Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats.
BACKGROUND
It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT2C receptor-dependent mechanism.


OBJECTIVE
We investigated whether Ro 60-0175, a nonselective 5-HT2B-2C agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT2C receptor's role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT2C antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer.


METHODS
Different groups of free-feeding rats were trained to associate discriminative stimuli (SDs) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld.


RESULTS
Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior.


CONCLUSIONS
These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT2C agonist in preventing cue-controlled cocaine-seeking and relapse.
Burbassi
Silvia
S
Experimental Psychopharmacology, Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
Cervo
Luigi
L
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001245:Association Learning / Q000187:drug effects* / Q000502:physiology; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003463:Cues; D004193:Discrimination Learning / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009042:Motivation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D012055:Reinforcement Schedule; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D013395:Sucrose
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005021:Ethylamines; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D013395:Sucrose