Cotransmitters: differential effects of serotonin (5-HT)-depleting drugs on levels of 5-HT and TRH and their receptors in rat brain and spinal cord.

Following codepletion of endogenous serotonin (5-HT, greater than 90%) and thyrotropin-releasing hormone (TRH, 66%) by neonatal treatment with the serotonergic neurotoxin, 5,7-dihydroxytryptamine (DHT), a 33% (n = 12, P less than 0.01) increase in specific TRH receptor binding was observed in adult rat spinal cord (SC) homogenates. A 20-21% increase in TRH receptors was also observed in the medulla/pons (MP) (n = 12, P less than 0.05) and midbrain (MB) (n = 12, P less than 0.02), but no changes were detected in 6 rostral brain regions. The depletion of 5-HT after DHT-treatment was also accompanied by a 34-42% increase in 5-HT1 binding in the SC, MP and MB. Eadie-Hofstee analysis revealed that the changes in TRH receptor levels observed after DHT-lesions were due to an increase in receptor number rather than any significant changes in receptor affinity. Chronic treatment of adult rats with the 5-HT-depleting drugs, p-chlorophenylalanine (PCPA) and reserpine, produced a 90-97% decrease in 5-HT in the SC, MP and MB and elevated 5-HT1 binding above controls in these tissues. However, neither drug treatment caused any significant alterations in the levels of TRH or its receptors in any of these tissues. In conclusion, these results have provided further support for the coexistence of 5-HT and TRH in the MP and SC and revealed possible new areas of such colocalization in the MB. Furthermore, these data have demonstrated that only DHT-treatment, as apposed to PCPA or reserpine, can produce long-lasting codepletion of 5-HT and TRH with simultaneous compensatory up-regulation of their receptor systems in the SC and other caudal tissues.