Document text
Principal Investigator: Gary S. Aston-Jones
Organization: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
Fiscal Year: 2024
Award: $533,775
Funding agency: National Institute on Drug Abuse
Project Summary/Abstract
A large number of studies over the last 14 years show that orexin neurons play an important role in reward
processing and drug abuse. Although these studies show that orexin-1 receptor (OxR1) signaling is particularly
involved in the motivation for many drugs of abuse, none have linked this system to the persistent, chronically
relapsing nature of addiction. Here, we extend studies from the previous terms of this project to tackle this
important issue. We recently found that the intermittent access (IntA) cocaine self-administration paradigm
produces a strong, multiphenotype addiction-like state as well as increased numbers of orexin-expressing
neurons. Importantly we find that the IntA-induced increase in addiction behaviors and orexin expression are
persistent (>30d of abstinence). We also find that chronic administration of an OxR1 antagonist during IntA
blocks the increased demand that this paradigm normally produces. Here, we propose to more fully characterize
the IntA-linked addiction profile and induced-orexin neurons following 30d abstinence. We also will examine the
contribution of OxR1 and OxR2 signaling in ventral tegmental area (VTA) and paraventricular thalamus (PVT),
two reward-related areas previously linked to orexin function, in persistent addiction behaviors after IntA. Finally,
we will test whether the FDA-approved dual orexin receptor antagonist, Belsomra™ (suvorexant), is effective in
acutely decreasing addiction behaviors, and in preventing the transition from a moderate to a severe addiction
profile. Together, the proposed experiments are a natural and important extension of the prior studies in this
project and will represent an important step forward in the development of an orexin-based treatment for cocaine
addiction.
Terms: <Abstinence><Acute><Animals><Area><BAC clone><BACs><Bacterial Artificial Chromosomes><Behavior><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Count><Cell Number><Cell Signaling><Cells><Chronic><Clinical><Cocaine><Cocaine Addiction><Cocaine Dependence><Common Rat Strains><Cues><Data><Development><Disease><Disorder><Drug abuse><Drug usage><Drugs><Dynorphins><Economics><Encephalon><Exhibits><Extinction><FDA approved><Fiber><Hcrt protein><Hcrt/ORX><Hcrts/ORXs><Hypothalamic structure><Hypothalamus><Inferior Colliculus><Intracellular Communication and Signaling><Knowledge><Label><Lateral><Link><Medial><Medication><Methods><Modeling><Motivation><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neuropeptides><Paraventricular Nucleus of Thalamus><Paraventricular Thalamic Nucleus><Pattern><Peptides><Pharmaceutical Preparations><Phenotype><Play><Posterior Quadrigeminal Body><Punishment><Rat><Rats Mammals><Rattus><Receptor Protein><Receptor Signaling><Relapse><Resistance><Rewards><Role><Self Administered><Self Administration><Signal Transduction><Signal Transduction Systems><Signaling><Site><Structure of paraventricular nucleus of thalamus><System><Testing><Thalamic structure><Thalamus><Transgenic Organisms><Ventral Tegmental Area><abuse of drugs><abused drug><abused drugs><abuses drugs><addicted to cocaine><addiction><addiction to cocaine><addictive disorder><antagonism><antagonist><biological signal transduction><cocaine addicted><cocaine seeking><cocaine self-administration><cocaine use><developmental><drug abused><drug of abuse><drug use><drug/agent><drugs abused><drugs of abuse><economic><endophenotype><experiment><experimental research><experimental study><experiments><genetic approach><genetic strategy><hypocretin><hypocretin/orexin><hypocretins/orexins><hypothalamic><innervation><melanin-concentrating hormone><melanophore-concentrating hormone><melanosome concentrating hormone><nerve supply><neuronal><novel><orexin><orexin 1 receptor><prevent><preventing><receptor><resistant><reward processing><self-administer cocaine><social role><thalamic><transgenic><ventral tegmentum>