D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats

authors

• Krawczyk Michal
• Mason Xenos
• Debacker Julian
• Sharma Robyn
• Normandeau Catherine P.
• Hawken Emily R.
• Di Prospero Cynthia
• Chiang Cindy
• Martinez Audrey
• Jones Andrea A.
• Doudnikoff Evelyne
• Caille Stéphanie
• Bezard Erwan
• Georges François
• Dumont Éric C.

document type

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.

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