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The discovery of the third histamine receptor and the design of highly selective and potent ligands have not only clarified some aspects of histaminergic neurotransmission in brain: they have also provided us with useful experimental tools to modify this neurotransmission and, therefore, to establish more precisely its roles. Furthermore, in analogy with agents interacting with the two other histamine receptor subtypes, it can be safely anticipated that some of these compounds will constitute novel drugs for the therapeutic management of cerebral and peripheral disorders in humans.

The sensitivity of mast cells to H3-receptor modulation was studied in rat lung under various hormonal conditions. The heterogeneity of mast cell sub-populations in rat lung was assessed by the tissue content of rat mast cell protease I (RMCP I) and rat mast cell protease II (RMCP II). After 24 h fasting, concentrations of RMCP I were unchanged whereas the concentration of RMCP II was significantly reduced by 49%. The [3H]histamine (HA) synthesis was concomitantly decreased by 35%. In addition, the modulation of [3H]HA synthesis by the H3 receptor agonist, (R)alpha-methylHA and by the antagonist, thioperamide, observed in control rats, was lost in fasted rats. Single and repeated administrations of dexamethasone did not influence RMCPI concentrations, but decreased the concentrations of RMCP II with a parallel decrease in [3H]HA synthesis. The inhibitory effect of (R)alpha-methylHA on [3H]HA synthesis was also reduced. These results suggest that a subpopulation of RMCP II-containing mast cells, very sensitive to environmental factors, could be the mast cells synthesizing HA in an H3-receptor-dependent manner.

This finding suggests that a descending histaminergic pathway is interrupted by lesions of this type. This descending system would be responsible for the high density of terminals projecting in restricted areas of the brainstem.

The effects of (+/-) alpha-fluoromethylhistidine (alpha-FMH), a new histidine decarboxylase (HD) inhibitor, were investigated in vitro and in vivo. Following a preincubation with (+/-) alpha-FMH, brain HD-activity was progressively inhibited and could not be restored by dialysis, thus indicating the irreversible nature of this inhibition. Moreover, in vivo, a single intraperitoneal dose of 20 mg/kg of (+/-) alpha-FMH induced a complete and rapid loss of HD activity in gastric and brain tissues. The time-course of recovery was different according to the tissue studied. At a dose of 100 mg/kg (+/-) alpha-FMH did not modify histamine-N-methyl transferase (HMT), DOPA decarboxylase and glutamate decarboxylase activities. A high affinity binding of 3H-histamine was seen in particulate fractions from rat brains. The regional and subcellular distributions of these binding sites indicate that they are not related to HMT. They are likely to represent post-synaptic HA-receptors in view of their decrease after kainate-induced degeneration of neuronal perikarya in the striatum and their increase following interruption of the histaminergic inputs which suggested a denervation hypersensitivity. However, their pharmacological specificity was distinct from either H1- or H2-receptors and the possibility of a modified conformational state of HA-receptors was raised by the selective effect of guanylnucleotides.

A possible involvement of histamine (HA) in thermoregulation mechanisms is suggested by several observations: (a) hypothalamus is the richest brain region both in HA and histidine decarboxylase [1]; (b) cold stress accelerates hypothalamic HA turnover [2]; (c) stereotaxic injection of HA in rostral hypothalamus [3] produces a marked hypothermia. This hypothesis has been further explored by studying the effects on body temperature of intraventricular injections of HA, and some derivatives, agonists and antagonists as well as of treatments known to affect either synthesis or catabolism of brain HA. Intraventricular injection of HA (1-10 [zg) produced in mice a dose dependent decrease in colonic temperature the dose dependence being more apparent on the duration of hypothermia than on the amplitude. Methylation is the main catabolic pathway of brain HA; intraventricular injection of methylhistamine (5 ~zg) did not produce the hypothermia observed with the same dose of HA. In addition administration of amodiaquine (30 rag/ kg, i.p.) an inhibitor of HA methylation before intraventricular HA (2 ~g) produced a significant potentiation of the latter. N'-Methyl and N',N'dimethyl derivatives of HA had approximately the same hypothermic activity than HA, and betazole has been found ten times less active. In order to characterize the nature of the implicated receptors we have used antihistamines specific for H1 or H2 receptors. But with mepyramine (15 mg/kg, i.p.) or burimamide (50 mg/ kg, i.p.) either alone or in combination we could not block HA hypothermia. Among treatments modifying central metabolism of HA we have recently shown [4] that loading mice with L-histidine in doses (850 mg/kg) able to double brain HA level was without effect on temperature; furthermore, inhibitors ofhistidine decarboxylase such as brocresine and hydrazino-histidine unexpectedly induced a very marked hypothermia. These last results do not support the hypothesis of an involvement of endogenous HA in thermoregulation. However, on the other hand, the observation that amodiaquine and several antihistamines, which are inhibitors of HA methylation, produce a dose dependent hypothermia is in agreement with this hypothesis.

Since lesions placed more caudally failed to produce degeneration of terminals in the telencephalon, this suggests that histaminergic cell bodies are present in the upper mesencephalon or posterior hypothalamus.

These findings indicate that clonidine both stimulates H2-receptors and blocks adrenergic receptors in telencephalon.