title: Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats.
abstract: Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague-Dawley rats (n=12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0-10mg/kg) and MDPV (3.2mg/kg) facilitated ICSS. RTI-118 (3.2-32mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25-0.5mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298, USA. Electronic address: bonanojs@vcu.edu.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Bonano
authors.affiliation: Organic and Medicinal Chemistry, Research Triangle Institute, 3040 East Cornwallis Road, PO Box 12194, Research Triangle Park, NC 27709, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Runyon
authors.affiliation: Organic and Medicinal Chemistry, Research Triangle Institute, 3040 East Cornwallis Road, PO Box 12194, Research Triangle Park, NC 27709, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Hassler
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 1101 East Marshall Street, PO Box 980551, Richmond, VA 23298, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO Box 980613, Richmond, VA 23298, USA.
authors.forename: S
authors.initials: S
authors.lastname: Stevens Negus
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000009:adverse effects*; D016466:CHO Cells; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D011759:Pyrrolidines / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration / Q000379:methods; D012653:Self Stimulation / Q000187:drug effects*; D019966:Substance-Related Disorders / Q000188:drug therapy*; D014326:Tropanes / Q000494:pharmacology*; D000094982:Synthetic Cathinone
chemical_list: C095430:3-(4'-chlorophenyl)-2-(5'-phenyl-1',3',4'-oxadiazol-2'-yl)tropane; D052117:Benzodioxoles; D009479:Neuropeptides; D011759:Pyrrolidines; D018013:Receptors, Neuropeptide; D017473:Receptors, Opioid, kappa; D014326:Tropanes; D003042:Cocaine; D000094982:Synthetic Cathinone
keywords: Cocaine; Intracranial self-stimulation; Methylenedioxypyrovalerone; Neuropeptide S; RTI-118