Studies to investigate the role of 5-HT(2C) receptors on cocaine- and food-maintained behavior.
The present series of studies were designed to investigate the 5-HT(2C) receptor agonist Ro 60-0175 on cocaine- and food-maintained behavior in the rat. Ro 60-0175 (0.1-3 mg/kg, s.c.) reduced cocaine (15 mg/kg, i.p.)-induced hyperactivity. This inhibitory effect of Ro 60-0175 (1 mg/kg, s.c.) was completely blocked by pretreatment with the selective 5-HT(2C) antagonist SB 242,084 (0.5 mg/kg, i.p.). In further studies, Ro 60-0175 (1-3 mg/kg, s.c.) reduced responding for both food (45-mg Noyes pellet) and cocaine (0.25 mg/infusion) maintained under identical schedules of reinforcement (fixed ratio (5), time out 1 min, 60-min duration). The effect on food-maintained responding was blocked by SB 242,084 (0.5 mg/kg, i.p.). Ro 60-0175 (0.3-3 mg/kg, s.c.) also reduced the breakpoint for cocaine self-administration under a progressive ratio schedule of reinforcement. After a period of extinction training, where cocaine solution was substituted with saline, an acute priming injection of cocaine (15 mg/kg, i.p.) but not Ro 60-0175 (1 mg/kg, s.c.) reinstated cocaine responding. In this model of relapse, Ro 60-0175 (1-3 mg/kg, s.c.) pretreatment attenuated the priming effect of acute cocaine injection. In a final series of studies to examine the cataleptogenic properties of Ro 60-0175, very mild indices of catalepsy were observed at the 3 mg/kg dose only. These catalepsy scores were significantly lower than that produced by haloperidol (0. 5 mg/kg, s.c.). In further tests of motor function using the Rotarod, deficits were again seen at the 3 mg/kg dose, but not at lower doses. Taken together, these studies suggest that, in addition to reducing food intake, 5-HT(2C) receptor agonists reduce cocaine-reinforced behavior. This would be consistent with electrophysiological and biochemical evidence suggesting an important modulatory influence of 5-HT(2C) receptor activation on mesolimbic dopamine function.
Grottick
A J
AJ
PRBN-B, Pharmaceutical Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Fletcher
P J
PJ
Higgins
G A
GA
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D005021:Ethylamines / Q000494:pharmacology; D005502:Food; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000502:physiology*; D012055:Reinforcement Schedule; D017557:Ventral Tegmental Area / Q000502:physiology
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; D011985:Receptors, Serotonin; C103848:Ro 60-0175; D003042:Cocaine