After a 2-h incubation at room temperature, vacuum filtration was performed, and the filters were counted in a gamma counter. In vivo studies were carried out as described previously Adult male mice 12—16 weeks of age were anesthetized with isofluorane using a vaporizer Airco Inc. The catheter was tunneled through the neck and then placed in a subcutaneous pouch in the back.
After a minimum of 16 h recovery, the saline-filled catheter was removed from the pouch and connected to a Spectramed DTX Plus pressure transducer Spectramed, Oxnard, CA. Output from the pressure transducer was amplified using a Gould 8-channel recorder and digitized using a Data Translation Series DT analog-digital converter Marlboro, MA. Baseline heart rate and mean arterial blood pressure were recorded after a 1-h equilibration period when the animals were awake but not active.
In order to examine drug responses, drugs were administered through the carotid artery catheter. In order to measure heart rate and blood pressure during exercise, cannulated mice were challenged with a graded treadmill exercise protocol 19 on a Simplex II rodent treadmill Columbus Instruments, Columbus, OH. Treadmill activity was initiated at 3. Treadmill speed and inclination were then increased by 2. Mice that failed to complete the exercise protocol were excluded from the study.
In order to measure metabolic responses to exercise and exercise capacity, non-instrumented mice were challenged with the graded treadmill exercise protocol described above. Treadmill activity was initiated after the mice had equilibrated in the exercise chamber for 30—60 min. During the exercise protocol, oxygen consumption and carbon dioxide production were continuously monitored with an Oxymax gas analyzer Columbus Instruments, Columbus, OH. Stepwise increases in treadmill speed and inclination were made every 3 min until the mice stopped running from exhaustion. Exercise capacity was calculated as the total distance run by the animals during the exercise protocol.
Male mice, 12—13 weeks old, were used for these studies. On the day of study, food was removed from the cage at the beginning of the light cycle, and mice were studied 3—5 h later. The mouse was quickly removed from the box, and blood was collected by cardiac puncture with a guage needle. The mouse was then sacrificed via cervical dislocation.
The volume of the mouse was determined by attaching a weight to the mouse and measuring the water displacement. Density was calculated as the body weight divided by the volume. After the volume measurement, both epididymal fat pads were dissected from the animal and weighed. The proportional weight of the fat pads was calculated by dividing the fat pad weight by the total body weight. Free fatty acid levels were determined with an enzymatic colorimetric kit Wako Chemicals, Germany. Glycerol levels were determined with an enzymatic colorimetric kit Roche Molecular Biochemicals.
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Mice were placed in the cages at 5 p. The mice used for these studies had not been used for any previous experiments. Targeted clones were rescreened with a probe to the neomycin resistance gene to ensure that a single integration of the targeting vector had occurred data not shown.
Chimeric mice were generated with the targeted ES clones using the morula aggregation technique. Shown in Fig. B, Southern blot of tail DNA from offspring of a heterozygous knockout intercross. The upper trace represents heart rate, and the lower trace represents blood pressure.
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Isoproterenol was administered at the 1-min time mark. Epinephrine was administered at the 1-min time mark. The effects of exercise on heart rate and blood pressure are shown in Fig. For these experiments, catheterized mice were tested using a graded exercise treadmill protocol. A significant difference, however, was observed in the blood pressure response to exercise. During a graded treadmill exercise program, heart rate A and blood pressure B were monitored in mice through the arterial catheter.
In a separate set of experiments, metabolic responses to exercise and exercise capacity were measured in uncatheterized mice. Oxygen consumption and carbon dioxide production were continuously monitored while the mice exercised according to a graded treadmill exercise protocol Fig. The MWM is a spatial water navigation task requiring the rodent to learn and remember the location of an escape platform in a water arena in order to locate a hidden submerged platform in subsequent trials by using various spatial cues.
The escape latency is a measure of spatial working memory. The test is a reliable tool correlating with hippocampal synaptic plasticity as well as intact glutamate NMDA-receptor function The radial-arm maze is a test used to measure reference and working memory in rodents and relies on intact functioning of the prefrontal cortical, hippocampal and striatal interconnections to locate food rewards hidden in various radial-arm target sites The declarative memory processes underlying the NORT relies on the perirhinal cortex and the hippocampal complex — Brain-derived neurotrophic factor is the most prevalent neurotrophic growth factor in the CNS where it is especially important in regulating synaptic plasticity and various aspects underlying cognitive performance, memory, and mood , Acute and chronic stress purportedly have detrimental effects on rodent BDNF expression in the hippocampus, while altered BDNF levels are evident in depressive disorders 68 , and in schizophrenia , Brain-derived neurotrophic factor is also important in regulating C-fos and JunB expression, biomarkers of neuronal activity that play an important role in synaptic function , Upregulation of c-fos mRNA is induced by noxious stimuli, neurotransmitters, neurotrophins and other growth factors as well as learning and memory processes Jun-B is also involved in the regulation of emotional memory The PSD is a specialized matrix located at excitatory postsynaptic terminals, described as a macromolecular complex of several hundreds of proteins that act as a molecular switch for multiple interacting neurotransmitter signaling pathways These proteins in turn promote binding to a variety of molecules within the PSD necessary for signal transduction There is significant interest in the role of the PSD network in psychopharmacology and psychotropic drug action, although much of the extant evidence in support of this relates to DA and glutamate-dependent synaptic plasticity 45 , Despite this evidence, however, spinophilin is not yet known to be involved in major neuropsychiatric disorders or to by modulated by main psychopharmacologic treatments Although the specific role for PSD proteins in psychiatric illness remains speculative, clinical and preclinical studies have provided evidence for their involvement in aberrant synaptic plasticity [see Ref.
These processes are invariably associated with high-order cognitive alterations, which are essentially the core pathophysiology in a number of psychiatric diseases, including depression and schizophrenia — When considering a therapeutic strategy in psychiatric diseases, psychotropic-mediated modulation of PSD molecules may occur either directly or indirectly, the latter as a consequence of drug interaction with their target non-PSD receptors. Currently, there is no known agent that directly targets a PSD protein for therapeutic effect.
Since PSD molecules are modulated by antipsychotics and antidepressants — , as well as play a key role in behavioral response , , they represent putative targets for pharmacological action. Moreover, concurrent administration of antipsychotics and antidepressants may induce synergistic modulation of specific PSD molecules — , which provides at least conceptual support for targeting the PSD to address treatment resistance in mood and psychotic disorders.
Such data holds promise for application in treatment resistance, and further studies in this regard, but combined with co-assessment of PSD proteins, are warranted.
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Here, ORM was used as an add-on drug in patients already receiving donepezil, galantamine, rivastigmine or memantine. Significant improvements in episodic memory were observed, as well as a tendency to improve working memory. In addition, ORM produced significant improvement in perceived levels of distress with respect to symptoms of delusions, agitation and aggression, MDD, anxiety, disinhibition and other behavioral symptoms Moreover, there was a positive trend to lower caretaker distress scores which would also reflect reduced symptom severity and frequency These effects need to be corroborated using subtype-selective ligands with higher selectivity ratios, and subsequent testing on cognition in models of ADHD.
Bipolar disorder is a mood disorder characterized by mixed symptoms of MDD and mania, with both antidepressants and antipsychotics in combination with mood stabilizers advocated as standard first-line treatment. There is, however, limited clinical data in this respect and further patient trials are urgently needed. Some areas requiring further research include:.
An array of tools is now available to facilitate further research.
Although low selectivity vs. Further animal studies with this promising compound are eagerly awaited. However, this compound does not optimally enter the CNS. Both JP and ORM have since been used safely in preclinical studies in rodent models of neuropsychiatric illness and highlighted in this review. This compound has a binding affinity selectivity of over fold vs. An obvious application is determination of target engagement, through conducting receptor occupancy studies for novel drug candidate molecules for preclinical and clinical studies 62 , , The tracer could also be of potential value to investigate disease-related changes in receptor density and effects on neurotransmitter activity.
These compounds are being investigated for effects on peripheral vasoconstriction , Further behavioral and biological characterization, for example using -omics type molecular profiling, as well as regionally restricted genetic manipulation using genetic deletion technology in rats, would yield valuable data.
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The zebrafish is another platform of discovery that may provide a powerful model in which to study developmental and genetic factors that underlie human disease MU prepared the first draft of the manuscript, prepared all the figures and tables, as well as managed all subsequent changes and formatting. MS reviewed the manuscript and provided input on the manuscript design and content, as well as on the figures and tables. BH was the study leader and student supervisor to MU, developed the article concept and design, and finalized the manuscript for submission.
MS is an employee of Orion Pharma.
No funding was received by Orion Pharma for this, or previous work by these authors. ORM, which was used in recent studies by the authors and cited in this paper was sponsored by Orion Pharma. BH declares that, except for income from the primary employer and research funding from the below-mentioned organizations and agencies, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
The authors declare no other conflicts of interest. The grant-holder acknowledges that opinions, findings, and conclusions or recommendations expressed in any publication generated by NRF supported research are those of the authors, and that the NRF accepts no liability whatsoever in this regard. These funders have no other role in this study. Langer SZ. Trends Pharmacol Sci — Brain Res — Kalkman HO, Loetscher E. Eur J Pharmacol — Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.
J Psychopharmacol — J Clin Psychopharmacol —7. Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia: comparison with the atypical neuroleptic, clozapine. Br J Psychiatry —9.
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Adjunctive alpha2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission. Int J Neuropsychopharmacol — A double-blind study comparing idazoxan and bupropion in bipolar depressed patients. J Affect Disord — Dhir A, Kulkarni SK. Effect of addition of yohimbine alphareceptor antagonist to the antidepressant activity of fluoxetine or venlafaxine in the mouse forced swim test.
Pharmacology — Neuropsychopharmacology — Psychopharmacology — Arnsten AFT. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry e89— J Child Adolesc Psychopharmacol — Nature —4. Physiological significance of alpha 2 -adrenergic receptor subtype diversity: one receptor is not enough. Life Sci — Br J Pharmacol — Basic Clin Pharmacol Toxicol — ORM receptor pharmacology of a novel alpha2c-adrenergic receptor subtype selective antagonist with multi-therapeutic potential.
Neuropsychopharmacology S— Google Scholar. The alpha2C-adrenoceptor antagonist, ORM, has antipsychotic-like effects in social isolation reared rats and bolsters the response to haloperidol. Prog Neuropsychopharmacol Biol Psychiatry — The alpha2C-adrenoceptor antagonist, ORM, exerts antidepressant-like effects in the Flinders sensitive line rat. Behav Pharmacol — Neuropsychopharmacology —6.
Association between the alpha-2C-adrenergic receptor gene and attention deficit hyperactivity disorder in a Korean sample. Neurosci Lett — Alpha2C-adrenoceptor Del polymorphism and risk of psychiatric disorders: significant association with opiate abuse and dependence.
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