Pretreatment with serotonin 5-HT(3) receptor antagonists produces no observable blockade of long-term motor sensitization to cocaine in rats.
BACKGROUND
Serotonin 5-HT(3) receptor antagonists are proposed to serve as potential anti-addictive and anti-psychotic therapies.


OBJECTIVE
The present study re-examined the hypothesis that the activation of 5-HT(3) receptors is required for the development of long-term motor sensitization to repeated cocaine (COC).


METHODS
Rats were pretreated with vehicle (VEH) or one of three 5-HT(3) receptor antagonists, MDL 72222, Y-25130 or ondansetron, 30 min prior to seven daily COC or saline (SAL) injections. Three weeks later, animals were challenged with COC in a test for sensitization. For comparison, the effects of pretreatment with the dopamine (DA) receptor antagonist fluphenazine and a combination of fluphenazine and Y-25130 were assessed.


RESULTS
Pretreatment with ondansetron, Y-25130, fluphenazine and their combination significantly attenuated COC-induced behaviors during repeated treatment but not on the test for sensitization. MDL 72222 pretreatment enhanced motor sensitization on the test day. In repeated SAL rats, pretreatment with ondansetron, Y-25130 and fluphenazine+Y-25130 enhanced COC-induced rearing on the test for sensitization.


CONCLUSIONS
These data indicate the effects of 5-HT(3) receptor antagonists on both acute COC-induced motor behavior and COC-induced motor sensitization are compound-selective. As none of the 5-HT(3) receptor antagonists attenuated the magnitude of the sensitized motor response to COC in the long term, these data also indicate that like DA receptor activation, 5-HT(3) receptor activation is necessary for the full expression of acute COC-induced motor hyperactivity, but it is not required for the development of long-term motor sensitization.
Szumlinski
Karen K
KK
Department of Physiology and Neuroscience, Basic Science Building, Suite 403, Medical University of South Carolina, 173 Ashely Avenue, Charleston, SC 29425, USA. szumlink@musc.edu
Frys
Kelly A
KA
Kalivas
Peter W
PW
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule / Q000662:veterinary; D004347:Drug Interactions; D005476:Fluphenazine / Q000494:pharmacology; D007267:Injections; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D017294:Ondansetron / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014326:Tropanes / Q000494:pharmacology
D000779:Anesthetics, Local; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018492:Dopamine Antagonists; D010078:Oxazines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D014326:Tropanes; D017294:Ondansetron; C070671:azasetron; D003042:Cocaine; C042253:bemesetron; D005476:Fluphenazine