Inhibition of 5-HT2 receptor-mediated head-twitch response by cocaine via indirect stimulation of adrenergic alpha 2 and serotonergic 5-HT1A receptors.
Cocaine inhibits the 5-HT2-mediated (+/-)-DOI-induced head-twitch response (HTR) in mice in a dose-dependent manner. In order to investigate the possible inhibitory mechanism(s) of cocaine on 5-HT2 receptor function, we studied the effects of the selective adrenergic alpha 2 receptor antagonist yohimbine and the beta-adrenergic/5-HT1 receptor antagonist alprenolol, and the 5-HT3 antagonist ICS 205-930 on the inhibitory action of cocaine on the (+/-)-DOI-induced HTR. Neither yohimbine (0.1 and 0.5 mg/kg) nor alprenolol (10 mg/kg) pretreatment had any significant effect on the (+/-)-DOI-induced HTR. However, both antagonists prevented the inhibitory effects of cocaine on the (+/-)-DOI-induced HTR. The 5-HT3 antagonist ICS 205-930 neither produced HTR nor decreased the (+/-)-DOI-induced HTR frequency. The present results suggest that cocaine inhibits 5-HT2 receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and thus indirectly stimulating the respective inhibitory adrenergic alpha 2 and serotonergic 5-HT1A receptors. Furthermore, cocaine's 5-HT3 antagonist properties appear not to play a role in the inhibition of head-twitch behavior.
Darmani
N A
NA
Department of Pharmacology/Toxicology, Virginia Commonwealth University/Medical College of Virginia, Richmond 23298.
Martin
B R
BR
Pandey
U
U
Glennon
R A
RA
D000316:Adrenergic alpha-Agonists; D000526:Alprenolol / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013268:Stimulation, Chemical; D000077526:Tropisetron; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000662:Amphetamines; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D015016:Yohimbine; D012701:Serotonin; D000077526:Tropisetron; D000526:Alprenolol; D003042:Cocaine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D009638:Norepinephrine