“…Nevertheless, several interesting, novel common effects have emerged from our studies ( Table 1). All ADS tended to decrease the immunolabeling of Gas in the hippocampus, consistent with the recent report of post-receptor desensitization of hippocampal adenylyl cyclase activity following chronic DMI (Tionga and Richardson, 1990), and suggesting a coordinate downregulation of the p-adrenoceptor-Gs-adenylyl cyclase complex by ADS. In view of the well known hypercortisolemia and activation of the HPA axis observed in a subset of depressed patients, and the observation that chronic stress may play a role in the development of depression, it is noteworthy that the effects of ADS on Gas are the opposite of those observed with chronic glucocorticoid administration (Saito et al, 1989;Lesch and Lerer, 1991).…”
“…Nevertheless, several interesting, novel common effects have emerged from our studies ( Table 1). All ADS tended to decrease the immunolabeling of Gas in the hippocampus, consistent with the recent report of post-receptor desensitization of hippocampal adenylyl cyclase activity following chronic DMI (Tionga and Richardson, 1990), and suggesting a coordinate downregulation of the p-adrenoceptor-Gs-adenylyl cyclase complex by ADS. In view of the well known hypercortisolemia and activation of the HPA axis observed in a subset of depressed patients, and the observation that chronic stress may play a role in the development of depression, it is noteworthy that the effects of ADS on Gas are the opposite of those observed with chronic glucocorticoid administration (Saito et al, 1989;Lesch and Lerer, 1991).…”
“…Nevertheless, several interesting, novel common effects have emerged from our studies. All ADs tended to decrease the immunolabeling of Gas in the hippocampus, consistent with the recent report of post-receptor desensitization of hippocampal adenylyl cyclase activity following chronic DMI (Tiong and Richardson 1990), and suggesting a coordinate downregulation of the 13-adrenoceptor-Gs-adenylyl cyclase complex by ADs (Sugrue 1983;Suiser 1984). In view of the well known hypercortisolemia and activation of the HPA axis observed in a subset of depressed patients (Nemeroff 1987), and the observation that chronic stress may play a role in the development of depression, it is noteworthy that the effects of ADs on Got+ are the opposite of those observed with chronic glucocorticoid administration (Saito et ai 1989;Lesch and Lerer 1991).…”
Section: Idz Con Dmi "---40kdsupporting
confidence: 75%
“…The reason(s) for the failure to detect an alteration in the immunolabeling of Got~ or Goti following ADs in vitro, despite the functional evidence for attenuation of Gs function, is presently unclear. It is possible that the decrease in G% and Gotw2 concentrations in vivo require an intact integrated system (or at least presynaptic input); however, more recent in vivo studies have also demonstrated that ADs result in an early "uncoupling" of the 13-receptor from Gs, followed by changes in G~ function after chronic (> 3 wk) treatment (Okada et al 1986;Tiong and Richardson 1990). Thus, it remains possible that our failure to detect any alterations in the immunolabeling of Got, or GoL~ following in vitro incubation of C6 cells with either DMI or IDZ was due simply to the relatively short (5 day) incubation period.…”
Signal-transducing G proteins, heterotrimers formed of a, [3, and y subunits, are Psychopharmacologic research has traditionally focused on the ef,~ects of antidepressant drugs on individual neurotransmitters, and a variety of acute biochemical effects have been observed. Paralleling the recognition of the typically weeks-long latency to clinical response studies of antidepressant treatment actions have moved from a focus on disparate acute effects to an interest in possible common chronic, changes. Thus, in recent years,
“…This has been documented for beta-adrenergic receptors (Daws et al, 1998; Tiong and Richardson, 1990) and for A2AR using either antagonists or agonists to label the receptor (Barturen and Garcia-Sevilla, 1992; Deupree et al, 2007; Subhash et al, 2003). The response of the mature brain to alterations in NE level is the opposite of changes found in developing brain.…”
Alpha-2 adrenergic receptors (A2AR) regulate multiple brain functions and are enriched in developing brain. Studies demonstrate norepinephrine (NE) plays a role in regulating brain maturation, suggesting it is important in A2AR development. To investigate this we employed models of NE absence and excess during brain development. For decreases in NE we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a specific noradrenergic neurotoxin. Increased noradrenergic terminal density was produced by methylazoxymethanol acetate (MAM) treatment. A2AR density was assayed with [3H]RX821002 autoradiography. DSP4 lesions on postnatal day (PND) 3 produce A2AR decreases in many regions by PND 5. A2AR recover to control levels by PND 15 and 25 and there is no further change in total receptor density. We also assayed A2AR in brains lesioned with DSP4 on PND 13, 23, 33 and 43 and harvested 22 days post-lesion. A2AR levels remain similar to control at each of these time points. We examined A2AR functionality and high affinity state with epinephrine-stimulated [35S]GTPγS and [125 I]p-iodoclonidine autoradiography, respectively. On PND 25, control animals and animals lesioned with DSP4 on PND 3 have similar levels of [35S]GTPγS incorporation and no change in high affinity state. This is in contrast to increases in A2AR high affinity state produced by DSP4 lesions of mature brain. We next investigated A2AR response to increases in norepinephrine levels produced by MAM. In contrast to DSP4 lesions, increasing NE results in a large increase in A2AR. Animals treated with MAM on gestational day 14 had cortical [3H]RX821002 binding 100-200% greater than controls on PND 25, 35, 45, 55 and 65. These data indicate that NE regulation of A2AR differs in developing and mature brain and support the idea that NE regulates A2AR development and this has long term effects on A2AR function.
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