title: Intra-ventral tegmental area microinjections of urotensin II modulate the effects of cocaine.
abstract: Although the peptide urotensin II (UII) has well studied direct actions on the cardiovascular system, the UII receptor (UIIR) is expressed by neurons of the hindbrain. Specifically, the UIIR is expressed by the cholinergic neurons of the laterodorsal tegmentum (LDTg) and the pedunculopontine tegmentum (PPTg). These neurons send axons to the ventral tegmental area (VTA), for which the PPTg and LDTg are the sole source of acetylcholine. Therefore, it was hypothesized that UIIR activation within the VTA would modulate reward-related behaviors, such as cocaine-induced drug seeking. Intra-VTA microinjections of UII at high concentrations (1 nmole) established conditioned place preference (CPP), but also blocked cocaine-mediated CPP (10 mg/kg). When rats received systemic sub-effectual doses of cocaine (7.5 mg/kg) with intra-VTA injections of 1 or 10 pmole of UII CPP was formed. Furthermore, the second endogenous ligand for the UIIR, urotensin II-related peptide, had the same effect at the 10 pmole dose. The effects of low doses of UII were blocked by pretreatment with the UIIR antagonist SB657510. Furthermore, it was found that intra-VTA UII (10 pmole) further increased cocaine-mediated (7.5 mg/kg) rises in electrically evoked dopamine in the nucleus accumbens. Our study has found that activation of VTA-resident UIIR produces observable behavioral changes in rats, and that UIIR is able to modulate the effects of cocaine. In addition, it was found that UIIR activation within the VTA can potentiate cocaine-mediated neurochemical effects. Therefore, the coincident activation of the UII-system and cocaine administration may increase the liability for drug taking behavior.
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, NY 14214, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Mueller
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, NY 14214, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Kausch
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, NY 14214, USA.
authors.forename: T
authors.initials: T
authors.lastname: Markovic
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, NY 14214, USA.
authors.forename: D A A
authors.initials: DA
authors.lastname: MacLaren
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, NY 14214, USA; Research Institute on Addictions, State University of New York at Buffalo, NY 14214, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Dietz
authors.affiliation: Department of Biotechnology and Clinical Laboratory Sciences, State University of New York at Buffalo, NY 14214, USA.
authors.forename: J
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Toxicology, State University of New York at Buffalo, NY 14214, USA; Department of Psychology, State University of New York at Buffalo, NY 14214, USA; Research Institute on Addictions, State University of New York at Buffalo, NY 14214, USA. Electronic address: stewartc@buffalo.edu.
authors.forename: S D
authors.initials: SD
authors.lastname: Clark
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004298:Dopamine / Q000032:analysis; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008845:Microinjections; D009434:Neural Pathways / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D036361:Peptide Hormones / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012201:Reward; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D014579:Urotensins / Q000008:administration & dosage / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; C553589:SB 657510; D013449:Sulfonamides; D014579:Urotensins; C473142:Uts2r protein, rat; C479081:urotensin II-related peptide, rat; C029677:urotensin II; D003042:Cocaine; D004298:Dopamine
keywords: Cocaine; Conditioned place preference; Laterodorsal tegmentum; Pedunculopontine tegmentum; Urotensin II