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Principal Investigator: DAVID WEINSHENKER
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $463,811
Funding agency: National Institute on Drug Abuse
Project Summary
The opioid epidemic has been declared a national public health emergency. Current treatments have abuse
liability, target acute overdose only, and/or are ineffective for many people suffering from opioid addiction, and
new therapies are desperately needed. One promising target is the brain galanin system; reducing galanin
levels exacerbates morphine reward and withdrawal, while increasing galanin opposes opioid addiction-like
behaviors. However, the neuroanatomical source and target of this protective galanin have not been identified,
and the effects of galanin on voluntary opioid intake have not been investigated. The locus coeruleus (LC)
modulates the activity of the mesolimbic reward pathway and has been implicated in opioid addiction, and
80% of noradrenergic neurons in this nucleus co-express galanin. We have assembled a set of genetically
altered mice that either lack or overexpress galanin specifically in noradrenergic neurons to test the hypothesis
that LC-derived galanin suppresses the ability of opioids to disinhibit dopamine (DA) neurons in the ventral
tegmental area (VTA) and attenuates opioid reward/reinforcement, as well as acts in an autocrine manner to
prevent LC hyperactivity and reduces withdrawal symptoms. In Aim 1, we will use in situ hybridization to
determine the neurochemical identity of galanin receptor-expressing cells in the VTA, and slice and in vivo
electrophysiology to investigate the circuitry and cellular mechanisms underlying the ability of galanin to
oppose opioid-induced VTA DA neuron activity. In Aim 2, we will use the transgenic mice described above to
test the hypothesis that LC-derived galanin inhibits opioid reinforcement using an operant i.v. opioid self-
administration paradigm. In Aim 3, we will assess the ability of galanin to suppress LC hyperactivity, cellular
plasticity, and aversive symptoms during opioid withdrawal. Completion of these aims will lay the groundwork
for LC/galanin-based therapies for opioid addiction.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Acute><Adrenergic Receptor><Adrenoceptors><Agonist><Aminalon><Aminalone><Anatomic Sites><Anatomic structures><Anatomy><Attenuated><Autocrine Systems><Behavior><Behavioral><Behavioral Symptoms><Brain><Brain Nervous System><CNS plasticity><Cell Body><Cell Nucleus><Cells><Chronic><DA Neuron><Data><Disinhibition><Dopamine neuron><Dose><Electrophysiology><Electrophysiology (science)><Encephalon><Epinephrine Receptors><Frequencies><GABA><GAL gene><GAL-GMAP><GALN><GLNN><GMAP><Galanin><Goals><Human><Hyperactivity><In Situ Hybridization><Infumorph><KO mice><Kadian><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Laws><Levarterenol><Levonorepinephrine><Literature><Location><Locus Coeruleus><MS Contin><MSir><Maps><Measurement><Mediating><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular><Morphia><Morphine><Murine><Mus><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Neural Cell><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurocyte><Neuronal Plasticity><Neurons><Neuropeptides><Neurophysiology / Electrophysiology><Neurotransmitters><Noradrenaline><Norepinephrine><Nucleus><Nucleus Pigmentosus Pontis><Null Mouse><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Oramorph><Oramorph SR><Overdose><Pathway interactions><Persons><Pharmacology><Phase><Phenotype><Process><Property><Psychological reinforcement><Receptor Protein><Reinforcement><Research><Rewards><Rodent><Rodentia><Rodents Mammals><Roxanol><Self Administered><Self Administration><Slice><Source><Statex SR><Symptoms><System><Testing><Transgenic Mice><Transgenic Organisms><Transmission><Ventral Tegmental Area><Wild Type Mouse><Withdrawal><Withdrawal Symptom><abuse liability><abuse potential><addiction><addictive disorder><adenoreceptor><attenuate><attenuates><autocrine><blue nucleus><central nervous system plasticity><combat><conditioned place preference><dopaminergic neuron><electrophysiological><galanin prepropeptide><galanin receptor><galanin-message-associated peptide><galanin/GMAP prepropeptide><gamma-Aminobutyric Acid><in situ Hybridization Genetics><in situ Hybridization Staining Method><in vivo><locus ceruleus structure><mRNA><neural plasticity><neurochemical><neurochemistry><neuronal><neuroplastic><neuroplasticity><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><noradrenergic><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><opiate abuse><opiate consumption><opiate crisis><opiate drug abuse><opiate drug use><opiate exposure><opiate intake><opiate therapy><opiate use><opiate withdrawal><opioid abuse><opioid addiction><opioid consumption><opioid crisis><opioid dependence><opioid dependent><opioid detox><opioid detoxification><opioid drug abuse><opioid drug use><opioid epidemic><opioid exposure><opioid intake><opioid therapy><opioid use><opioid withdrawal><optogenetics><overexpress><overexpression><pathway><place conditioning><prevent><preventing><public health emergency><receptor><response><small molecule><transgenic><transmission process><ventral tegmentum><wildtype mouse><γ-Aminobutyric Acid>