Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness

Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep–wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep–wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident–intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HATMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.

Mechanism of action of narcolepsy medications

The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.

Involvement of Tuberomamillary Histaminergic Neurons in Isoflurane Anesthesia

Background The brain histaminergic system plays a critical role in maintenance of arousal. Previous studies suggest that histaminergic neurotransmission might be a potential mediator of general anesthetic actions. However, it is not clear whether histaminergic tuberomamillary nucleus (TMN) is necessarily involved in the sedative/hypnotic effects of general anesthetics. Methods Male Long Evans rats underwent either TMN orexin-saporin/sham lesion or implantation of intracerebroventricular cannula 2 weeks before the experiment. The behavioral endpoint of loss of righting reflex was used to assess the hypnotic property of isoflurane, propofol, pentobarbital, and ketamine in animals. Histaminergic cell loss was assessed by adenosine deaminase expression in the TMN using immunohistochemistry. Results Rats with bilateral TMN orexin-saporin lesion induced an average 72% loss of histaminergic cells compared with sham-lesion rats. TMN orexin-saporin lesion or intracerebroventricular administration of triprolidine (an H1 receptor antagonist) decreased the 50% effective concentration for loss of righting reflex value and prolonged emergence time to isoflurane anesthesia. However, TMN orexin-saporin lesion had no significant effect on the anesthetic sensitivity to propofol, pentobarbital, and ketamine. Conclusions These findings suggest a role of the TMN histaminergic neurons in modulating isoflurane anesthesia and that the neural circuits for isoflurane-induced hypnosis may differ from those of γ-aminobutyric acid-mediated anesthetics and ketamine.