5-HT3 receptor-active drugs alter development of spinal serotonergic innervation: lack of effect of other serotonergic agents.
Our work has focused on identifying the type of serotonin receptor through which serotonin acts as a developmental signal in the central nervous system. Previously, we have found that the regulation of development of ascending serotonergic neurons is through the balance of two serotonin receptors. One, the 5-HT1a receptor, releases a growth factor from astroglial cells. The other receptor is related to a release-regulating autoreceptor and can be stimulated indirectly by serotonin releasers such as fenfluramine. In the present study, we examined the receptors which regulate development of the descending neurons by treating pregnant rats with selective serotonergic drugs, from gestation day 12 until birth. Pups were subsequently tested for alterations in development by nociceptive testing (tail-flick latency) and by determining the binding of 3H-paroxetine, an indicator of serotonin terminal density, in spinal cord. Our results show that agents stimulating the 5-HT1a receptor (8-OH-DPAT) or the 5-HT1b receptor (TFMPP) or substances which release serotonin (fenfluramine) had no effect on the development of spinal serotonergic pathways. However, agents acting on the 5-HT3 receptor did--the agonist phenylbiguanide (PG) increased latency on tail-flick testing (postnatal days 10 and 30), while the antagonist, MDL 72222, decreased latency (postnatal days 10 and 18). Interestingly, both the agonist and the antagonist significantly increased 3H-paroxetine binding on postnatal day 18. Our results are discussed in terms of a possible mechanism by which 5-HT3 receptors may influence development.
Bell
J
J
Department of Psychiatry and Behavioral Sciences, State University of New York, Stony Brook 11794.
Zhang
X N
XN
Whitaker-Azmitia
P M
PM
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000375:Aging; D000818:Animals; D001645:Biguanides / Q000494:pharmacology*; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008431:Maternal-Fetal Exchange; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D017374:Paroxetine; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014326:Tropanes / Q000494:pharmacology*
D001645:Biguanides; D007004:Hypoglycemic Agents; D010879:Piperazines; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013764:Tetrahydronaphthalenes; D014326:Tropanes; C018406:1-(3-trifluoromethylphenyl)piperazine; D005277:Fenfluramine; D012701:Serotonin; D017374:Paroxetine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C042253:bemesetron; C008846:phenyl biguanide