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Eric Dumont |Cocaine self-administration reveals a dopamine D1/Src-dependent LTP at GABA synapses

Abstract :

Are animal models of experimenter or passive administration of drugs of abuse adequate to understand the neurobiological basis of addiction?
We previously demonstrated that in the bed nucleus of the stria terminalis (BST), a limbic structure robustly innervated by dopamine-rich regions of the midbrain, cocaine or sucrose-induced changes in excitatory transmission only occurs in rats trained to self-administer the rewards (Dumont et al., 2005). Here, I will summarize a series of experiments that demonstrate that dopaminergic modulation of inhibitory transmission in the oval BST (ovBST) switched from a pre-synaptic D2-like reduction to a mainly post-synaptic D1-like and src tyrosine kinases-dependent long-lasting increase in GABAA-inhibitory post-synaptic currents (IPSC) amplitude only in rats maintaining cocaine self-administration. This switch was specific to the reinforcing properties of cocaine during the maintenance phase of self-administration since dopaminergic modulation of GABAA-IPSC was normal upon acquisition of cocaine self-administration, maintenance of operant responding for sucrose, or when cocaine infusions were not contingent upon lever pressing (yoke). These synaptic events causally linked with the reinforcing properties of cocaine since intra-BST D1-dopaminergic receptor blockade reduced cocaine, not sucrose, self-administration under a schedule of reinforcement (progressive-ratio) where the effort (number of lever presses) to obtain the next drug infusion increases exponentially. Therefore, in the rodent model of cocaine self-administration, which has robust predictive value and faces validity for human drug addiction, there is a specific switch in dopaminergic modulation of GABAergic transmission in a limbic brain region intrinsic to the neural circuits underlying the reinforcing properties of drugs of abuse. 

Selected publications

What is the bed nucleus of the stria terminalis?Dumont EC.Prog Neuropsychopharmacol Biol Psychiatry. 2009 Nov 13;33(8):1289-90. Epub 2009 Jul 12. No abstract available.
Morphine produces circuit-specific neuroplasticity in the bed nucleus of the stria terminalis.Dumont EC, Rycroft BK, Maiz J, Williams JT.Neuroscience. 2008 Apr 22;153(1):232-9. Epub 2008 Feb 6.
Nuclei-and condition-specific responses to pain in the bed nucleus of the stria terminalis.Morano TJ, Bailey NJ, Cahill CM, Dumont EC.Prog Neuropsychopharmacol Biol Psychiatry. 2008 Apr 1;32(3):643-50. Epub 2007 Nov 12.
Self-administration enhances excitatory synaptic transmission in the bed nucleus of the stria terminalis.Dumont EC, Mark GP, Mader S, Williams JT.Nat Neurosci. 2005 Apr;8(4):413-4. Epub 2005 Feb 27.

François Georges