Author: Thomas Kilduff

As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy.

Development of therapeutics for narcolepsy has been challenged by historical misunderstanding of the disease, its many disparate symptoms and, until recently, its unknown etiology.

Early in 1998, we (and others) described the same hypothalamic neuropeptides, respectively called the hypocretins or orexins, which were discovered using two different approaches.

We compared electroencephalogram and behavioral phenotypes of rats and mice with homozygous deletion of Cntnap2, a gene associated with cortical dysplasia-focal epilepsy and autism spectrum disorders.

Hypocretin 1 and 2 (Hcrts; also known as orexin A and B), excitatory neuropeptides synthesized in cells located in the tuberal hypothalamus, play a central role in the control of arousal.

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wake-promoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity.

We hypothesized that HCRT antagonists induce sleep, in part, through disfacilitation of BF neurons; consequently, ALM should have reduced efficacy in BF-lesioned (BFx) animals.

We used a full-length knock-in HD model to determine early changes in the electroencephalogram (EEG) and sleep that may predict the onset and progression of the disease.

The neurological basis for narcolepsy resides in the degeneration of the hypothalamic neurons that produce the neuropeptide hypocretin, but how and why these specific cells die is one of the most important, unanswered questions in the field.

Control of sleep and wakefulness involves multiple systems, each of which presents vulnerability to sleep/wake dysfunction that may predispose to physical and/or neuropsychiatric disorders.

Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties.

Cortical interneurons, immunoreactive for neuronal nitric oxide synthase (nNOS) and the receptor NK1, express the functional activity marker Fos selectively during sleep. NREM sleep ‘pressure’ is hypothesized to accumulate…