We recently found that animals made dependent on morphine exhibit increased drug preference 5 weeks after withdrawal. These results reveal that prior prolonged drug exposure and withdrawal alters behavioral and neural responsivity to subsequent drug administration for a substantial period of time. This observation establishes a simple behavioral model of the well-established clinical observation that former addicts have a high liability for future relapse. Our goal is to identify the neural changes that underlie this long-term alteration of drug responsivity. We hypothesize that this increased drug preference after prior exposure and withdrawal is due at least in part to changes in pathways converging on the ventrolateral bed nucleus of the stria terminalis (vBNST). In particular, we hypothesize that norepinephrine innervation of the vBNST from the A2 neurons in the nucleus tractus solitarius, or corticotropin releasing hormone inputs from the amygdala or intrinsic BNST neurons, plays a role in potentiating activity of the vBNST in response to drug-associated stimuli. We recently found an excitatory amino acid pathway from the vBNST to the ventral tegmental area; this projection strongly activates dopaminergic neurons and may therefore play a pivotal role in expression of the enhanced drug preference. We propose a set of coordinated anatomical, neurophysiological and behavioral experiments to test these hypotheses. Results of these studies will provide important new insights into neural mechanisms underlying conditioned drug seeking and relapse in abstinent addicts, a major 3roblem in treatment and prolonged abstinence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA006214-24
Application #
8263775
Study Section
Special Emphasis Panel (NSS)
Program Officer
Volman, Susan
Project Start
1992-08-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
24
Fiscal Year
2012
Total Cost
$425,194
Indirect Cost
$136,927
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Lopez, Marcelo F; Moorman, David E; Aston-Jones, Gary et al. (2016) The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain Res 1636:74-80
Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2016) Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner. Eur J Neurosci 43:710-20
Bentzley, Brandon S; Aston-Jones, Gary (2016) Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential. Addict Biol :
McGlinchey, Ellen M; James, Morgan H; Mahler, Stephen V et al. (2016) Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking. J Neurosci 36:8700-11
Bentzley, Brandon S; Aston-Jones, Gary (2015) Orexin-1 receptor signaling increases motivation for cocaine-associated cues. Eur J Neurosci 41:1149-56
Kaufling, Jennifer; Aston-Jones, Gary (2015) Persistent Adaptations in Afferents to Ventral Tegmental Dopamine Neurons after Opiate Withdrawal. J Neurosci 35:10290-303
Moorman, David E; Aston-Jones, Gary (2015) Prefrontal neurons encode context-based response execution and inhibition in reward seeking and extinction. Proc Natl Acad Sci U S A 112:9472-7
Mahler, Stephen V; Vazey, Elena M; Beckley, Jacob T et al. (2014) Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 17:577-85
Cason, Angie M; Aston-Jones, Gary (2014) Role of orexin/hypocretin in conditioned sucrose-seeking in female rats. Neuropharmacology 86:97-102
Mahler, Stephen V; Hensley-Simon, Megan; Tahsili-Fahadan, Pouya et al. (2014) Modafinil attenuates reinstatement of cocaine seeking: role for cystine-glutamate exchange and metabotropic glutamate receptors. Addict Biol 19:49-60

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