David Feifel

University of California San Diego, USA

Abstract

[O10] Neurotensin: it’s not your father’s therapeutic target

David Feifel, MD, PhD, Paul D. Shilling, PhD, Gilia Melendez, MA; University of California San Diego, USA

Neurotensin (NT) is a 13 amino-acid neuropeptide that acts as a neurotransmitter in the CNS. It is localized in a number of areas highly relevant to neuropsychiatric disorders.
Early interest in NT stemmed almost exclusively from its apparent ability to regulate dopamine pathways in the brain and, more specifically, to inhibit the effects of dopamine agonists such as apomorphine and amphetamine. Based upon this action, it was suggested that NT is an “endogenous antipsychotic.” The proposed mechanism of action for NT’s antipsychotic-like effects is an inhibitory coupling of NT1 receptors with D2 receptors on the same postsynaptic membranes in the nucleus accumbens such that activation of NT1 receptors by endogenous NT produces a conformation change in nearby D2 receptors that reduces their affinity for dopamine. 

For the past decade, we have been exploring the therapeutic potential of NT agonists using chemically stabilized, active hexapeptide fragments of NT that have the ability to penetrate the brain after systemic administration. Several such preclinical, proof-of-principle studies have revealed a much broader range of therapeutic-like effects than can be accounted for by the mechanism of indirect D2 antagonism. Taken together, these findings suggest that NT plays a role in modulating neural circuits downstream to the site of action of current antipsychotics and that NT agonists can modulate a number of non-dopamine neurotransmitter systems including serotonin, acetylcholine and glutamate. These findings also suggest that NT agonists would have therapeutic efficacy in a number of conditions not previously associated with NT including, treatment refractory psychosis, bipolar disorder, anxiety, depression, obesity, and disorders associated with cognitive impairment.

In summary, the preclinical evidence supporting NT agonists as a novel class of medication with potential benefits in a number of CNS disorders has accrued progressively over two decades and efforts now need to be marshaled toward the goal of developing NT agonists with properties suitable for commercial development including testing in humans.

Keywords:  Neurotensin, Antipsychotic  

Biography

Dr David Feifel is a Professor of Psychiatry and Neuroscience, at the University of California, San Diego. He is the Director of the Neuropsychiatry Service at UCSD Medical Center. In addition to caring for patients, teaching medical students and residents, Dr. Feifel engages in translational research related to the exploration of neuropeptide systems as potential therapeutic targets for neuropsychiatric disorders. In this pursuit he heads a basic psychopharmacology research laboratory as well as a clinical psychopharmacology research program, both of which are located on the campus of UCSD Medical Center.