.
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