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Group 1 imipramine 25mg with mastercard anxiety symptoms stories depression men, nel consists of multimeric combinations of the various P2X comprising the P2X and P2X receptors, has high ATP subunits to form a nonselective pore permeable to Ca2 , 1 3 affinity for ATP (EC 1 M) and is rapidly activated K , and Na that mediates rapid (approximately 10-milli- 50 and desensitized. Group 2 includes the P2X2, P2X4, P2X5, second) neurotransmission events. Available evidence indi- and P2X6 receptors that have lower ATP affinity (EC50 cates that functional P2X receptors are trimeric, in contrast 10 M), have a slow desensitization profile, and exhibit to the typical pentameric structure of other LGICs (38). The only receptor in Group addition to putative P2X1 to P2X7 homomers, P2X1/5, 3 is the P2X7 LGIC, which has low ATP affinity (EC50 P2X2/3, and P2X4/6 functional heteromers have been identi- 300 – 400 M) and shows little or no desensitization on fied (1,39). P2X5 and P2X6 receptors do not appear to exist agonist exposure. Unlike other LGICs, such as nAChRs, the 5-hydroxytryptamine (5-HT3) receptor, little P2X Receptors is known regarding the agonist (ATP) binding site on P2X P2X receptors are ATP-gated LGICs formed from various receptor constructs or of ancillary sites that may modulate P2X subunits that share a common motif of two transmem- receptor function. Like the amiloride-sensitive The utility of current P2-receptor antagonists, such as epithelial Na channel, P2X receptor subunits have a large PPADS, DIDS, reactive blue-2, and suramin (Fig. These compounds can also inhibit the receptor has a rank order of activation in which 2MeSATP ectonucleotidases responsible for ATP breakdown, thus ATP -meATP and is localized to a subset of confounding receptor characterization (40). Radioligand- sensory neurons that includes the dorsal root, trigeminal, binding assays for P2 receptors are also far from robust; and nodose ganglia (1). It has similar properties to the P2X1 available ligands binding to cell lines lack any type of P2 subtype including -meATP sensitivity and rapid desensi- receptor (41). The use of high throughput screening tech- tization kinetics. P2X2 and P2X3 subunits can form a func- niques to identify novel ligands thus depends on functional tional heteromeric P2X2/3 receptor in vitro (39) that com- fluorescence assays such as FLIPR (fluorescence imaging bines the pharmacologic properties of P2X3 ( -meATP plate redder) rather than binding. P2X4 receptors are activated by 2MeSATP and are the following: TNP-ATP, a noncompetitive, reversible are only weakly activated by -meATP. The rat and allosteric antagonist at P2X1 and P2X3 receptors with nano- human homologues of the P2X4 receptor differ in their molar affinity (42) that also has weak activity at P2X4 and sensitivity to suramin and PPADS; the human P2X4 recep- P2X7 receptors; Ip5I, a potent, selective P2X1 antagonist tor is weakly sensitive, and the rat P2X4 receptor is insensi- (Ki 100 nM) antagonist (43); KN-62, a potent (IC50 tive to these P2X-receptor antagonists (1). The P2X4 recep- 9 to 13 nM), noncompetitive antagonist of the human P2X7 tor is present in rat hippocampus, superior cervical ganglion, receptor that is inactive at the rat P2X7 receptor (44). The spinal cord, bronchial epithelium, adrenal gland, and testis, ATP analogue, A3P5PS (Fig. The agonist profile for the P2X5 nist–competitive antagonist at the turkey erythrocyte P2Y1 receptor is ATP 2MeSATP ADP with -meATP receptor (27), with the derivative, MRS 2179 being a full being inactive. This receptor does not exhibit rapid desensi- P2Y1-receptor antagonist (IC50 330 nM). AR-C 69931- tization kinetics but is blocked by suramin and PPADS. The P2X6 receptor is present P2X1 receptors are activated by 2MeSATP, ATP, and in the superior cervical ganglion, cerebellar Purkinje cells, -meATP (Fig. P2X1 subunits are present in cial dorsal horn neurons of lamina II, and trigeminal, dorsal the dorsal root, in trigeminal and celiac ganglia, and in root, and celiac ganglia (1). The P2X2 receptor is activated by functional heteromers in vitro (39). It is present in brain, spinal cord, before it was cloned (47), is present in the superior cervical superior cervical ganglia, and adrenal medulla. P2X2-1, ganglion and spinal cord, mast cells, and macrophages (48). P2X2-2, P2X2-3R, and P2X2-3 receptors are splice variants of Cerebral artery occlusion results in an increase in P2X7 im- the P2X2 receptor that have been localized, among other munoreactivity in the stroke-associated penumbral region places, to the cochlear endothelium, an area in the ear associ- (49). The P2X7 receptor has a long (240 amino acid) intra- ated with sound transduction (46). P2X1 and P2X2 recep- cellular C-terminal region that allows the receptor to form TABLE 15. CLASSIFICATION OF P2Y RECEPTORS Agonist Rank Order Potency Antagonist Rank Order Potency P2Y 2-MeSADP > 2-MeSATP > HT-AMP MRS2179 > isoPPADS > A3 P5 P′ ′ ≥ PPADS suramin 1 > ADP > ADPβS > ATP > α,β-meATP > UTP inactive P2Y2 ATP = UTP (100) > ATPγS = Ap4A P2Y4 UTP ≥ UTPγS > ATP PPADS > reactive blue 2 > suramin > ATP (human) P2Y6 UDP >> UTP ≥ 2-MeSADP Suramin > PPADS P2Y11 ATP > ADP >>> UTP P2Y12 ADP AR-C 69931MX = CT5054 >>> ATP P2Y13 ADP 2Me5ADP >> ATP Chapter 15: Purinergic Neurotransmission 199 a large nonselective cytolytic pore on prolonged or repeated MITOCHONDRIAL PURINE RECEPTORS? Exposure of the P2X7 receptor to ATP for brief periods (1 to 2 seconds) results in transient In addition to functioning as the key source of ATP within pore opening that mediates cell-to-cell communication.
The location and sequence of the genetic element responsible The overall importance of the CYP3A subfamily of drug- metabolizing enzymes buy cheap imipramine 25mg on line anxiety 4th, particularly in the field of psycho- for CYP3A4 expression have been identified, as well as a pharmacology, has become increasingly evident over the last regulatory segment located on the 5′ flanking region corre- decade (6–9,63–69) (Table 38. Its high substrate capacity is a consequence of liver (70) (Table 38. Within the CYP3A subfamily, both the relatively high value of maximum reaction velocity CYP3A4 is the most important in the adult human, in terms (Vmax, expressed in nanomoles of product produced per unit of drug-metabolizing activity as well as quantitative domi- time per milligram of protein) in a Michaelis-Menten rela- nance. CYP3A5, another CYP3A isoform, is also detected tionship, as well as the high quantitative abundance of the protein in hepatic tissue. The low-affinity characteristic is reflected in the high Km value (substrate concentration cor- responding to 50% of Vmax) in a Michaelis-Menten relation- TABLE 38. One consequence is that CYP3A-mediated metabo- FOR HUMAN CYP3A lism usually is not 'saturable' at substrate concentrations within the therapeutic range, because this range is likely to Contribution of CYP3A to Net Clearance be far below the reaction Km. Furthermore, in situations in Complete or which CYP3A is one of several cytochromes contributing Nearly Complete Partial Small to metabolism [e. However, this is not in- Bromazepam Clonazepam variably true. Nefazodone is a CYP3A substrate, but Km Nefazodone Zolpidem values for production of the various metabolites are rela- Trazodone Citalopram Reboxetine Haloperidol tively low (74), and kinetics are nonlinear (75). Midazolam Buspirone Clozapine has a low Km for the principal pathway (76,77), and there Gepirone Olanzapine is evidence of nonlinear kinetics at higher concentrations Adinazolam Mirtazapine in humans (78). Quetiapine Amitriptyline Significant quantities of CYP3A exist in gastrointestinal Sildenafil Imipramine (GI) tract mucosa (65,69,79). The quantitative expression/ 38: Pharmacokinetics, Pharmacodynamics, and Drug Disposition 515 TABLE 38. REPRESENTATIVE DRUGS HAVING CLINICALLY IMPORTANT EFFECTS ON THE HUMAN CYP ENZYMES Drug Inhibition of: Induction of: Azole antifungals Ketoconazole CYP3A Itraconazole CYP3A Fluconazole CYP3A, 2C9 Terbinafine CYP2D6 Antidepressants Fluoxetine CYP2D6 Paroxetine CYP2D6 Fluvoxamine CYP1A2, 2C19, 3A Nefazodone CYP3A St. Relativecontributions of CYP3Aenzymes present Antipsychotics in gastrointestinal (GI) tract mucosa, and in the liver, to net bio- Perphenazine CYP2D6 availability (F) of orally administered midazolam and triazolam. Anticonvulsants Both of these compounds have net F values of less than 50% (29% Carbamazepine CYP3A for midazolam, 44% for triazolam). Both compounds undergo Antithrombotics approximately 50% extraction during passage through the G. However midazolam undergoes another 38% ex- traction across the liver, compared to only 12% for triazolam. Antiinfectives Erythromycin CYP3A Clarithromycin CYP3A Ciprofloxacin CYP1A2 Rifampin CYP3A activity of GI tract CYP3A is not correlated with its expres- Viral protease inhibitors sion/activity in liver, even though the expressed protein is Ritonavir CYP3A CYP3A identical at the two sites. For a number of moderate or high- Nonnucleoside reverse transcriptase inhibitors Delavirdine CYP3A clearance CYP3A substrates (e. For low-clearance CYP3A substrates Cimetidine CYP3A having oral bioavailability in the range of 80% to 90% or Omeprazole CYP2C19 greater (e. Inhibition and induction by other drugs or chemicals may modify CYP3A activity both in vitro and in vivo (Table 38. Identification of these compounds is of clear clinical cleoside reverse transcriptase inhibitor delavirdine also are importance, because it may allow anticipating of drug inter- potent CYP3A inhibitors (88–91). A component of grape- actions that may be either potentially hazardous or of thera- fruit juice inhibits CYP3A in the GI tract (92). Inhibiting drugs may of CYP3A include carbamazepine, rifampin, phenobarbital, also be used for investigating the relative contribution of nevirapine, dexamethasone, St. Ritonavir is an inducer as well as an inhibitor, tion of hepatic and GI tract CYP3A to overall presystemic yielding a net effect on CYP3A metabolism that is difficult extraction (81). Among the most potent CYP3A inhibitors to predict (88–91,93–95). These compounds produce 'reversible' inhibi- tion studies of CYP3A activity is that distributions are uni- tion, by a competitive, noncompetitive, or mixed mecha- modal, without evidence of genetic polymorphic regulation nism. Other potent inhibitors, such as the macrolide anti- (96,97).
J magnetic resonance spectroscopy of the temporal lobes in Magn Reson Imaging 1998;8:841–846 buy 75 mg imipramine fast delivery anxiety symptoms ear ringing. Psychiatry spectroscopy of the left temporal and frontal lobes in schizophre- Res 1999;92:45–56. It is in this arena that functional neuroimaging has had the broadest HISTORIC PERSPECTIVE application and greatest impact in psychiatry. This now ex- tensive body of work has left no doubt that schizophrenia Functional neuroimaging studies utilize the fact that neu- is associated with measurable, objective signs of altered brain ronal activation results in regionally increased blood flow function, and clinical and pathophysiologic correlations and metabolism. This can be measured either by radiotracer have begun to emerge. Increasingly, it appears that dysfunction oglobin to oxyhemoglobin imaged by magnetic resonance of a system of functionally and/or structurally intercon- techniques (the blood oxygenation level dependent [BOLD] nected cortical and limbic brain regions is present to lesser effect). This work began in earnest some 50 years ago with or greater degrees, producing more or less psychopathology the pioneering studies of Seymour Kety and colleagues who in individual patients, and that certain brain regions, such developed the first reproducible, quantitative technique for as frontal cortex, may play a special role in this larger picture. When this method was applied to ticularly cognitive impairment. Although it is likely that at schizophrenia (1), these investigators found no alteration in least some of the functional abnormalities are generative of the overall average CBF level in patients, a result that has these features and not simply a response to them, clarifica- largely been confirmed by more recent studies; however, tion of this 'chicken versus egg' issue must be a crucial this finding did not rule out the existence of neurophysio- component of any research program in this area, and the logically meaningful changes in specific brain structures. Current functional ment of rigorous methods that could differentiate the func- neuroimaging has much to offer in guiding this quest, par- tional level of specific cortical regions, albeit with only 2- ticularly when combined with new information now avail- cm anatomic accuracy at best (2). This method, administra- able from other fields such as genetics and cognitive science. The resulting findings delineate their relationship to other neurobiological and of functional abnormality in the frontal lobe spurred a shift clinical properties of the illness, discuss conceptual issues in focus throughout many research domains in the field that and controversies, examine methodologic considerations remains a prevailing force today. In the 1980s, the advent (including technical constraints), summarize new tech- of tomographic methods, such as single photon emission computed tomography (SPECT) and PET, which both use radioactive compounds as tracers, brought improved in- Karen Faith Berman: National Institute of Mental Health, Intramural terregional spatial resolution on the order of 5 to 6 mm Research Program, Bethesda, Maryland and allowed measurement of subcortical regional function. A particular advantage ing (fMRI) has emerged as the premier technique for neu- for research in schizophrenia is that neural activity during ropsychiatric functional neuroimaging. By taking advantage correct and incorrect trials can be measured separately and of the differential paramagnetic properties of oxyhemoglo- compared, allowing more incisive study of the mechanism bin versus deoxyhemoglobin and the altered ratio between of cognitive failure and better experimental control of po- them that occurs when blood volume and blood flow change tential confounds based in performance discrepancies that in response to neural activation, BOLD fMRI uses intrinsic often occur between patient and control groups. Event- properties of the blood itself rather than an extrinsic contrast related fMRI has very recently come into wide use in neu- or tracer agent, to generate maps of brain function. It is, roimaging of cognitive systems in healthy subjects, but as thus, entirely noninvasive, and measurements can be re- of this writing has had only limited application to the study peated over time, conferring significant advantage in experi- of schizophrenia. In this approach, blood flow and other measures advance brought further improvements in spatial resolution such as MR spectroscopy, neuroreceptor measurements, and as well as enhanced temporal resolution, which, although electrophysiology (with MEG or EEG) are determined in still slow (several seconds) compared to neuronal signaling the same patients. One example of the richness of the data (on the order of 200 ms), improved to the degree that event- that can be gleaned is the use of PET or fMRI to measure related neural activity could be recorded with anatomic blood flow in conjunction with EEG or MEG. PET and precision heretofore unavailable with electrophysiologic fMRI allow localization of the brain regions that work to- methods. On the other hand, EEG and MEG TECHNICAL PERSPECTIVE have relatively poorer spatial resolution, but provide fine time resolution (i. Combining these meth- As can be seen in the preceding brief history, over the years ods, together with the application of the advanced computa- the sophistication of the questions that could be asked and tional cross-registration and source localization techniques the hypotheses about schizophrenia that could be tested that now exist, provides exponentially more information have paralleled the development of new brain imaging tech- than any of these techniques alone. For example, this allows nologies and analytic methods. This parallel development the determination of the sequence in which various finely is evident in the evolution of the science from the search localized regions are activated during cognition and the test- for regionally specific pathologic function to that in neural ing of the hypothesis that this sequence of events is altered systems, and from measures sensitive only to static patho- in schizophrenia. Although this specific multimodal ap- physiology to explorations of the dynamic interplay among proach has not been applied in schizophrenia, other exam- regions in those neural systems. Therefore, a brief discussion ples are described in the following. New Vistas in Data Analysis The analytic approaches for the two data collection modali- New Vistas in Data Acquisition ties discussed, event-related fMRI and fusion of spatial and Event-related fMRI is a relatively recent class of experimen- temporal neurofunctional data (i. Another recent set of analytic methods ad- fMRI and PET approaches that blocked together relatively dresses the growing appreciation that the transduction be- long (e.
