title: Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation.
abstract: Previous investigations indicate that the dopamine-β-hydroxylase (DBH) inhibitors disulfiram and nepicastat suppress cocaine-primed reinstatement of cocaine self-administration behaviour. Moreover, both inhibitors increase dopamine release in the rat medial prefrontal cortex (mPFC) and markedly potentiate cocaine-induced dopamine release in this region. This study was aimed to clarify if the suppressant effect of DBH inhibitors on cocaine reinstatement was mediated by the high extracellular dopamine in the rat mPFC leading to a supra-maximal stimulation of D1 receptors in the dorsal division of mPFC, an area critical for reinstatement of cocaine-seeking behaviour. In line with previous microdialysis studies in drug-naïve animals, both DBH inhibitors potentiated cocaine-induced dopamine release in the mPFC, in the same animals in which they also suppressed reinstatement of cocaine seeking. Similar to the DBH inhibitors, L-DOPA potentiated cocaine-induced dopamine release in the mPFC and suppressed cocaine-induced reinstatement of cocaine-seeking behaviour. The bilateral microinfusion of the D1 receptor antagonist SCH 23390 into the dorsal mPFC not only prevented cocaine-induced reinstatement of cocaine seeking but also reverted both disulfiram- and L-DOPA-induced suppression of reinstatement. Moreover, the bilateral microinfusion of the D1 receptor agonist chloro-APB (SKF 82958) into the dorsal mPFC markedly attenuated cocaine-induced reinstatement of cocaine seeking. These results suggest that stimulation of D1 receptors in the dorsal mPFC plays a crucial role in cocaine-induced reinstatement of cocaine seeking, whereas the suppressant effect of DBH inhibitors and L-DOPA on drug-induced reinstatement is mediated by a supra-maximal stimulation of D1 receptors leading to their inactivation.
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.|'Guy Everett Laboratory', University of Cagliari, Italy.|Center of Excellence 'Neurobiology of Addiction', University of Cagliari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Center of Excellence 'Neurobiology of Addiction', University of Cagliari, Italy.|Institute of Neuroscience-Cagliari, National Research Council (CNR), Italy.
authors.forename: Liana
authors.initials: L
authors.lastname: Fattore
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Antinori
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Saba
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.|'Guy Everett Laboratory', University of Cagliari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.|Center of Excellence 'Neurobiology of Addiction', University of Cagliari, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Fratta
authors.affiliation: Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Italy.|'Guy Everett Laboratory', University of Cagliari, Italy.|Institute of Neuroscience-Cagliari, National Research Council (CNR), Italy.
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D004221:Disulfiram / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological; D007093:Imidazoles / Q000494:pharmacology*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors*; D012646:Self Administration; D013871:Thiones / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; D015259:Dopamine Agents; D018765:Dopamine Uptake Inhibitors; D007093:Imidazoles; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D013871:Thiones; D007980:Levodopa; C071262:SK&F 82958; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D004221:Disulfiram; C109487:nepicastat; D004298:Dopamine
keywords: Cocaine-seeking reinstatement; DBH inhibitor; L-DOPA; microdialysis; noradrenaline