title: Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors.
abstract: Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine-stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for GHR and GHR receptors (GHR-Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats, sustaining either pharmacologic antagonism or genetic ablation of GHR-Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR-R1 receptor antagonist), and 20 minutes later, with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine-induced hyperlocomotion. In a second study, adult wild-type (WT) or mutant rats sustaining ENU-induced knockout of GHR-R [GHR-R ((-/-) )] received daily injections (i.p.) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR-R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR-R function in the GHR-R ((-/-) ) rats, a separate feeding experiment was conducted in which WT rats, but not GHR-R ((-/-) ) rats, were noted to eat more after a systemic injection of 15 nmol GHR than after vehicle. These results suggest that GHR-R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. GHR is an orexigenic gut peptide that is transported across the blood-brain barrier and interacts with GHR-Rs located on ventral tegmental dopamine neurons.
authors.affiliation: Department of Psychology, Behavioral Neuroscience Program, Texas A&M University, College Station, TX 77843-4235, USA.
authors.forename: P Shane
authors.initials: PS
authors.lastname: Clifford
authors.forename: Juan
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Destri
authors.initials: D
authors.lastname: Schul
authors.forename: Samuel
authors.initials: S
authors.lastname: Hughes
authors.forename: Tracey
authors.initials: T
authors.lastname: Kniffin
authors.forename: Nigel
authors.initials: N
authors.lastname: Hart
authors.forename: Shoshana
authors.initials: S
authors.lastname: Eitan
authors.forename: Luc
authors.initials: L
authors.lastname: Brunel
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Fehrentz
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wellman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; C569751:N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide; D054440:Receptors, Ghrelin; D014230:Triazoles; D003042:Cocaine; D005998:Glycine