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Receptor Modulation (receptor + modulation)
Selected AbstractsDirect Evidence for Imidazoline (I1) Receptor Modulation of Ethanol Action on Norepinephrine-Containing Neurons in the Rostral Ventrolateral Medulla in Conscious Spontaneously Hypertensive RatsALCOHOLISM, Issue 4 2007Guichu Li Background: Enhancement of the rostral ventrolateral medulla (RVLM) presympathetic (norepinephrine, NE) neuronal activity represents a neurochemical mechanism for the pressor effect of ethanol. In this study, we tested the hypothesis that ethanol action on RVLM presympathetic neurons is selectively influenced by the signaling of the local imidazoline (I1) receptor. To support a neuroanatomical and an I1 -signaling selectivity of ethanol, and to circumvent the confounding effects of anesthesia, the dose-related neurochemical and blood pressure effects of ethanol were investigated in the presence of selective pharmacological interventions that cause reduction in the activity of RVLM or nucleus tractus solitarius (NTS) NE neurons via local activation of the I1 or the ,2 -adrenergic receptor in conscious spontaneously hypertensive rats. Results: Local activation of the I1 receptor by rilmenidine (40 nmol) or by the I1/,2 receptor mixed agonist clonidine (1 nmol), and local activation of the ,2 -adrenergic receptor (,2AR) by the pure ,2AR agonist , -methylnorepinephrine (, -MNE, 10 nmol) caused reductions in RVLM NE, and blood pressure. Intra-RVLM ethanol (1, 5, or 10 ,g), microinjected at the nadir of the neurochemical and hypotensive responses, elicited dose-dependent increments in RVLM NE and blood pressure in the presence of local I1,but not ,2 -receptor activation. Only intra-NTS , -MNE, but not rilmenidine or clonidine, elicited reductions in local NE and blood pressure; ethanol failed to elicit any neurochemical or blood pressure responses in the presence of local activation of the ,2AR within the NTS. Conclusion: The findings support the neuroanatomical selectivity of ethanol, and support the hypothesis that the neurochemical (RVLM NE), and the subsequent cardiovascular, effects of ethanol are selectively modulated by I1 receptor signaling in the RVLM. [source] New insights into adenosine receptor modulation of myocardial ischemia-reperfusion injuryDRUG DEVELOPMENT RESEARCH, Issue 1-2 2001Robert D. Lasley Abstract The cardioprotective effects of adenosine in numerous experimental models have been well described and there is evidence that adenosine is beneficial in the clinical setting. However, the exact mechanism by which adenosine exerts its beneficial effects in reversibly and irreversibly injured myocardium has not been determined. In addition, with the exception of the A1 receptor, there is not universal agreement on the involvement of adenosine receptor subtypes. This review summarizes recent findings in our laboratory on the role of the A3 and A2a receptors in adenosine cardioprotection and compartmentation of cardiomyocyte adenosine receptor signaling. Drug Dev. Res. 52:357,365, 2001. © 2001 Wiley-Liss, Inc. [source] Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanismsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2009V. I. Chefer Abstract Mu opioid receptor (MOR) regulation of somatodendritic dopamine neurotransmission in the ventral tegmental area (VTA) was investigated using conventional microdialysis in freely moving rats and mice. Reverse dialysis of the MOR agonist DAMGO (50 and 100 ,m) into the VTA of rats produced a concentration-dependent increase in dialysate dopamine concentrations. Basal dopamine overflow in the VTA was unaltered in mice lacking the MOR gene. However, basal ,-aminobutyric acid (GABA) overflow in these animals was significantly increased, whereas glutamate overflow was decreased. Intra-VTA perfusion of DAMGO into wild-type (WT) mice increased dopamine overflow. GABA concentrations were decreased, whereas glutamate concentrations in the VTA were unaltered. Consistent with the loss of MOR, no effect of DAMGO was observed in MOR knockout (KO) mice. These data provide the first direct demonstration of tonically active MOR systems in the VTA that regulate basal glutamatergic and GABAergic neurotransmission in this region. We hypothesize that increased GABAergic neurotransmission following constitutive deletion of MOR is due to the elimination of a tonic inhibitory influence of MOR on GABAergic neurons in the VTA, whereas decreased glutamatergic neurotransmission in MOR KO mice is a consequence of intensified GABA tone on glutamatergic neurons and/or terminals. As a consequence, somatodendritic dopamine release is unaltered. Furthermore, MOR KO mice do not exhibit the positive correlation between basal dopamine levels and the glutamate/GABA ratio observed in WT mice. Together, our findings indicate a critical role of VTA MOR in maintaining an intricate balance between excitatory and inhibitory inputs to dopaminergic neurons. [source] RANTES stimulates inflammatory cascades and receptor modulation in murine astrocytesGLIA, Issue 1 2002Yi Luo Abstract Cultured mouse astrocytes respond to the CC chemokine RANTES by production of chemokine and cytokine transcripts. Stimulation of astrocytes with 1 nM RANTES or 3,10 nM of the structurally related chemokines (eotaxin, macrophage inflammatory protein-1, and -, [MIP-1,, MIP-1,]) induced transcripts for KC, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-, (TNF-,), MIP-1,, MIP-2, and RANTES in a chemokine and cell-specific fashion. Synthesis of chemokine (KC and MCP-1) and cytokine (TNF-,) proteins was also demonstrated. RANTES-mediated chemokine synthesis was specifically inhibited by pertussis toxin, indicating that G-protein-coupled chemokine receptors participated in astrocyte signaling. Astrocytes expressed CCR1 and CCR5 (the redundant RANTES receptors). Astrocytes derived from mice with targeted mutations of either CCR1 or CCR5 respond after RANTES stimulation, suggesting multiple chemokine receptors may separately mediate RANTES responsiveness in astrocytes. Preliminary data suggest activation of the MAP kinase pathway is also critical for RANTES-mediated signaling in astrocytes. Treatment with RANTES specifically modulated astrocyte receptors upregulating intercellular adhesion molecule 1 (ICAM-1) and downregulating CX3CR1 expression. Thus, after chemokine treatment, astrocytes release proinflammatory mediators and reprogram their surface molecules. The combined effects of RANTES may serve to amplify inflammatory responses within the central nervous system. GLIA 39:19,30, 2002. © 2002 Wiley-Liss, Inc. [source] The newly synthesized linoleic acid derivative DCP-LA ameliorates memory deficits in animal models treated with amyloid-, peptide and scopolaminePSYCHOGERIATRICS, Issue 4 2005Tetsu NAGATA Abstract Background:, In our earlier study, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis -double bonds, facilitated hippocampal synaptic transmission by stimulating glutamate release from presynaptic terminals as mediated via ,7 acetylcholine (Ach) receptors under the influence of protein kinase C. The present study assessed the possibility of using DCP-LA as a cognitive enhancer in animal models. Methods:, Amyloid-,1,40 peptide (300 pM/day) or saline was continuously injected in the right lateral ventricle of rats for 2 weeks. Then, the water maze test was carried out, once per day for 7 days, 1 h after the intraperitoneal injection with DCP-LA or saline. In a different set of experiments, rats were intraperitoneally injected with scopolamine (1 mg/kg) and the water maze test was performed twice per day, with the first test taking place 1 h after the intraperitoneal injection with DCP-LA, galantamine or saline, and the second test starting 2 min after the end of the first. Results:, Continuous intraventricular injection with amyloid-,1,40 peptide in the rat lateral ventricle prolonged the latency for acquisition in the water maze test. DCP-LA (1 mg/kg, intraperitoneal (i.p.)) significantly improved the impairment, which reached a level similar to the latency for sham. Furthermore, DCP-LA (1 mg/kg, i.p.) significantly ameliorated learning and memory deficits in rats treated with scopolamine and was, if not more, effective than galantamine, a modest inhibitor of acetylcholinesterase with nicotinic ACh receptor modulation. Conclusion:, The results of the present study show that DCP-LA ameliorates learning and memory deficits induced by amyloid-,1,40 peptide or scopolamine. DCP-LA may thus offer new hope for dementia patients. [source] GABAB receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneuronsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2003Saobo Lei Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABAB receptor-mediated responses at both synapse types. Postsynaptic GABAB receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (P30) suggesting developmental regulation. In young animals, the GABAB receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd2+, implicating presynaptic voltage-gated Ca2+ channels as a target for baclofen modulation. In contrast, although Cd2+ prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca2+ channels contributed equally to GABAB receptor-mediated inhibition of EPSCs, more P/Q-type Ca2+ channels were involved in GABAB receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABAB receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types. [source] Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious ratBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009MJ Jugus Background and purpose:, Cyclooxygenase inhibitors function to reduce levels of prostaglandin E2 (PGE2) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP3 receptor for PGE2. Experimental approach:, The activity of the EP3 receptor agonist GR63799X, and EP3 receptor antagonists, CM9 and DG041, at recombinant EP3 receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP3 receptor modulation. Key results:, GR63799X dose-dependently (0.001,1 mg·kg,1) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg·kg,1) and DG041 (30 mg·kg,1) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP3 receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9. Conclusions and implications:, These data support the EP3 receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP3 receptor activity in regulating urine flow. [source] Tachykinin receptor modulation of cyclooxygenase-2 expression in human polymorphonuclear leucocytesBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009M Gallicchio Mandarin translation of abstract Background and purpose:, We investigated the ability of natural and synthetic selective NK receptors agonists and antagonists to modulate cyclooxygenase-2 (COX-2) expression in human polymorphonuclear leucocytes (PMNs). Experimental approach:, The presence of all three tachykinin in PMNs was assessed by Western blot and PCR techniques. Natural and synthetic ligands selective for the tachykinin receptors were used to modulate COX-2 protein (measured with Western blotting) and activity [as prostaglandin E2 (PGE2) output]. Effects of substance P (SP) on phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-,B) activation were studied to analyse the signalling pathway involved in COX-2 up-regulation mediated by SP. Key results:, Stimulation of NK receptors with the natural ligands SP, neurokinin A (NKA) and neurokinin B, in the pmol·L,1 -µmol·L,1 concentration range, modulated COX-2 expression and PGE2 release in a concentration- and time-dependent manner. Experiments with synthetic selective agonists [Sar9, Met(O2)11]SP, [,-Ala8] NKA(4-10), senktide or selective antagonists L703,606, SR48,968 or SR142801, confirmed that COX-2 up-regulation was mediated by NK receptors. We found that mainly p38, p42 and p46 MAPKs were phosphorylated by SP and SB202190, PD98059 and SP600125, which are selective inhibitors of these kinases, blocked SP-induced COX-2 expression. SP also induced nuclear translocation of NF-,B concentration-dependently, with a maximum effect at 1 nmol·L,1. Conclusions and implications:, Human PMNs possess functional NK1, NK2 and NK3 receptors, which mediate the induction of COX-2 expression and NF-,B activation by SP. Mandarin translation of abstract [source] | |||||||||||||