RESUMO
Extensive evidence indicates the influence of the cholinergic system on emotional processing. Previous findings provided new insights into the underlying mechanisms of long-term anxiety, showing that rats injected with a single systemic dose of pilocarpine--a muscarinic receptor (mAChR) agonist--displayed persistent anxiogenic-like responses when evaluated in different behavioral tests and time-points (24 h up to 3 months later). Herein, we investigated whether the pilocarpine-induced long-term anxiogenesis modulates the HPA axis function and the putative involvement of NMDA receptors (NMDARs) following mAChRs activation. Accordingly, adult male Wistar rats presented anxiogenic-like behavior in the elevated plus-maze (EPM) after 24 h or 1 month of pilocarpine injection (150 mg/kg, i.p.). In these animals, mAChR activation disrupted HPA axis function inducing a long-term increase of corticosterone release associated with a reduced expression of hippocampal GRs, as well as consistently decreased NMDAR subunits expression. Furthermore, in another group of rats injected with memantine--an NMDARs antagonist (4 mg/kg, i.p.)--prior to pilocarpine, we found inhibition of anxiogenic-like behaviors in the EPM but no further alterations in the pilocarpine-induced NMDARs downregulation. Our data provide evidence that behavioral anxiogenesis induced by mAChR activation effectively yields short- and long-term alterations in hippocampal NMDARs expression associated with impairment of hippocampal inhibitory regulation of HPA axis activity. This is a novel mechanism associated with anxiety-like responses in rats, which comprise a putative target to future translational studies.
Assuntos
Ansiedade/patologia , Emoções/fisiologia , Hipocampo/patologia , Receptores Muscarínicos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Western Blotting , Emoções/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pilocarpina/farmacologia , Ratos , Ratos Wistar , Receptores Muscarínicos/química , Transmissão Sináptica/efeitos dos fármacosRESUMO
Alterations in cellular immune function are associated with depression and have been related to changes in endocrine function. We carried out a study to: (i) reliably assess the hypothalamic-pituitary-adrenal (HPA) axis function in treatment resistant depression (TRP); (ii) evaluate whether depression was associated with changes on T-cell proliferation and cytokine production; and (iii) assessed the sensitivity of lymphocytes to glucocorticoids (GC)s in vitro. Thirty-six pharmacologically treated inpatients diagnosed with TRP and 31 healthy controls took part in the study. Salivary cortisol was measured hourly from 0800 to 2200 h both before and after dexamethasone (DEX) intake and the patients were classified into HPA axis suppressors and nonsuppressors. The following were measured in vitro: (a) phytohemagglutinin-induced T-cell proliferation; (b) cytokine production (interleukin-2 and tumor necrosis factor-alpha, TNF-alpha); and (c) lymphocyte sensitivity to both cortisol and DEX. Basal morning cortisol levels from patients and controls did not differ nor did their T-cell proliferation and cytokine production. Ten out of 36 patients were classified as nonsuppressors and presented a significantly higher post-DEX salivary cortisol levels than suppressors, 82.0 vs 8.9 nM/l/h (p <0.001). Cells of nonsuppressors produced significantly less TNF-alpha compared to suppressors, 299.8 vs 516.9 pg/ml (p < 0.05). Remarkably, GC-induced suppression of lymphocyte proliferation and cytokine production were generally less marked in depressives compared with controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and suggest that lymphocyte steroid resistance may be associated with TRP.
Assuntos
Antidepressivos/uso terapêutico , Depressão/imunologia , Resistência a Medicamentos , Glucocorticoides/farmacologia , Imunidade/efeitos dos fármacos , Glândulas Suprarrenais/efeitos dos fármacos , Adulto , Idoso , Antidepressivos/farmacologia , Células Cultivadas , Citocinas/biossíntese , Depressão/tratamento farmacológico , Dexametasona/administração & dosagem , Feminino , Humanos , Hidrocortisona/análise , Hipotálamo/efeitos dos fármacos , Interleucina-2/biossíntese , Ativação Linfocitária , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fito-Hemaglutininas/farmacologia , Hipófise/efeitos dos fármacos , Saliva/química , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Alterations in immune function are associated with major depression and have been related to changes in endocrine function. We investigated whether alterations in immune function were associated with altered basal hypothalamic-pituitary-adrenal (HPA) function (salivary cortisol) and lymphocyte sensitivity to dexamethasone (DEX) intake (1 mg PO). The latter was explored by comparing the impact of DEX-induced changes on peripheral lymphocyte redistribution and expression of adhesion molecules (beta2 integrins and L-selectin). The study included 36 inpatients with treatment-resistant major depression (unipolar subtype) and 31 matched healthy controls. The dexamethasone suppression test (DST) was carried out and used to classify 10 patients as HPA axis non-suppressors. The latter presented significantly higher post-DEX salivary cortisol levels than DST suppressors, 82.0 vs. 8.9 nM l(-1) h(-1). No differences in basal salivary cortisol levels were found between patients and controls. Changes in cell redistribution (CD4(+), CD8(+), CD19(+), CD56(+) and HLADR(+) cells) after DEX administration were more prominent in controls than in patients, but the effects of DEX varied dependent on whether patients exhibited DEX-induced suppression of cortisol secretion. Glucocorticoid-induced suppression of adhesion molecule expression was also generally less marked in patients than controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and further suggest that lymphocyte steroid resistance is associated with drug-resistant depression.