title: D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats.
abstract: Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction.
authors.affiliation: Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Michal
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Xenos
authors.initials: X
authors.lastname: Mason
authors.forename: Julian
authors.initials: J
authors.lastname: DeBacker
authors.forename: Robyn
authors.initials: R
authors.lastname: Sharma
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Normandeau
authors.forename: Emily R
authors.initials: ER
authors.lastname: Hawken
authors.forename: Cynthia
authors.initials: C
authors.lastname: Di Prospero
authors.forename: Cindy
authors.initials: C
authors.lastname: Chiang
authors.forename: Audrey
authors.initials: A
authors.lastname: Martinez
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Jones
authors.forename: Évelyne
authors.initials: É
authors.lastname: Doudnikoff
authors.forename: Stephanie
authors.initials: S
authors.lastname: Caille
authors.forename: Erwan
authors.initials: E
authors.lastname: Bézard
authors.forename: François
authors.initials: F
authors.lastname: Georges
authors.forename: Éric C
authors.initials: ÉC
authors.lastname: Dumont
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D009496:Neurotensin / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D009496:Neurotensin; D005680:gamma-Aminobutyric Acid; D003042:Cocaine; D004298:Dopamine