title: Rate-dependent effects of monoamine releasers on intracranial self-stimulation in rats: implications for abuse liability assessment.
abstract: 'Rate dependency' in the discipline of behavioral pharmacology describes a phenomenon wherein the effect of a drug on the rate of a behavior varies systematically as a function of the baseline, predrug rate of that behavior. Historically, rate-dependency studies have compared drug effects on different baseline rates of behavior maintained either by different schedules of reinforcement or during sequential segments of a fixed-interval schedule. The current experiment generated different baseline rates of behavior by altering frequency of electrical stimulation in an intracranial self-stimulation assay. Amphetamine and 10 other monoamine releasers were analyzed for their ability to produce rate-dependent effects in this assay. There were three main findings. First, all compounds produced rate-dependent effects at some dose. Second, one parameter of rate-dependency plots (peak Y-intercept of the regression line) correlated with in-vitro neurochemical data on selectivity of these compounds to release dopamine versus serotonin (P<0.025, R=0.50). Lastly, a correlation between peak Y-intercept and breakpoints under a progressive-ratio procedure in nonhuman primates was also significant (P<0.05, R=0.64). Overall, these results extend the rate-dependent effects of monoamine releasers to behavior maintained under intracranial self-stimulation and suggest that, at least for monoamine releasers, the Y-intercept parameter of rate-dependency plots might be a useful metric of drug reward and predictor of drug self-administration measures of drug reinforcement.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Clayton T
authors.initials: CT
authors.lastname: Bauer
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000008:administration & dosage; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine / Q000494:pharmacology; D009639:Norethandrolone / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D012055:Reinforcement Schedule; D012653:Self Stimulation / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000661:Amphetamine; D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D004298:Dopamine; D005277:Fenfluramine; D008694:Methamphetamine; D009639:Norethandrolone; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors