Activation of 5HT1A receptors attenuates tachycardia induced by restraint stress in rats

Activation of 5HT1A receptors attenuates tachycardia induced by restraint stress in rats
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   doi:10.1152/ajpregu.00464.2007 294:132-141, 2008. First published Oct 24, 2007;  Am J Physiol Regulatory Integrative Comp Physiol Kotchabhakdi and Eugene Nalivaiko Sukonthar Ngampramuan, Mathias Baumert, Mirza Irfan Beig, Naiphinich   You might find this additional information useful... 22 articles, 3 of which you can access free at: This article cites http://ajpregu.physiology.org/cgi/content/full/294/1/R132#BIBLincluding high-resolution figures, can be found at: Updated information and services http://ajpregu.physiology.org/cgi/content/full/294/1/R132 can be found at:  and Comparative Physiology American Journal of Physiology - Regulatory, Integrative about Additional material and information http://www.the-aps.org/publications/ajpreguThis information is current as of January 13, 2008 . http://www.the-aps.org/.ISSN: 0363-6119, ESSN: 1522-1490. Visit our website at Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society. ranging from molecules to humans, including clinical investigations. It is published 12 times a year (monthly) by the Americanilluminate normal or abnormal regulation and integration of physiological mechanisms at all levels of biological organization, publishes srcinal investigations that The American Journal of Physiology - Regulatory, Integrative and Comparative Physiology   on J  an u ar  y 1  3  ,2  0  0  8  a j   pr  e g u. ph  y  s i   ol   o g y . or  gD  ownl   o a d  e d f  r  om   Activation of 5-HT 1A  receptors attenuates tachycardia induced by restraintstress in rats Sukonthar Ngampramuan, 1 Mathias Baumert, 2 Mirza Irfan Beig, 3 Naiphinich Kotchabhakdi, 1 and Eugene Nalivaiko 3 1  Neuro-Behavioural Biology Centre, Institute of Science and Technology for Research and Development, Mahidol University,Salaya Nakron Pathom, Thailand;  2 Centre for Biomedical Engineering, School of Electrical and Electronic Engineering,University of Adelaide, and   3  Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, Australia Submitted 29 June 2007; accepted in final form 19 October 2007 Ngampramuan S, Baumert M, Beig MI, Kotchabhakdi N,Nalivaiko E.  Activation of 5-HT 1A  receptors attenuates tachycardiainduced by restraint stress in rats.  Am J Physiol Regul Integr CompPhysiol  294: R132–R141, 2008. First published October 24, 2007;doi:10.1152/ajpregu.00464.2007.—To better understand the centralmechanisms that mediate increases in heart rate (HR) during psycho-logical stress, we examined the effects of systemic and intramedullary(raphe region) administration of the serotonin-1A (5-HT 1A ) receptoragonist 8-hydroxy-2-(di- n -propylamino)tetraline (8-OH-DPAT) oncardiac changes elicited by restraint in hooded Wistar rats withpreimplanted ECG telemetric transmitters. 8-OH-DPAT reduced basalHR from 356    12 to 284    12 beats/min, predominantly via anonadrenergic, noncholinergic mechanism. Restraint stress causedtachycardia (an initial transient increase from 318    3 to 492    21beats/min with a sustained component of 379    12 beats/min).  -Adrenoreceptor blockade with atenolol suppressed the sustainedcomponent, whereas muscarinic blockade with methylscopolamine(50   g/kg) abolished the initial transient increase, indicating thatsympathetic activation and vagal withdrawal were responsible for thetachycardia. Systemic administration of 8-OH-DPAT (10, 30, and 100  g/kg) attenuated stress-induced tachycardia in a dose-dependentmanner, and this effect was suppressed by the 5-HT 1A  antagonistWAY-100635 (100  g/kg). Given alone, the antagonist had no effect.Systemically injected 8-OH-DPAT (100   g/kg) attenuated the sym-pathetically mediated sustained component (from  85  19 to  32  9 beats/min) and the vagally mediated transient (from   62    5 to  25  3 beats/min). Activation of 5-HT 1A  receptors in the medullaryraphe by microinjection of 8-OH-DPAT mimicked the antitachycardiceffect of the systemically administered drug but did not affect basalHR. We conclude that tachycardia induced by restraint stress is due toa sustained increase in cardiac sympathetic activity associated with atransient vagal withdrawal. Activation of central 5-HT 1A  receptorsattenuates this tachycardia by suppressing autonomic effects. At leastsome of the relevant receptors are located in the medullary raphe-parapyramidal area.serotonin; psychological stress; heart rate; sympathetic; medullaryraphe THAT PSYCHOLOGICAL STRESS  consistently elicits sympatheticallymediated tachycardic responses is firmly established, but thecentral mechanisms generating increases in cardiac sympa-thetic activity remain poorly understood (6). In addition to atheoretical interest, this issue is of major clinical importance,inasmuch as the ability to suppress potentially deleteriousincreases in cardiac sympathetic activity at its srcin, in thebrain, would be a valuable alternative to widely used  -block-ers. Few attempts have been made to reach this goal, mainlybecause of a lack of knowledge of the localization and phar-macological sensitivity of presympathetic cardiomotor neu-rons. Recent evidence indicates that the final medullary relayfor the descending pathways that activate the heart duringstress is located in the raphe-parapyramidal area and thatrelevant cardiomotor neurons are sensitive to, and could beinhibited by, serotonin-1A (5-HT 1A ) receptor agonists (13, 23).Involvement of 5-HT 1A  receptors in cardiovascular controlis well documented, and the consensus is that their activationresults in central sympatholytic effects (see Refs. 10 and 14 forreviews). Most of the relevant studies were conducted inanesthetized animals; in conscious animals, drug effects werestudied in the quiet awake state. Two recent studies havedemonstrated that activation of 5-HT 1A  receptors attenuatescardiovascular changes elicited by psychological stresses (13,20). In both of these studies, it was suggested, but not proven,that the antitachycardic effects of 5-HT 1A  agonists were me-diated by suppression of the stress-elicited activation of cardiacsympathetic nerves.Restraint is a well-established experimental paradigm forprovoking psychological stress in rats. Restraint consistentlyelicits a robust rise in arterial pressure and heart rate (HR) (1,5, 12). However, the autonomic mechanisms mediating re-straint-induced tachycardia have not been characterized, andthe effects of 5-HT agonists on restraint-induced cardiac ef-fects have not been tested.We have therefore pursued the following aims in this study: 1 ) to determine how cardiac vagal and sympathetic activitycontribute to tachycardia induced by restraint stress,  2 ) to testwhether activation of 5-HT 1A  receptors could prevent thistachycardia and to determine the mechanisms that might beinvolved,  3 ) to identify a potential location of relevant 5-HT 1A receptors, and  4 ) to determine whether these receptors areactivated during restraint by intrinsically released 5-HT. In thisstudy, we used the selective 5-HT 1A  agonist 8-hydroxy-2-(di- n -propylamino)tetraline (8-OH-DPAT). MATERIALS AND METHODS Male hooded Wistar rats (280–320 g body wt) were used in allexperiments. All efforts were made to reduce animal pain or discom-fort. Experiments were conducted in accordance with the European Address for reprint requests and other correspondence: E. Nalivaiko, Dept.of Human Physiology, Flinders Medical Centre, Bedford Park 5042 SA,Australia (e-mail: eugene.nalivaiko@flinders.edu.au).The costs of publication of this article were defrayed in part by the paymentof page charges. The article must therefore be hereby marked “ advertisement  ”in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.  Am J Physiol Regul Integr Comp Physiol  294: R132–R141, 2008.First published October 24, 2007; doi:10.1152/ajpregu.00464.2007.0363-6119/08 $8.00 Copyright  ©  2008 the American Physiological Society http://www.ajpregu.orgR132   on J  an u ar  y 1  3  ,2  0  0  8  a j   pr  e g u. ph  y  s i   ol   o g y . or  gD  ownl   o a d  e d f  r  om   Community Council Directive of 24 November 1986 (86/609/EEC)and were approved by the Flinders University Animal Welfare Com-mittee. Preliminary Surgery Preliminary surgery was conducted under isoflurane (1.5% in100% oxygen) anesthesia. Carprofen (5 mg/kg) was used as ananalgesic after the surgery. Telemetric ECG radio transmitters(model TA11CA-F40, Data Sciences International) were implantedinto the peritoneal cavity. Electrodes were placed according to themethod described by Sgoifo (16): on the internal surface of thexiphoid process and in the mediastinum along the trachea at the levelof the left ventricle. These placements permit recovery of 95–99% of heartbeats, even in vigorously moving animals. In some animals,during the same surgical session, a stainless steel guide cannula wasstereotaxically positioned 2.8 mm caudal to the interaural line at themidline, inserted vertically to the IV ventricle, fixed to the skull withstainless steel screws and dental cement, and closed with an obturator.Animals recovered from anesthesia and were returned to the animalhouse for   1 wk before experimental studies. They were kept on areverse 12:12-h light-dark cycle.  Experimental Protocol Experiments were carried out between 9 AM and 2 PM. ECGprobes were switched on, and the animals remained in their homecages for   1 h. Drugs were administered subcutaneously, diluted in0.5 ml of Ringer solution ( experiments 1–7  ), or microinjected into themedullary raphe ( experiments 8–10 ).  Experiment 1: does systemic treatment with 8-OH-DPAT affect basal HR?  In the first group of rats ( n  6), 8-OH-DPAT (100  g/kg)or, on different days, Ringer solution was administered and recordingswere obtained for 1 h. Similar injections were made in the second( n    6) and third ( n    6) groups after   -adrenergic blockade withatenolol (2 mg/kg) or a combined muscarinic and  -adrenergic block-ade with methylscopolamine bromide (50   g/kg)    atenolol (2mg/kg), respectively.  Experiment 2: does systemic treatment with 8-OH-DPAT affect stress-induced tachycardia?  On different days, 8-OH-DPAT (10, 30or 100  g/kg) or Ringer solution was administered, and 15 min laterthe rats ( n    7) were placed in a restrainer (60-mm-ID transparentplastic tube) for 30 min.  Experiment 3: does systemic treatment with 8-OH-DPAT affect stress-induced tachycardia after 5-HT  1A  receptor blockade with WAY-100635? Before the restraint, animals ( n    6) received, on different days, thefollowing combination of drugs:  1 ) Ringer solution  Ringer solution,  2 )Ringer solution    8-OH-DPAT (100   g/kg), or  3 ) WAY-100635   8-OH-DPAT (both at 100  g/kg).  Experiment 4: does systemic treatment with WAY-100635 affect stress-induced tachycardia?  Before restraint, animals ( n    6) re-ceived, on different days, WAY-100635 (100   g/kg) or Ringersolution.  Experiment 5: does autonomic blockade affect restraint-induced cardiac responses?  Before restraint, animals ( n    8) received, ondifferent days:  1 ) Ringer solution,  2 ) atenolol (2 mg/kg), or  3 )methylscopolamine bromide (50  g/kg).  Experiment 6: does systemic treatment with 8-OH-DPAT affect stress-induced tachycardia after vagal blockade?  Before restraint,animals ( n    6) received, on different days, the following combina-tion of drugs at 10-min intervals:  1 ) methylscopolamine (50  g/kg)  Ringer solution or  2 ) methylscopolamine (50  g/kg)  8-OH-DPAT(100  g/kg).  Experiment 7: does systemic treatment with 8-OH-DPAT affect stress-induced tachycardia after    -adrenergic blockade?  Before re-straint, animals ( n    6) received, on different days, the followingcombination of drugs at 10-min intervals:  1 ) atenolol (2 mg/kg)   Ringer solution or  2 ) atenolol (2 mg/kg)  8-OH-DPAT (100  g/kg).  Experiment 8: does intracerebral microinjection of 8-OH-DPAT affect basal HR?  Animals ( n  6) received an intramedullary micro-injection of 8-OH-DPAT (1 nmol in 100 nl) or, on a different day, theequivalent volume of sterile Ringer solution, and recordings werecontinued for 1 h. An injection cannula (0.2-mm-OD stainless steelwire; Small Parts) was inserted 11 mm below the surface of the skull.Injections were made using a hand-held syringe, and the injectionvolume was assessed by observation of the meniscus in a glasscapillary attached to the injection cannula. Injections were madeslowly (  20 s), and the cannula remained in place for 1 min afterinjection.  Experiment 9: does intracerebral microinjection of 8-OH-DPAT affect stress-induced tachycardia?  Before restraint, animals receivedan intramedullary microinjection of 8-OH-DPAT (1 nmol in 100 nl)or, on a different day, the equivalent volume of sterile Ringersolution. Another five animals (control group) were injected sim-ilarly at a site that was 2.5 mm more dorsal (8.5 mm below thesurface of the skull). Microinjections were performed as describedfor  experiment 8  ( n    8).  Experiment 10: does 5-HT  1A  receptor blockade with WAY-100635 prevent antitachycardic effects of intramedullary microinjection of 8-OH-DPAT?  Before restraint, animals ( n    6) received, on differentdays, the following combination of drugs:  1 ) Ringer solution (subcu-taneously)  Ringer solution (brain microinjection, 100 nl),  2 ) Ringersolution (subcutaneously)    8-OH-DPAT (brain microinjection, 1nmol in 100 nl), or  3 ) WAY-100635 (100  g/kg sc)  8-OH-DPAT(brain microinjection, 1 nmol in 100 nl).Thus this study was conducted in 77 rats (57 with systemic and 20with intramedullary administration of 8-OH-DPAT). Each animalcohort was used for just one type of experiment. All experimentalprocedures were performed   48 h apart. To avoid serial effects, weused a counterbalanced or rotational design. All chemicals wereobtained from Sigma. Visualization of Microinjection Sites Medullary microinjection sites were labeled with horseradish per-oxidase (100 nl of 0.1% solution), which was administered into themedulla immediately after the termination of the last experiment viathe same injection cannula. Rats were euthanized with pentobarbitalsodium (Lethabarb) and perfused transcardially with formaldehydefixative. Brains were removed and cut into 50-  m-thick sections.Horseradish peroxidase was visualized by incubation of sections in0.05% solution of diaminobenzidine for 10 min, with the subsequentaddition of a 0.01% solution of hydrogen peroxide. Sections weredried, dehydrated in alcohol, mounted on slides, stained with neutralred, and photographed.  Data Acquisition and Analysis Analog ECG signals were digitized at 400 Hz and acquired usinga PowerLab analog-to-digital converter and Chart 5.4 software(ADInstruments). HR was calculated from the ECG records using thesame software. After removal of artifacts, HR was automaticallyaveraged for every minute. Spectral indexes of HR variability werecomputed using the HR variability (HRV) module of the Chart 5.4software. The low-frequency band was set at 0.15–1.0 Hz and thehigh-frequency (HF) band at 1.0–3.0 Hz. HF power is a measure of vagally mediated respiratory sinus arrhythmia. We also computed theroot mean square of the beat-to-beat interval differences (RMSSD), astandard HRV index reflecting fast vagal modulation of the interbeatintervals. To characterize the recovery of HR after handling-relatedtachycardia, we used the time period during which HR fell to 50% of the peak increase ( t  1   ⁄   2 ). The dose dependence of 8-OH-DPAT-inducedeffects was assessed using linear regression. Group data were ana-lyzed by ANOVA, with Fisher’s protected  t  -test and with the signif-icance threshold set at the 0.05 level. Values are means  SE. R133 ACTIVATION OF 5-HT 1A  RECEPTORS REDUCES TACHYCARDIA IN STRESS  AJP-Regul Integr Comp Physiol  •  VOL 294  •  JANUARY 2008  •  www.ajpregu.org   on J  an u ar  y 1  3  ,2  0  0  8  a j   pr  e g u. ph  y  s i   ol   o g y . or  gD  ownl   o a d  e d f  r  om   RESULTS  Effect of Systemic 8-OH-DPAT on Basal HRand HRV Indexes Subcutaneous injection of vehicle or 8-OH-DPAT (100  g/kg) caused transient tachycardia of similar magnitude.After the drug, HR fell within 10–15 min to a level signifi-cantly lower than basal and remained at this low level from  15 to 40 min after injection (Fig. 1  A ). In contrast, after thevehicle, reversion of injection-induced tachycardia was quiteslow; therefore, from 15 to 40 min after injection, HR was stilldifferent from the basal level and the corresponding valuesafter 8-OH-DPAT. There was also a significant difference inthe speed of HR decay from the peak:  t  1   ⁄   2  2.5  0.7 and 13  1.2 min after vehicle and drug, respectively ( P  0.01,  n  6).8-OH-DPAT substantially and significantly elevated HRV in-dexes that reflect vagal modulation of the HR RMSSD (1.6  0.1 and 4.8  0.7 ms after vehicle and drug, respectively,  P  0.01,  n  6) and HF power of the HRV (0.9  0.2 and 4.9  0.3 ms 2 after vehicle and drug, respectively,  P  0.05,  n  6).We then determined whether 8-OH-DPAT-induced brady-cardia could be prevented by  -adrenergic blockade (Fig. 1  B ).Administration of atenolol caused short-duration tachycardia,so that 15 min later, just before the injection of vehicle or8-OH-DPAT, HR did not differ from basal values for bothconditions. This second injection provoked tachycardic re-sponses that were smaller than those following the first injec-tion. Although after the vehicle, HR continued to fall, brady-cardia after the drug was more prominent, with a clear down-ward deflection (Fig. 1  B ). We compared HR during the periodof maximal action of 8-OH-DPAT (detected in the previousexperiment); the values were significantly different betweenthe two conditions and, also, for each of them, were lower thanthe corresponding basal (pre-atenolol) values.Next, we tested whether 8-OH-DPAT-induced bradycardiapersists after a combined vagal and sympathetic blockade (Fig.1 C  ). Administration of methylscopolamine caused sustainedtachycardia; injection of atenolol 10 min later caused a fall inHR after small injection-related tachycardia. The time courseof HR change did not differ for both conditions before the thirdinjection. As shown in Fig. 1 C  , 8-OH-DPAT still produced asubstantial bradycardic effect, so that at the peak of this effect,HR values were significantly different from correspondingvalues after the vehicle and from the basal (pre-scopolamine)values.  Effect of Systemic 8-OH-DPAT on Cardiac Responses Elicited by Restraint Stress In this experiment ( n  7), we tested whether activation of 5-HT 1A  receptors with 8-OH-DPAT (administered systemi-cally at 10, 30, and 100  g/kg) affects restraint-induced cardiacresponses. Mean group data are shown in Fig. 2  A , and valuesare presented in Table 1. Tachycardia associated with drug orvehicle administration reverted to the basal level within 15min, so the prerestraint values were not different between thefour conditions. After vehicle, restraint stress caused tachycar-dia, which peaked at   500 beats/min within 1–1.5 min andthan started to decline, approaching the steady-state levelwithin 10–15 min and remaining at this level (or sometimesslowly declining) until the end of the restraint. We will thusrefer to these data points as “peak restraint” and “steady-staterestraint.” Effects of pretreatment with 8-OH-DPAT dependedon the dose. After 10   g/kg 8-OH-DPAT, restraint-inducedtachycardia did not differ from the control condition. At 30  g/kg, 8-OH-DPAT substantially reduced the steady-state in-crease in HR, and at 100  g/kg, 8-OH-DPAT attenuated initialpeak tachycardia and the steady-state increase in HR (Table 1).Figure 2  B  shows results of the linear regression analysis. Fig. 1. Systemic 8-hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT, 100  g/kg sc) reduces basal heart rate (HR) when given alone (  A ), after  -adren-ergic blockade with atenolol (  B ), and after combined   -adrenergic and mus-carinic-cholinergic blockade with atenolol and methylscopolamine ( C  ). Exper-iments were conducted in 3 separate groups of rats ( n    6 in each group).Mean values are presented near corresponding traces. Significantly differentfrom preinjection basal level: * P  0.05; ** P  0.01. Significantly differentfrom vehicle for the same time point: # P  0.05; ## P  0.01. R134  ACTIVATION OF 5-HT 1A  RECEPTORS REDUCES TACHYCARDIA IN STRESS  AJP-Regul Integr Comp Physiol  •  VOL 294  •  JANUARY 2008  •  www.ajpregu.org   on J  an u ar  y 1  3  ,2  0  0  8  a j   pr  e g u. ph  y  s i   ol   o g y . or  gD  ownl   o a d  e d f  r  om    Effect of Systemic 8-OH-DPAT on Restraint-Induced Tachycardia After Selective Blockade of 5-HT  1A  Receptors To determine whether selective blockade of 5-HT 1A  recep-tors prevents antitachycardic effects of 8-OH-DPAT duringstress, we compared restraint-induced changes in HR in threeconditions using the following drug combinations:  1 ) Ringersolution  Ringer solution, 2) Ringer solution  8-OH-DPAT,and  3 ) WAY-100635    8-OH-DPAT. Prerestraint, peak, andsteady-state values did not differ between Ringer solution   Ringer solution and WAY-100635  8-OH-DPAT; both were,however, substantially and significantly different from Ringersolution    8-OH-DPAT (Fig. 3, Table 1). Thus selectiveblockade of 5-HT 1A  receptors completely abolished the effectsof 8-OH-DPAT.  Effects of Systemically Administered WAY-100635on Restraint-Induced Tachycardia To test whether there are any 5-HT 1A  receptor-dependentcardiac effects due to intrinsic 5-HT release during stress, wesubjected rats to the restraint after injection of vehicle orWAY-100635 (100   g/kg sc), a selective 5-HT 1A  receptorantagonist. We found no differences between vehicle and drugconditions (Fig. 4;  n  6).  Effects of Autonomic Blockade on Restraint-Induced Tachycardia In the next set of experiments ( n    8), we addressed thefollowing question: Which autonomic components mediaterestraint-induced tachycardia? Rats were subjected to the re-straint 15 min after injection of atenolol, methylscopolamine,or vehicle (Fig. 5, Table 2). After vehicle, the restraint pro-voked tachycardic responses similar to those described above.In animals with sympathetic blockade, restraint provoked onlya small transient tachycardia, and during the second half of restraint, HR did not differ from prerestraint or basal values.Administration of methylscopolamine caused a rapid rise in theHR that persisted. Subjecting rats to the restraint after vagalblockade caused initial tachycardia, with HR significantlyhigher than in restrained animals injected with vehicle. Aftervagal blockade, the increase in HR for the “steady-state”component (vs. prerestraint values) was significantly greaterthan after Ringer solution (Table 2). For vehicle and methyl-scopolamine conditions, steady-state values were significantlydifferent from prerestraint values ( P  0.01).  Effects of Systemic 8-OH-DPAT on Restraint-Induced Tachycardia After Sympathetic Blockade After sympathetic blockade with atenolol, 8-OH-DPAT orvehicle was administered before the restraint ( n    6; Fig. 6).The vehicle injection provoked a small and short-durationtachycardia, so that before the restraint, HR did not differ fromthe basal level. In vehicle-treated animals, restraint elicitedonly an initial transient tachycardic component of moderateamplitude. Injection of 8-OH-DPAT caused slow and long-lasting bradycardia, so that before the restraint, HR was sig-nificantly different from the basal level and the prerestraintvalue in vehicle-treated animals. After 8-OH-DPAT, restraintprovoked a small transient tachycardic response (  25    3beats/min) that was significantly different from the response tovehicle injection (  62  5 beats/min,  P  0.01,  n  6). Thetime course of 8-OH-DPAT-elicited bradycardia was similar tothat in  experiment 1  (i.e., drug alone).  Effects of Systemic 8-OH-DPAT on Restraint-Induced Tachycardia After Vagal Blockade In six animals, administration of methylscopolamine causeda rapid increase in HR. Effects of a subsequent injection of 8-OH-DPAT did not differ from those of vehicle injection, sothat the prerestraint values for both conditions were not differ-ent (see Fig. 8). Restraint-induced tachycardia was substan-tially and significantly attenuated in 8-OH-DPAT-treated ani-mals, in terms of absolute values (Fig. 7) and the magnitude of the increase (  85  19 and  32  9 beats/min after vehicleand drug, respectively,  P  0.01,  n  6). After reaching peak values, HR began to fall, with a time course similar for bothconditions, so that steady-state values were also significantlydifferent from each other, but they were not different fromcorresponding prerestraint values (although there was a ten-dency for a fall for the drug condition, with  P  0.062).  Effects of Intramedullary Microinjection of 8-OH-DPAT on Basal HR Apart from a short-lasting tachycardia associated with han-dling, microinjection of Ringer solution or 8-OH-DPAT into Fig. 2. Systemic pretreatment with 8-OH-DPAT attenuates tachycardia elic-ited by restraint stress.  A : changes in HR in animals ( n    7) pretreated, ondifferent days, with vehicle or 8-OH-DPAT (10, 30, and 100  g/kg sc). Valuesare presented in Table 2.  B : regression analysis of data from  A  showing dosedependence of 8-OH-DPAT action for peak ( top ) and steady-state ( bottom )components of restraint-induced tachycardia. R135 ACTIVATION OF 5-HT 1A  RECEPTORS REDUCES TACHYCARDIA IN STRESS  AJP-Regul Integr Comp Physiol  •  VOL 294  •  JANUARY 2008  •  www.ajpregu.org   on J  an u ar  y 1  3  ,2  0  0  8  a j   pr  e g u. ph  y  s i   ol   o g y . or  gD  ownl   o a d  e d f  r  om 
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