Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649
Introduction
Although the role of histaminergic neurons in schizophrenia and in the effects of antipsychotic drugs has been less studied than those of other aminergic neurons, the topic deserves attention. In agreement, histamine neuron activity seems to be enhanced in both rodent models of schizophrenia (changes elicited by dopamine-releasing or glutamate-blocking drugs) of the human disease.
A single administration of methamphetamine markedly increases tele-methylhistamine (t-MeHA) levels, an index of histamine neuron activity, in the cerebral cortex, striatum and hypothalamus [1], a response resulting from the stimulation of histaminergic neurons by endogenous dopamine activating selectively D2 receptors. In agreement, this effect was completely blocked by haloperidol, a D2/D3-receptor antagonist, but remained unchanged either after administration of nafadotride used at a dose inducing a selective blockade of the D3 receptor [2], or in the brain of mice lacking functional D3 receptors. D2-like receptor binding sites are detected in the tuberomammillary nucleus [3], in which D3 receptors could not be detected (J. Diaz, personal communication). Therefore, endogenous dopamine may directly activate histamine neurons by interacting with D2 receptors located upon their perikarya or dendrites [2], onto which dopamine-containing axons emanating from the ventral tegmental area or substantia nigra project [4]. D2 receptors located on histaminergic nerve endings do not seem to be involved since apomorphine fails to significantly affect histamine release from slices of rat cerebral cortex [5].
In rats or mice receiving methamphetamine repeatedly and showing locomotor sensitization, the basal activity of histaminergic neurons is persistently enhanced, presumably as a result of persistent enhancement of dopamine release onto the tuberomamillary neurons [6], [1].
Phencyclidine (PCP), a non-selective “psychotogenic” NMDA receptor antagonist, significantly enhances t-MeHA levels in various mouse brain regions [7], [8]. Furthermore, the effect of PCP is mimicked by MK-801, another NMDA open-channel blocker displaying higher potency and selectivity [9]. In addition, histidine decarboxylase mRNA expression is increased by PCP administration in the tuberomammillary nucleus [9].
Levels of t-MeHA are significantly elevated in the cerebrospinal fluid of patients with chronic schizophrenia [10] whereas H1 receptor-mediated responses are blunted [11], [12] and H1-receptor binding reduced in cortical areas of these patients [13], possibly reflecting a down-regulation of the receptor consequent to over stimulation by endogenous histamine.
In addition, antipsychotic drugs (APDs) affect histaminergic neurotransmission in various ways: (1) a large number of APDs are potent H1-receptor antagonists, a feature which confers them sedative and pro-obesity side-effects; (2) typical APDs tend to inhibit histaminergic neuron activity, whereas atypical APDs have opposite effects as a result of their 5-HT2A antagonism [14].
The above information suggests the interest of testing agents affecting selectively histaminergic neurotransmission in psychotic states. So far, only the (negative) effects of H1-receptor antagonists of the first generation, i.e. the brain-penetrating “antihistamines”, were assessed since neither H2- nor H3-receptor antagonists crossing the blood–brain barrier were introduced in the clinics. Since potent and selective H3-receptor antagonists/inverse agonists are now currently available for this purpose, we have addressed these questions using BF2.649 i.e. 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, a potent and selective inverse agonist at the histamine H3 receptor [15].
Section snippets
Changes in plasma and tissue levels of BF2.649 after oral administration to mice
Male Swiss mice (25 ± 1 g, R. Janvier, Le Genest Saint Isle, France) were dosed p.o. with 10 mg/kg BF2.649 after overnight fasting. At times of 0.5, 1.5, 3 and 8 h post dose, 0.8–1.0 ml blood samples from each carbon dioxide-anaesthetized mouse were withdrawn by cardiac puncture using heparinized syringes. Blood samples were placed on wet ice for 30 min and centrifuged at 3000 rpm for 10 min at +4 °C to obtain plasma. Brain and heart samples were dissected, weighed and immediately frozen in liquid
Pharmacokinetics of BF2.649
Mice receiving BF2.649 at a 10 mg/kg dose presented maximal concentrations (Cmax) 30 min after oral administration with Cmax values of 441 ± 69 ng/ml in plasma, 10346 ± 1099 ng/g in brain and 4092 ± 527 ng/g in heart (Fig. 1). BF2.649 had a plasmatic elimination half-life of ∼120 min. AUC values calculated for plasma, brain and heart were respectively of 1475, 34686 and 13735 ng h/ml. These results demonstrated oral absorption of BF2.649 and high brain exposure, evidenced by AUCbrain/AUCplasma and Cmaxbrain/C
Discussion
BF2.649 appears as a potent inverse agonist at the human and, although slightly less so, at the rodent histamine H3 receptor, which activates cerebral histamine release in vivo at low oral dosage with ED50 dose of 1.6 mg/kg and a maximal effect elicited at 10 mg/kg, p.o. [15] and 3–5 mg/kg, i.p. (not shown). In agreement we find here that the drug displays a high degree of brain penetration in mice as judged by brain/plasma ratios of over 25 when either Cmax or AUC values are considered. It is
Acknowledgments
The authors thank the experimental and technical contributions of C. Buda, J.-P. Sastre and G. Guidon.
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