RESUMO
BACKGROUND AND PURPOSE: Recent evidence suggests that 5-HT(2C) receptor activation may inhibit midbrain 5-HT neurones by activating neighbouring GABA neurones. This hypothesis was tested using the putative selective 5-HT(2C) receptor agonist, WAY 161503. EXPERIMENTAL APPROACH: The effect of WAY 161503 on 5-HT cell firing in the dorsal raphe nucleus (DRN) was investigated in anaesthetised rats using single unit extracellular recordings. The effect of WAY 161503 on DRN GABA neurones was investigated using double label immunohistochemical measurements of Fos, glutamate decarboxylase (GAD) and 5-HT(2C) receptors. Finally, drug occupancy at 5-HT(2A) receptors was investigated using rat positron emission tomography and ex vivo binding studies with the 5-HT(2A) receptor radioligand [(11)C]MDL 100907. KEY RESULTS: WAY 161503 caused a dose-related inhibition of 5-HT cell firing which was reversed by the 5-HT(2) receptor antagonist ritanserin and the 5-HT(2C) receptor antagonist SB 242084 but not by the 5-HT(1A) receptor antagonist WAY 100635. SB 242084 pretreatment also prevented the response to WAY 161503. The blocking effects of SB 242084 likely involved 5-HT(2C) receptors because the drug did not demonstrate 5-HT(2A) receptor occupancy in vivo or ex vivo. The inhibition of 5-HT cell firing induced by WAY 161503 was partially reversed by the GABA(A) receptor antagonist picrotoxin. Also, WAY 161503 increased Fos expression in GAD positive DRN neurones and DRN GAD positive neurones expressed 5-HT(2C) receptor immunoreactivity. CONCLUSIONS AND IMPLICATIONS: These findings indicate that WAY 161503 inhibits 5-HT cell firing in the DRN in vivo, and support a mechanism involving 5-HT(2C) receptor-mediated activation of DRN GABA neurones.
Assuntos
Inibição Neural , Neurônios/metabolismo , Núcleos da Rafe/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Serotonina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Potenciais de Ação/efeitos dos fármacos , Aminopiridinas/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Antagonistas GABAérgicos/farmacologia , Glutamato Descarboxilase/análise , Imuno-Histoquímica , Indóis/farmacologia , Masculino , Inibição Neural/efeitos dos fármacos , Neurônios/química , Neurônios/efeitos dos fármacos , Picrotoxina/farmacologia , Piperazinas/farmacologia , Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas c-fos/análise , Pirazinas/metabolismo , Pirazinas/farmacologia , Piridinas/farmacologia , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Núcleos da Rafe/química , Núcleos da Rafe/citologia , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina/análise , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Ritanserina/farmacologiaRESUMO
1. Systemic administration of phenethylamine-derived, 5-hydroxytryptamine(2) (5-HT(2)) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2. The 5-HT(2) receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10-100 micro g kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by >80%. 3. Pretreatment with the 5-HT(2) receptor antagonist ritanserin (1 mg kg(-1) i.v.) completely blocked the action of DOI. The 5-HT(2A) receptor antagonist MDL 100,907 (0.2 mg kg(-1) i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT(2B/C) receptor antagonist SB 206553 (0.5 mg kg(-1) i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4. Pretreatment with the peripherally acting 5-HT(2) receptor antagonist BW 501C67 (0.1 mg kg(-1) i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOI-induced rise in mean arterial blood pressure. 5. These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT(2A) receptor-subtype, but that 5-HT(2B/C) receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT(2) receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.
Assuntos
Núcleos da Rafe/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2B de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Mistura de Alfaxalona Alfadolona , Animais , Hidrato de Cloral , Relação Dose-Resposta a Droga , Masculino , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Serotonina/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Rising expenditures on health care in the U.S. have been facilitated by the fundamental problems of asymmetric information and insurance-induced moral hazard. If managed care is to succeed, it must take both into account through strategies such as information-based consumer education and provider risk-sharing. Because larger networks offer significant advantages in implementing such strategies, hospital mergers, physician-hospital alliances, and economies of scale are major trends in the evolution of managed care.
