title: Cocaine-induced endocannabinoid release modulates behavioral and neurochemical sensitization in mice.
abstract: The endocannabinoid system has been implicated in the development of synaptic plasticity induced by several drugs abused by humans, including cocaine. However, there remains some debate about the involvement of cannabinoid receptors/ligands in cocaine-induced plasticity and corresponding behavioral actions. Here, we show that a single cocaine injection in Swiss-Webster mice produces behavioral and neurochemical alterations that are under the control of the endocannabinoid system. This plasticity may be the initial basis for changes in brain processes leading from recreational use of cocaine to its abuse and ultimately to dependence. Locomotor activity was monitored with photobeam cell detectors, and accumbens shell/core microdialysate dopamine levels were monitored by high-performance liquid chromatography with electrochemical detection. Development of single-trial cocaine-induced behavioral sensitization, measured as increased distance traveled in sensitized mice compared to control mice, was paralleled by a larger stimulation of extracellular dopamine levels in the core but not the shell of the nucleus accumbens. Both the behavioral and neurochemical effects were reversed by CB1 receptor blockade produced by rimonabant pre-treatments. Further, both behavioral and neurochemical cocaine sensitization were facilitated by pharmacological blockade of endocannabinoid metabolism, achieved by inhibiting the fatty acid amide hydrolase enzyme. In conclusion, our results suggest that a single unconditioned exposure to cocaine produces sensitization through neuronal alterations that require regionally specific release of endocannabinoids. Further, the present results suggest that endocannabinoids play a primary role from the earliest stage of cocaine use, mediating the inception of long-term brain-adaptive responses, shaping central pathways and likely increasing vulnerability to stimulant abuse disorders.
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Mereu
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tronci
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Chun
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Thomas
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Green
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.affiliation: Psychobiology Section, Molecular Targets & Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Tanda
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D059333:Central Nervous System Sensitization; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D063388:Endocannabinoids / Q000378:metabolism*; D051379:Mice; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D063387:Cannabinoid Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D003042:Cocaine; D000077285:Rimonabant; D004298:Dopamine
keywords: Behavioral sensitization; cannabinoid CB1 receptors; cocaine addiction; endocannabinoids; in vivo dopamine microdialysis; nucleus accumbens
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