Stimulation of 5-HT(1B) receptors enhances cocaine reinforcement yet reduces cocaine-seeking behavior.
Paradoxically, stimulation of 5-HT(1B) receptors (5-HT(1B)Rs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5-HT(1B)R agonist, CP94253, on cocaine reinforcement and cocaine-primed reinstatement, predicting that CP94253 would enhance cocaine-seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine-seeking behavior (operant responses without cocaine reinforcement). Next, they were pre-treated with CP94253 (3-10 mg/kg, s.c.) and either tested for cocaine-primed (10 or 2.5 mg/kg, i.p.) or cue-elicited reinstatement of extinguished cocaine-seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self-administered cocaine doses (0-1.5 mg/kg, i.v.) were examined. Cocaine dose-dependently reinstated cocaine-seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue-elicited reinstatement. In contrast, CP94253 shifted the self-administration dose-effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine-seeking behavior). In subsequent control experiments, CP94253 decreased open-arm exploration in an elevated plus-maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5-HT(1B)Rs produces opposite effects on cocaine reinforcement and cocaine-seeking behavior, and further suggest that 5-HT(1B)Rs may be a novel target for developing medications for cocaine dependence.
Pentkowski
Nathan S
NS
Department of Psychology, Arizona State University, USA.
Acosta
Jazmin I
JI
Browning
Jenny R
JR
Hamilton
Elizabeth C
EC
Neisewander
Janet L
JL
D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005108:Extinction, Psychological; D006213:Hallucinogens / Q000494:pharmacology*; D008297:Male; D009042:Motivation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects*; D012054:Reinforcement, Psychology; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage
D006213:Hallucinogens; D044302:Receptor, Serotonin, 5-HT1B; D013549:Sweetening Agents; D013395:Sucrose; D003042:Cocaine