Histaminergic receptor blockade

Many clinically available drugs that modify sleep-wake cycles and appetite act through the histaminergic system. Blockade of brain H receptors induces drowsiness and other signs of central nervous system depression... 

Histamine was previously mentioned as a putative neurotransmitter (Chapter 12). It may have a role in sedation and wakefulness. In fact, drowsiness had been implicated previously with a possible inhibition of histamine-N-methyltransferase by antihistamines and subsequently with the blockade of central histaminergic receptors as well. However, it... 

A physiological role of hypothalamic histaminergic neurons have been established in a number of studies, which has shown that HA participates in the mediation of the ACTH and P-END responses to stimuli such as stress, immune system activation and suckling. This conclusion is based on findings, which show that inhibition of neuronal HA synthesis by a-fluoromethylhistidine (a-FMH), blockade of postsynaptic HI or H2 receptors and lesion of the tuberomammillary nuclei reduced or prevented the hormone response to these stimuli [16,29-32, S0e-Jensen (unpublished observations)]. 

In summary, H3 receptors play an important role in the histaminergic regulation of the secretion of ACTH and other POMC-derived peptides since their activation inhibits the hormone response to various physiological stimuli, which is in accordance with the finding that an inhibition of the histaminergic system by blockade of synthesis or postsynaptic receptors exert a similar effect as activation of H3 receptors. 

The available data indicate that systemic administration of H3 receptor agonists oppose the stimulatory effect of endogenous HA on PRL secretion and that this effect, which is prevented by concomitant blockade of the H3 receptors, occurs on presynaptic histaminergic neurons rather than on other aminergic neurons. At least, the effect is not exerted via activation of H3 heteroreceptors on serotonergic neurons. 

Hyperosmolality induced by dehydration stimulates expression of AVP mRNA in the SON and PVN as well as AVP secretion from the posterior pituitary lobe [73], These effects are inhibited by blockade of HA synthesis by a-FMH or by blockade of H1 or H2 receptor antagonists [72-73]. Furthermore, dehydration increases mRNA for the HA synthesizing enzyme histidine decarboxylase in the tuberomammillary nuclei [73] and augments neuronal HA turnover in the hypothalamus [72]. These findings strongly indicate that histaminergic neurons are involved in the mediation of the AVP response to dehydration-induced hyperosmolality. 

Histaminergic neurons may be involved in the mediation of the OT response to physiological stimuli. Thus, blockade of the histaminergic system by a-FMH or HI or H2 receptor antagonists inhibited the dehydration-induced increase in OT mRNA in the SON and peripheral OT release in male rats [73, Kjaer et al. (unpublished observations)] and the suckling-induced OT release in lactating female rats [32], Furthermore, suckling increased histidine decarboxylase mRNA in the tuberomammillary nuclei [32]. 

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