Drugs of abuse share an ability to enhance dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to downstream targets, including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Direct stimulation of VTA DA neurons is reinforcing and sufficient to trigger the array of molecular, cellular, and behavioral adaptations that define addiction. The actions of drugs of abuse are opposed by inhibitory G protein signaling pathways in the reward circuitry. Psychostimulants can weaken inhibitory G protein signaling in VTA DA neurons and layer 5/6 pyramidal neurons of the prelimbic cortex (PLC), via a selective reduction in the cell surface expression of G protein-gated inwardly rectifying K+ (GIRK) channels. Genetic suppression of GIRK channel activity in drug-nave mice evokes some of the cellular adaptations and behavioral outcomes typically associated with repeated drug exposure, supporting the outlook that GIRK channels are critical and exploitable contributors to innate addiction barriers. The goals of this project are to use new tools and approaches to gain refined insights into the mechanisms mediating the recruitment of GIRK-dependent signaling by drugs of abuse, and to investigate the therapeutic potential associated with enhancing GIRK channel activity in a neuron- and/or channel subtype-specific fashion. There are two specific aims: (1) To probe the recruitment and therapeutic potential of GIRK-dependent feedback to VTA DA neurons. Loss-of-function mutants, including mice lacking GIRK channels in DA neurons, suggest that the unique GIRK channel subtype found in VTA DA neurons is a key regulator of behavioral sensitivity to drugs of abuse. This premise will be tested using intersectional viral manipulations to enhance or suppress GIRK-dependent signaling selectively in VTA DA neurons, followed by behavioral assessments in non-contingent and response-contingent tests involving cocaine. In parallel, the therapeutic potential of novel activators of the unique VTA DA neuron GIRK channel subtype will be evaluated. Lastly, an in vivo optogenetic approach will be used to test whether phasic VTA DA activity is sufficient to engage and suppress GIRK-dependent signaling in VTA DA neurons. (2) To reveal the mechanisms and relevance of a GIRK-dependent feedforward inhibitory circuit in the PLC. Although work in the initial project period established that GIRK-dependent signaling in layer 5/6 PLC pyramidal neurons is an addiction barrier, how and when this barrier is engaged is unclear. Optogenetic and chemogenetic approaches will be used to test the working model that phasic activation of VTA DA neurons evokes a feedforward inhibitory circuit involving the D1R-dependent activation of layer 5/6 PLC GABA interneurons, which tempers the parallel DA-dependent activation of adjacent pyramidal neurons. The proposed studies also test the predictions that repeated engagement of this feedforward circuit is sufficient to trigger the suppression of GIRK channel activity in layer 5/6 PLC pyramidal neurons, and that strengthening GIRK-dependent signaling in these neurons confers resilience to the addictive effects of cocaine.

Public Health Relevance

Despite the profound toll that substance abuse exacts on the individual and society, there are few therapeutic options to treat addiction. Efforts to understand the molecular and cellular mechanisms underlying addiction have shown that inhibitory signaling pathways in the reward circuitry of the brain oppose the cellular and behavioral effects of drugs of abuse. The proposed research employs interdisciplinary approaches and novel research tools to better understand the inhibitory signaling pathways that moderate the actions of drugs of abuse, while also evaluating the therapeutic potential associated with strengthening these innate barriers to treat addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA034696-09
Application #
10113568
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Berton, Olivier
Project Start
2013-08-01
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
9
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Tipps, Megan; Marron Fernandez de Velasco, Ezequiel; Schaeffer, Allee et al. (2018) Inhibition of Pyramidal Neurons in the Basal Amygdala Promotes Fear Learning. eNeuro 5:
Luján, Rafael; Aguado, Carolina; Ciruela, Francisco et al. (2018) Differential association of GABAB receptors with their effector ion channels in Purkinje cells. Brain Struct Funct 223:1565-1587
Marron Fernandez de Velasco, Ezequiel; Carlblom, Nicholas; Xia, Zhilian et al. (2017) Suppression of inhibitory G protein signaling in forebrain pyramidal neurons triggers plasticity of glutamatergic neurotransmission in the nucleus accumbens core. Neuropharmacology 117:33-40
McCall, Nora M; Kotecki, Lydia; Dominguez-Lopez, Sergio et al. (2017) Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice. Neuropsychopharmacology 42:707-715
Marron Fernandez de Velasco, Ezequiel; Zhang, Lei; N Vo, Baovi et al. (2017) GIRK2 splice variants and neuronal G protein-gated K+ channels: implications for channel function and behavior. Sci Rep 7:1639
Victoria, Nicole C; Marron Fernandez de Velasco, Ezequiel; Ostrovskaya, Olga et al. (2016) G Protein-Gated K+ Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning. Biol Psychiatry 80:796-806
Munoz, Michaelanne B; Padgett, Claire L; Rifkin, Robert et al. (2016) A Role for the GIRK3 Subunit in Methamphetamine-Induced Attenuation of GABAB Receptor-Activated GIRK Currents in VTA Dopamine Neurons. J Neurosci 36:3106-14
Montandon, Gaspard; Ren, Jun; Victoria, Nicole C et al. (2016) G-protein-gated Inwardly Rectifying Potassium Channels Modulate Respiratory Depression by Opioids. Anesthesiology 124:641-50
Marron Fernandez de Velasco, Ezequiel; Hearing, Matthew; Xia, Zhilian et al. (2015) Sex differences in GABA(B)R-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex. Neuropharmacology 95:353-60
Marron Fernandez de Velasco, Ezequiel; McCall, Nora; Wickman, Kevin (2015) GIRK Channel Plasticity and Implications for Drug Addiction. Int Rev Neurobiol 123:201-38

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