Postsynaptic Α-adrenoceptors Research Articles

The regulatory effects of mesedin and beditin alpha2-adrenoblockers on the functional activity of the nervous, cardiovascular, and endocrine systems in rats under the hypoxic conditions.

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1ml of blood in 30, 90, and 180min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.

Therapeutic new targets for stress urinary incontinence in the central nervous system

Stress urinary incontinence (SUI) is a common and bothersome problem among middle-aged women. However, there are few useful drugs for SUI. Urethral hypermobility and intrinsic sphincter deficiency are two main causes of SUI. Various animal models of SUI, such as vaginal distention, pudendal nerve injury, or ovariectomy, have been developed to study the pathophysiology of SUI. In addition, we have previously reported that cerebral infarction rats also induce SUI. Leak point pressure measurements are the most commonly used methods to evaluate the urethral dysfunction in SUI animal models. Originally, we have developed microtransducer-tipped catheter measurements of urethral activity during sneezing. Previous or our basic research has clarified potential strategies for pharmacotherapy of SUI in the central nervous system. Therapeutic targets include adrenergic and serotonergic (5-HT) receptors in the spinal cord, which stimulate pudendal nerve innervating the external urethral sphincter and/or sympathetic nerve innervating urethral smooth muscle. Activation of α1-adrenoceptors, 5-HT2C, or 5-HT7 receptors enhances the reflex at the spinal cord level whereas pre- or postsynaptic α2-adrenoceptors and/or 5-HT1A receptors inhibit the reflex. We have recently reported that stimulation of the spinal μ-opioid receptors by tramadol also enhances the reflex. Thus, we review the recent advances in basic SUI research and potential targets for pharmacotherapy of SUI in the central nervous system.

Partial inhibition of catecholamine activity and enhanced responsiveness to NMDA after sustained administration of vortioxetine

Vortioxetine is a multimodal drug that blocks serotonin (5-HT) reuptake and directly modulates 5-HT receptors. The effects of subacute and long-term administration of vortioxetine on various aspects of catecholamine and glutamate systems were investigated using single-unit extracellular recordings and microiontophoresis in the rat brain. The firing rate of dopamine (DA) neurons was significantly decreased (26%) after 14, but not 4 days of vortioxetine administration (vortioxetine-containing chow, 1.8 g/kg vortioxetine). Same 14- and 4-day regimens of vortioxetine decreased the firing activity of norepinephrine (NE) neurons (by 27% and 41%, respectively). For DA and NE neurons, 14-day vortioxetine exposure also decreased the number of bursts per minute, without changing the number of spikes per burst, percentage of spike firing in burst and the number of spontaneously active neurons per track. However, this vortioxetine-induced suppression of DA and NE neuronal activity is less than that obtained in previous studies with the selective 5-HT reuptake inhibitor (SSRI) escitalopram. In the CA3 region of the hippocampus, 14 days of vortioxetine exposure did not change the sensitivity of postsynaptic α2-adrenoceptors nor did it increase the tonic activation of α1-and α2-adrenoceptors. Vortioxetine administration for 14 days increased the N-methyl-d-aspartate (NMDA)-, but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-evoked responses of CA3 pyramidal neurons. Taken together, the results of the current study suggest that vortioxetine might produce a lesser inhibition of DA and NE neuronal activity when compared to those induced by escitalopram as reported in previous studies.

Pre- and postsynaptic effects of brimonidine on isolated rabbit iris dilator muscles.

PurposeBrimonidine is an imidazoline compound used for the treatment of glaucoma, but having very little effect on pupil diameter. Like para-aminoclonidine, most imidazoline compounds interact with postsynaptic α-adrenoceptors and cause pupil dilatation. Therefore, as part of an investigation of the mechanism of action of brimonidine on pupil diameter, the present study was initiated to measure, in vitro, the relative potency of brimonidine on the pre- and postsynaptic α-adrenoceptors of rabbit iris dilator muscle.MethodsThe contractile activity of brimonidine and its effect on twitch contraction evoked by electrical field stimulation were studied in isolated rabbit iris dilator muscles by isometric tension recording.ResultsBrimonidine significantly inhibited the twitch contraction of the dilator muscle caused by field stimulation, without affecting the response to exogenously applied phenylephrine. Compared to phenylephrine, brimonidine caused only a small contractile response with % maximum contraction values of <10%.ConclusionThese results suggest that brimonidine may act on nerve endings to inhibit adrenergic neurotransmission with very little effect on postsynaptic α-adrenoceptors. This may indicate that brimonidine reduced the pupil diameter just a little, thus improving night vision.

Norepinephrine Drives Persistent Activity in Prefrontal Cortex via Synergistic α1 and α2 Adrenoceptors

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control

Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic α₂ adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established. This study tested the effect of the postsynaptic α₂ adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex. Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, cross-over design. Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response-related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions. These results provide evidence that guanfacine stimulation of postsynaptic α₂ adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the α₂ adrenoceptor agonist treatment of attention-deficit hyperactivity disorder.

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords: IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE

Chronic Opioid Potentiates Presynaptic but Impairs Postsynaptic N-Methyl-d-aspartic Acid Receptor Activity in Spinal Cords: IMPLICATIONS FOR OPIOID HYPERALGESIA AND TOLERANCE

Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems

Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory α1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 μs, 30 s on-5 min off). The results of the present study revealed that 2-wk VNS significantly increased extracellular NE levels in the prefrontal cortex and the hippocampus and enhanced the tonic activation of post-synaptic α2-adrenoceptors on pyramidal neurons. The electrophysiological experiments revealed a significant decrease in ventral tegmental area DA neuronal firing rate after long-term VNS; extracellular DA levels were nevertheless increased in the prefrontal cortex and nucleus accumbens. Chronic VNS significantly increased extracellular 5-HT levels in the dorsal raphe but not in the hippocampus and prefrontal cortex. In conclusion, the effect of VNS in increasing the transmission of monoaminergic systems targeted in the treatment of resistant depression should be involved, at least in part, in its antidepressant properties observed in patients not responding to many antidepressant strategies.

Electrophysiological impact of trazodone on the dopamine and norepinephrine systems in the rat brain

Previous study has documented the long-term effects of the antidepressant trazodone on the serotonin (5-HT) system. The present work examined the impact of sustained trazodone on ventral tegmental area (VTA) dopamine (DA) and locus ceruleus (LC) norepinephrine (NE) neurons firing activity, and characterized its effects at 5-HT2C, 5-HT2A receptors and α1- and α2-adrenoceptors. Electrophysiological recordings were carried out in anesthetized rats. Subcutaneously implanted minipumps delivered vehicle or trazodone (10mg/kg/day) for 2 or 14days. Administration of trazodone for 2 and 14days did not alter the firing activity of DA neurons. Systemic injection of trazodone, however, reversed the inhibitory effect of the 5-HT2C receptor agonist Ro 60,0175 on the DA neuronal firing, suggesting an antagonistic action of trazodone at this receptor. Administration of trazodone for 2days significantly enhanced the NE neurons firing. Despite a return of the NE neurons firing rate to the baseline following 14-day trazodone, the percentage of neurons discharging in burst was increased by this regimen. Administration of trazodone for 14days enhanced the tonic activation of postsynaptic α2-adrenoceptors, as indicated by the disinhibitory effect of the α2-adrenoceptor antagonist idazoxan on hippocampus pyramidal neurons firing. The inhibitory effect of acute trazodone on dorsal raphe (DR) 5-HT neurons firing was shown to be through the 5-HT1A receptor. Systemic injection of trazodone reversed the inhibitory action of 5-HT2A agonist DOI on the NE neurons firing rate, indicating its antagonistic action at 5-HT2A receptors. The enhancement in α2-adrenergic transmission by trazodone, and its 5-HT2A and 5-HT2C receptor antagonism may contribute to its therapeutic action in major depression.

Neuroendocrine Assessment of Serotonergic, Dopaminergic, and Noradrenergic Functions in Alcohol‐Dependent Individuals

Alcohol dependence has been associated with reduced function of serotonin, dopamine as well as noradrenaline activities in several neuroendocrine studies. To our knowledge, there is, however, no study investigating all these 3 systems with the use of neuroendocrine methods in one and the same alcohol-dependent individual. Alcohol-dependent individuals (n = 42) and controls (n = 28) participated in the neuroendocrine test series. Central serotonergic neurotransmission was assessed by the prolactin (PRL) response to citalopram (CIT). The postsynaptic DRD2 function was measured by the growth hormone (GH) response to apomorphine (APO) and the postsynaptic α2-adrenoceptor function by GH response to clonidine (CLON). In the alcohol-dependent individuals, the PRL concentrations were significantly lower at the time points 240 minutes and 300 minutes after CIT administration and mean delta PRL value was significantly reduced by 45% in comparison with controls. There were no significant differences in APO-GH and CLON-GH concentrations at any time points or in mean delta GH values between the groups. An impaired monoaminergic profile, including all 3 systems, was significantly more frequent in alcohol-dependent individuals than controls (43% vs. 6% respectively). The monoaminergic dysfunction was restricted to an impairment of the serotonergic system, suggesting that this system is especially vulnerable to long-term and excessive alcohol consumption. Moreover, impaired monoaminergic profiles, including low responses in 2 or 3 systems, were more frequently observed in alcohol-dependent individuals than in controls. Such impaired profiles may be of clinical importance, but further studies are needed.

Action of indoramin on pre- and postsynaptic alpha-adrenoceptors in pithed rats.

Journal Article Action of indoramin on pre- and postsynaptic α-adrenoceptors in pithed rats Get access D R Algate, D R Algate Wyeth Laboratories, Huntercombe Lane South, Taplow, Maidenhead, Berks, UK Correspondence: Wyeth Laboratories, Huntercombe Lane South, Taplow, Maidenhead, Berks, U.K. Search for other works by this author on: Oxford Academic Google Scholar J F Waterfall J F Waterfall Wyeth Laboratories, Huntercombe Lane South, Taplow, Maidenhead, Berks, UK Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 30, Issue 1, September 1978, Pages 651–652, https://doi.org/10.1111/j.2042-7158.1978.tb13351.x Published: 12 April 2011 Article history Received: 06 April 1978 Published: 12 April 2011

The effects of bromocriptine on pre-synaptic and post-synaptic alpha-adrenoceptors in the mouse vas deferens.

Noradrenaline (NA) and dopamine (DA) contracted the mouse vas deferens and reduced the responses to low frequency nerve stimulation (0.1 Hz). The relative potencies of antagonists suggested that these effects were due to stimulation of post-synaptic and pre-synaptic alpha-adrenoceptors respectively. Bromocriptine produced a non-competitive antagonism of contractile responses to NA (pD2' = 7.6) and DA (pD2' = 8.0) but had no effect on responses to carbachol. Bromocriptine also reduced single twitch responses of the vas to low frequency field stimulation (0.1 Hz), but did not affect stimulation at higher frequencies (1--20 Hz). Yohimbine selectively and rapidly reversed the inhibiting effects of bromocriptine on single twitches, although they could not easily be reversed by washing. Bromocriptine produced a yohimbine-reversible reduction in the stimulated overflow of tritium from vasa previously loaded with 3H--NA. Thus the mouse vas deferens does not appear to contain specific DA receptors and the results suggest that bromocriptine acts as a pre-synaptic alpha-adrenoceptor agonist and post-synaptic alpha-adrenoceptor antagonist in this tissue.

A Comparative Study on the Pre- and Postsynaptic α-Adrenoceptor Antagonist Activity of the 2R-And 2S-Enantiomers of Wb4101

A Comparative Study on the Pre- and Postsynaptic α-Adrenoceptor Antagonist Activity of the 2R-And 2S-Enantiomers of Wb4101

Repeated treatment with amitriptyline reduces immobility in the behavioural 'despair' test in rats by activating dopaminergic and beta-adrenergic mechanisms.

Seven days of treatment with amitriptyline 10 mg kg-1 day-1, reduced the immobility time in the behavioural 'despair' test in rats. 0.5, but not 0.25 mg kg-1 haloperidol significantly counteracted the reduction of immobility caused by amitriptyline. Its anti-immobility effect was reduced by 50 and 100 mg kg-1 sulpiride, another blocker of dopamine receptors, and 5 mg kg-1 (+/-)-propranolol, a beta-adrenolytic drug. Prazosin, 3 mg kg-1, an antagonist of post-synaptic alpha-adrenoceptors, had no effect. It is suggested that dopaminergic and beta-adrenoceptors mediate the anti-immobility effect of repeated amitriptyline treatment in rats.

Effects of α2-adrenergic drugs on small intestinal motility in the horse: An in vitro study

The effects of selective α(2)-agonists (xylazine, detomidine and medetomidine) and antagonists (yohimbine and atipamezole) on in vitro small intestine motility in the horse were evaluated. Samples of equine jejunum were placed in isolated organ baths and drug-induced modifications of motility were measured by means of an isotonic transducer. All tested α(2)-agonists dose-dependently reduced both spontaneous and electrically-evoked phasic contractions. Conversely, α(2)-antagonists were ineffective when tested alone, and showed a heterogeneous and dose-independent ability to inhibit agonist activity. In particular, the antagonism exerted by higher concentrations of both yohimbine and atipamezole against α(2)-agonists was weaker than when lower concentrations were used. The data are indicative of the presence of both pre- and post-synaptic α(2)-adrenoceptors with inhibitory activity on equine jejunum motility, and support a possible therapeutic utility of these drugs in horse intestinal disorders associated with hypermotility.

Metaplasticity of Hypothalamic Synapses following In Vivo Challenge

Neural networks that regulate an organism's internal environment must sense perturbations, respond appropriately, and then reset. These adaptations should be reflected as changes in the efficacy of the synapses that drive the final output of these homeostatic networks. Here we show that hemorrhage, an in vivo challenge to fluid homeostasis, induces LTD at glutamate synapses onto hypothalamic magnocellular neurosecretory cells (MNCs). LTD requires the activation of postsynaptic alpha2-adrenoceptors and the production of endocannabinoids that act in a retrograde fashion to inhibit glutamate release. In addition, both hemorrhage and noradrenaline downregulate presynaptic group III mGluRs. This loss of mGluR function allows high-frequency activity to potentiate these synapses from their depressed state. These findings demonstrate that noradrenaline controls a form of metaplasticity that may underlie the resetting of homeostatic networks following a successful response to an acute physiological challenge.

Propofol-induced Dyskinesias Controlled with Dexmedetomidine during Deep Brain Stimulation Surgery

for the next 5 min. At this point, 1.5 g/kg dexmedetomidine was administered as a loading dose over 20 min. The patient’s dyskinesias subsided within 18 –20 min of dexmedetomidine infusion. The dexmedetomidine infusion rate was then reduced to 1.2 g kg 1 h 1 for another 10 min, after which it was continued at a rate of 0.2– 0.5 g kg 1 h 1 . When the infusion was stopped just before the microelectrode recordings, dyskinesias recurred. The dexmedetomidine infusion was restarted with good control of dyskinetic movements and titrated to keep the patient sufficiently awake to answer questions. Specifically, during microstimulation at the end of microelectrode recording for each tract, the patient was asked whether he experienced paresthesias or pulling in the muscles of his face, arms, or legs. During macrostimulation at the time of placement of the DBS electrodes, he was asked to move his fingers or toes. This allowed satisfactory placement of bilateral subthalamic nucleus DBS electrodes. Approximately an hour after surgery, the patient had another brief episode of dyskinesias that subsided spontaneously while he was in the postoperative care unit. The patient was off dexmedetomidine infusion at this time. The patient did well postoperatively and was discharged home without further problems. During his follow-up visit at 5 weeks, he reported improvement of all symptoms, indicating satisfactory DBS function.

Activation of subfornical organ neurons in rats through pre- and postsynaptic α-adrenoceptors

The effects of noradrenaline (NA) and its analogs on subfornical organ (SFO) neurons in rat slice preparations were investigated by using whole cell patch-clamp recording. In the current-clamp mode, the application of NA at 10-100 microM produced membrane depolarization (63%, 17 responsive neurons/27 neurons tested) and hyperpolarization (22%, 6/27 neurons). In the voltage-clamp mode, NA application at 1-100 microM produced inward currents (69%, 42/61 neurons) and outward currents (23%, 14/61 neurons). These currents remained in the presence of TTX or both glutamate and GABA receptor antagonists. In most of the neurons (25/31 neurons) showing inward currents in the presence of NA, the membrane conductance was not changed by voltage ramps or hyperpolarizing pulse stimulation. Similar responses were obtained by the application of the alpha1-agonist phenylephrine. The phenylephrine-induced inward currents were inhibited by the alpha1-antagonist prazosin. The alpha2-agonist clonidine decreased the frequency of spontaneous GABAergic inhibitory postsynaptic currents (4/10 neurons). In addition, RT-PCR assay and immunohistochemical staining showed the existence of alpha1-adrenoceptors in the SFO. The results suggest that SFO neurons in rats are activated postsynaptically through alpha1-adrenoceptors and that the activation is enhanced by suppressing GABAergic inhibitory synaptic inputs through presynaptic alpha2-adrenoceptors.

Modulation of neurons in the paraventricular thalamic nucleus by α2 adrenoceptor agonists: evidence for physiological and morphological heterogeneity

The paraventricular thalamic nucleus (PVT) receives dense noradrenergic input, but little is known about α2 adrenoceptors (ARs) in this nucleus. We have investigated effects of the agonist α-methyl-norepinephrine (m-NE) on PVT neurons in vitro. Based on their physiological and morphological characteristics, three distinct classes of PVT neurons have been identified. The first class exhibits membrane hyperpolarization on stimulation with m-NE (0.05–25 µM). This hyperpolarizing effect is observed in the presence of tetrodotoxin (TTX; 0.5–1 µM), blocked by yohimbine (1 µM) and mimicked by clonidine (10 µM), which indicates that it is mediated by postsynaptic α2 ARs. Further experiments indicate that it is mediated through an increase in G protein-coupled K+ conductance. In a second class of neurons, m-NE (0.05–25 µM) induces a slow membrane depolarization that is mimicked by phenylephrine (5 µM) and blocked by prazosin (75 nM), which indicates the involvement of α1 ARs. The third class of neurons is insensitive to m-NE (5–25 µM), and has a lower input resistance and a larger dendritic tree compared to the two other classes. The three types of neurons differ in their resting properties, and their firing patterns are changed by m-NE. These findings indicate anatomical and functional specialization of PVT neurons.

Synthesis and α 1-antagonist activity of derivatives of 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone

The synthesis and evaluation of the biological activity of new 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoceptors of isolated rat vas deferens.