Addiction is a major health concern, and its chronic relapsing nature is perhaps its most insidious aspect. Exposure to drug-associated cues is a risk factor for relapse, and understanding how the brain processes these cues may lead to addiction therapies. Here, I examine the role of projections from the ventral pallidum (VP) to ventral tegmental area (VTA) in a rat self-administration/cue-induced reinstatement model of relapse. I will employ novel, viral-based means of controlling this pathway, including designer receptors (DREADDs) that inhibit neuronal activity when an otherwise inert drug (CNO) is administered, and opsins, which allow control of neuronal activity with light. I have found that projections from the rostral portion of VP (RVP) to VTA are activated during cued reinstatement, and that DREADD-based inactivation of RVP and its VTA projections specifically block this behavior. Here, I explore the mechanisms by which RVP-VTA projections mediate cued reinstatement, and how RVP inputs modulate VTA activity. In the K99 Aims, I propose confirming and extending my findings that inhibiting RVP projections to VTA in particular with DREADDs specifically blocks cued reinstatement. Next, I propose electrophysiologically examining how RVP inputs to VTA modulate firing of VTA dopamine and non-dopamine neurons, and how inhibiting this pathway affects VTA neuronal activity. With the training in electrophysiology and opto/pharmacogenetic modulation of brain circuits I receive during the K99 period, I will employ these techniques to further determine the functional roles of the RVP-VTA circuit in cued reinstatement during the R00 period. First, I will determine whether RVP projections to VTA require dopamine in order to have effects on reinstatement behavior, using a transgenic rat line allowing expression of DREADDs specifically in dopamine neurons. Next, I will examine the temporal relationship of RVP-VTA projection activity to transient cue presentations in the reinstatement context using inhibitory optogenetic techniques. I will determine whether phasic, cue-locked activation, or tonic activation of RVP inputs is necessary for conditioned stimuli to elicit reinstatement. These experiments will therefore characterize the mechanisms of the novel, functionally-identified RVP-VTA pathway, which is crucially involved in cue-induced reinstatement of cocaine seeking in a rat model of relapse in addiction.

Public Health Relevance

Addiction is a chronic relapsing disorder, and here we examine in rats a little-studied brain circuit that allows drug-associated cues to cause relapse. We do so by inserting new, synthetic receptors into brain regions, allowing us to control them in a very precise manner. This technique has substantial promise for advancing our understanding of the brain, and as a potential future treatment for addiction and other psychiatric disorders in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
3R00DA035251-05S1
Application #
9479923
Study Section
Special Emphasis Panel (NSS)
Program Officer
Pariyadath, Vani
Project Start
2015-06-15
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
5
Fiscal Year
2017
Total Cost
$9,158
Indirect Cost
$678
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
James, Morgan H; McGlinchey, Ellen M; Vattikonda, Asrita et al. (2018) Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core. Int J Neuropsychopharmacol 21:89-94
Bolton, Jessica L; Ruiz, Christina M; Rismanchi, Neggy et al. (2018) Early-life adversity facilitates acquisition of cocaine self-administration and induces persistent anhedonia. Neurobiol Stress 8:57-67
Farrell, Mitchell R; Schoch, Hannah; Mahler, Stephen V (2018) Modeling cocaine relapse in rodents: Behavioral considerations and circuit mechanisms. Prog Neuropsychopharmacol Biol Psychiatry 87:33-47
Schoch, H; Huerta, M Y; Ruiz, C M et al. (2018) Adolescent cannabinoid exposure effects on natural reward seeking and learning in rats. Psychopharmacology (Berl) 235:121-134
Mahler, Stephen V; Aston-Jones, Gary (2018) CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience. Neuropsychopharmacology 43:934-936
Mahler, Stephen V (2018) Stay alert, don't get hurt. Nat Neurosci 21:3-5
Smith, Kyle S; Bucci, David J; Luikart, Bryan W et al. (2016) DREADDS: Use and application in behavioral neuroscience. Behav Neurosci 130:137-55
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
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