Modulation of the stimulus effects of (+)amphetamine by the 5-HT6 antagonist MS-245.
5-HT(6) serotonin receptors are distributed within some dopamine terminal regions in the brain leading to suggestions that they might influence dopaminergic function. In the present study, the 5-HT(6) antagonist 5-methoxy-N,N-dimethyl-N(1)-benzenesulfonyltryptamine (MS-245) was without effect when administered (3.0-7.5 mg/kg) to rats trained to discriminate (+)amphetamine (1.0 mg/kg) from saline vehicle in a two-lever drug discrimination task. Administered in combination, 0.3 mg/kg (i.e., the ED(50) dose) of (+)amphetamine plus 5.0 mg/kg of MS-245 elicited 95% amphetamine-appropriate responding. Similar studies were conducted using rats trained to discriminate cocaine (8.0 mg/kg) from saline vehicle, but a combination of 2.0 mg/kg (i.e., the ED(50) dose) of cocaine together with relatively low doses of MS-245 resulted in the percent response (approximately 50%) expected from administration of this dose of cocaine or in disruption of the animals' behavior. The present results confirm findings from other laboratories that 5-HT(6) antagonists can modulate amphetamine-induced behavioral actions, and further extend these findings to an example of a different structural class of 5-HT(6) antagonists and to a different behavioral paradigm. Taken together, the data suggest that 5-HT(6) serotonin agents (or at least MS-245) could have potential clinical application in therapies that involve modulation of dopamine neurotransmission.
Pullagurla
Manik
M
Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia Campus, Virginia Commonwealth University, 554A Smith Building, 410 North 12th Street, Richmond, VA 23298-0540, USA.
Bondareva
Tatiana
T
Young
Richard
R
Glennon
Richard A
RA
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014363:Tryptamines / Q000494:pharmacology*
C419803:N1-benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014363:Tryptamines; C097216:serotonin 6 receptor; D000661:Amphetamine