scholarly journals The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

2021 ◽  
Author(s):  
◽  
Dane Aronsen
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Receptor Activation ◽  
Self Administration ◽  
Response Curves ◽  
Ru 24969 ◽  
Gr 127935 ◽  
Way 100635

<p>Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse.   Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed.  Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed.   Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors.   Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.</p>

scholarly journals The role of 5-HT1A and 5-HT1B receptors in MDMA self-administration

2021 ◽  
Author(s):  
◽  
Dane Aronsen
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Drugs Of Abuse ◽  
Receptor Activation ◽  
Self Administration ◽  
Response Curves ◽  
Ru 24969 ◽  
Gr 127935 ◽  
Way 100635

<p>Rationale: 3,4-methylenedioxymethamphetamine (MDMA) is a less efficacious reinforcer than other drugs of abuse. However, following repeated self-administration, responding increases for some animals and efficacy becomes comparable to other drugs of abuse. MDMA-stimulated serotonin (5-HT) release was negatively associated with acquisition of MDMA self-administration, and a neurotoxic 5-HT lesion reduced the latency to acquire self-administration. These findings suggest that MDMA-produced 5-HT release is an important component of self-administration. The receptor mechanisms are not, however, well understood, although it has often been suggested that the mechanism involves 5-HT-mediated inhibition of dopamine. Both 5-HT1A and 5-HT1B receptors are well localised to regulate dopamine release, and both have been implicated in modulating the reinforcing effects of many drugs of abuse.   Objectives: The first objective was to establish specific behavioural assays to reflect 5-HT1A and 5-HT1B receptor activation. Then, using the established behavioural assays, the aim was to determine the role of 5-HT1A and 5-HT1B receptors in the acquisition of MDMA self-administration. The impact of substantial MDMA self-administration on 5-HT1A and 5-HT1B receptors was also assessed.  Methods: Firstly, dose-effect relationships for the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT (0 – 3.0 mg/kg) and the hyperactive and adipsic response to the 5-HT1B/1A receptor agonist, RU 24969 (0 – 3.0 mg/kg) were determined. Selectivity of these responses was determined by co-administration of the 5-HT1A receptor antagonist, WAY 100635, or the 5-HT1B/1D receptor antagonist, GR 127935. Secondly, a pretreatment regimen of the RU 24969 (2 × 3.0 mg/kg/day, 3 days), which had been suggested to down-regulate 5-HT1B/1A receptors, was administered prior to self-administration testing. The effect of this manipulation on both the acquisition of MDMA self-administration, and the behavioural responses to 5-HT1A and 5-HT1B receptor activation, was measured. A further study measured behavioural responses to 5-HT1A or 5-HT1B receptor agonists prior to self-administration, to determine whether the variability in these responses would predict the variability in the latency to acquisition of MDMA self-administration. Lastly, the effect of substantial MDMA self-administration (350 mg/kg) on dose-response curves for the behavioural effects of 5-HT1A or 5-HT1B receptor activation was assessed.   Results: The hyperactive response to the 5-HT1B/1A receptor agonist, RU 24969, was blocked by the 5-HT1A receptor antagonist, WAY 100635, but not the 5-HT1B receptor antagonist, GR127935. Similarly, the hyperactive response to the 5-HT1A receptor agonist, 8-OH-DPAT, was dose-dependently blocked by WAY 100635. GR 127935, but not WAY 100635, blocked the adipsic response to RU 24969. Repeated administration of RU 24969 produced rightward shifts in the dose-response curves for 8-OH-DPAT-produced hyperactivity and RU 24969-produced adipsia, and also greatly facilitated the acquisition of MDMA self-administration. However, there was no correlation between latency to acquire MDMA self-administration and the hyperactive response to 8-OH-DPAT or the adipsic response to RU 24969, and MDMA self-administration failed to alter these behavioural response to activation of 5-HT1A or 5-HT1B receptors.   Conclusions: The hyperactive response to 8-OH-DPAT and the adipsic response to RU 24969 reflect activation of 5-HT1A and 5-HT1B receptors, respectively. The variability in acquisition of MDMA self-administration was reduced by a treatment that also down-regulated 5-HT1A and 5-HT1B receptors, however there was no further indication that these receptors play a critical role in the self-administration of MDMA. Instead, it seems likely that other 5-HT receptors have a greater impact on MDMA self-administration.</p>

scholarly journals Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

2021 ◽  
Author(s):  
◽  
Caleb Carati
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Sch 23390 ◽  
High Dose ◽  
Gbr 12909 ◽  
Self Administration ◽  
Drug Seeking ◽  
Skf 81297 ◽  
Pre Treatment

<p>It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.</p>

scholarly journals Methamphetamine Self-Administration: Neurochemical Consequences and Behavioural Effects

2021 ◽  
Author(s):  
◽  
Caleb Carati
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Sch 23390 ◽  
High Dose ◽  
Gbr 12909 ◽  
Self Administration ◽  
Drug Seeking ◽  
Skf 81297 ◽  
Pre Treatment

<p>It has been suggested that methamphetamine (MA) self-administration is dependent on dopaminergic mechanisms, and that exposure to high doses of methamphetamine is toxic to central dopamine (DA) and serotonin (5-HT) neurons. Most studies, however, have utilised a short duration, high dose, experimenter-administered MA exposure regime, which is not representative of exposure that results from MA use in humans. The present studies sought to investigate the effects of self-administered MA on brain monoamine levels following a short and longer withdrawal period, and to determine the role of D1- and D2-like receptors in the maintenance of MA self-administration and in relapse to MA-seeking. The effects of self-administered MA (0.1 mg/kg/infusion) on tissue monoamine levels were determined in rats either 24 hours or seven days following 20 daily six hour sessions. A yoked-control self-administration protocol was employed to determine the effects of response contingency. The effect of pre-treatment with the D1-like receptor antagonist, SCH 23390 (0.0; 0.01; 0.02 mg/kg; subcutaneous [SC]), or the D2-like receptor antagonist, eticlopride (0.0; 0.0125; 0.025; 0.05 mg/kg; intraperitoneal [IP]) on MA self-administration reinforced according to a fixed ratio (FR) 1, and progressive ratio (PR; 0.2 mg/kg MA) schedule was determined. The effect of these pharmacological manipulations on relapse to MA-seeking was also determined. Additionally, the role of DA in drug-seeking was examined by measuring the effect of priming injections of the direct D1 receptor agonist, SKF 81297 (0.0; 1.0; 2.0; 4.0 mg/kg; IP), the direct D2 receptor agonist, quinpirole (0.0; 1.0 mg/kg; IP), or the DA transporter (DAT) inhibitor, GBR 12909 (0.0; 1.0; 10.0 mg/kg; IP), on MA-seeking behaviour. Self-administered MA produced a transient decrease in tissue levels of DA and an increase in DA turnover. This effect was produced at 24 hours, but not seven days following the final self-administration session. Similar effects were produced in yoked rats that received the same, non-contingent exposure to MA. Pre-treatment with SCH 23390, but not eticlopride, produced a significant alteration in the dose-response curve of MA self-administration reinforced on an FR1 schedule, and reduced MA produced BPs on the PR schedule. MA-seeking was produced by MA, cocaine and GBR 12909. SCH 23390 pre-treatment significantly reduced drug-primed MA-seeking, whereas eticlopride had no significant effect. Finally, neither SKF 81297, nor quinpirole significantly increased MA-seeking. These findings suggest that self-administered MA does not produce the extensive neurotoxicity seen following high-dose experimenter-administered treatment regimes. The finding that pre-treatment with a D1-, but not a D2-like receptor antagonist altered the maintenance of MA self-administration suggests that neuroadaptations take place as a function of MA self-administration, rendering this behaviour more reliant on D1-like receptor mechanisms. This idea is further supported by the finding that a D1-, but not a D2-like antagonist reduced drug-primed MA-seeking, and that priming injections with a D2 agonist failed to increase MA-seeking behaviour. These results are in contrast to the literature on self-administration and reinstatement of drug-seeking following self-administration of other drugs of abuse, and suggest that dependence on different drugs may become mediated by different DA receptor mechanisms.</p>

scholarly journals Adenosine A1receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart

1999 ◽  
Vol 276 (2) ◽  
pp. H341-H349 ◽  
Author(s):  
Gavin R. Norton ◽  
Angela J. Woodiwiss ◽  
Robert J. McGinn ◽  
Mojca Lorbar ◽  
Eugene S. Chung ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
Physiological Role ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Perfused Rat Hearts

Presently, the physiological significance of myocardial adenosine A2a receptor stimulation is unclear. In this study, the influence of adenosine A2a receptor activation on A1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10−8 M)-elicited contractile responses (+dP/d t max) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10−7 M), but not the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10−7 M). The A2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10−5 M attenuated the antiadrenergic effect of the selective A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 × 10−7 M)-elicited increases in intracellular Ca2+concentration ([Ca2+]i) transients but did not influence Iso-induced changes in [Ca2+]itransients in the absence of exogenous adenosine. These results indicate that adenosine A2areceptor antagonists enhance A1-receptor-induced antiadrenergic responses and that A2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A2a receptors in the normal mammalian myocardium is to reduce A1 receptor-mediated antiadrenergic actions.

scholarly journals Monoacylglycerol lipase inhibition attenuates acute and anticipatory nausea in rats

SURG Journal ◽  
2014 ◽  
Vol 7 (3) ◽  
pp. 21-29
Author(s):  
Rachel I. Downey ◽  
Cheryl L. Limebeer ◽  
Heather I. Morris ◽  
Linda A. Parker
Keyword(s):  
Receptor Antagonist ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Monoacylglycerol Lipase ◽  
Anticipatory Nausea ◽  
Acute Nausea ◽  
Sr 141716 ◽  
Cb1 Receptor Antagonist ◽  
Lipase Inhibition

This study investigates the role of the endocannabinoid 2-arachidonyl glycerol (2-AG) in regulating acute and anticipatory nausea in rats using the conditioned gaping model. The animals were systemically pretreated with MJN110, a selective monoacylglycerol lipase (MAGL) inhibitor, to enhance endogenous levels of 2-AG. Acute nausea was assessed using the taste reactivity model in which a flavour, saccharin, was paired with the administration of the emetic agent, lithium chloride (LiCl). Anticipatory nausea was assessed using a model of contextually elicited conditioned gaping in which a context was paired with the emetic agent, LiCl. Results indicated that MJN110 at the 10.0 mg kg-1 and 20.0 mg kg-1 dosage significantly attenuated acute and anticipatory nausea, as displayed by the significant reduction in mean number of gapes. This suppression was mediated by CB1 receptor activation as displayed by reversal of such effects when MJN110 was coadministered with the CB1 receptor antagonist, SR 141716. The results suggest that enhancement of endogenous 2-AG levels by MAGL inhibition may have anti-emetic potential. Keywords: 2-arachidonyl glycerol; monoacylglycerol lipase; endocannabinoid; nausea; conditioned gaping; CB1 receptor

Role of endothelin ETB receptor activation in angiotensin II-induced hypertension: effects of salt intake

2001 ◽  
Vol 281 (5) ◽  
pp. H2218-H2225 ◽  
Author(s):  
Jennifer R. Ballew ◽  
Gregory D. Fink
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Salt Intake ◽  
Receptor Activation ◽  
Salt Sensitivity ◽  
Male Rats ◽  
Ang Ii ◽  
High Salt Intake ◽  
Induced Hypertension

We showed recently that endothelin (ET)A receptors are involved in the salt sensitivity of ANG II-induced hypertension. The objective of this current study was to characterize the role of endothelin ETB receptor activation in the same model. Male rats on fixed normal (2 meq/day) or high (6 meq/day) salt intake received a continuous intravenous infusion of ANG II or salt only for 15 days. During the middle 5 days of the infusion period, rats were given either the selective ETB receptor antagonist A-192621 or the nonselective endothelin receptor antagonist A-182086 (both at 24 mg · kg−1 · day−1intra-arterially). Infusion of ANG II caused a greater rise in arterial pressure in rats on high-salt intake. The administration of A-192621 increased arterial pressure further in all rats. The chronic hypertensive effect of A-192621 was not significantly affected by salt intake or ANG II. The administration of A-182086 lowered arterial pressure chronically only in rats on normal salt intake receiving ANG II. Thus the salt sensitivity of ANG II-induced hypertension is not caused by changes in ETB receptor function.

scholarly journals Activation of NTS A2a adenosine receptors differentially resets baroreflex control of renal vs. adrenal sympathetic nerve activity

2009 ◽  
Vol 296 (4) ◽  
pp. H1058-H1068 ◽  
Author(s):  
Tomoko K. Ichinose ◽  
Donal S. O'Leary ◽  
Tadeusz J. Scislo
Keyword(s):  
Receptor Antagonist ◽  
Adenosine Receptors ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Response Curves ◽  
Nerve Activity ◽  
Baroreflex Control ◽  
A2a Adenosine Receptors ◽  
Stimulation Of

The role of nucleus of solitary tract (NTS) A2a adenosine receptors in baroreflex mechanisms is controversial. Stimulation of these receptors releases glutamate within the NTS and elicits baroreflex-like decreases in mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas inhibition of these receptors attenuates HR baroreflex responses. In contrast, stimulation of NTS A2a adenosine receptors increases preganglionic adrenal sympathetic nerve activity (pre-ASNA), and the depressor and sympathoinhibitory responses are not markedly affected by sinoaortic denervation and blockade of NTS glutamatergic transmission. To elucidate the role of NTS A2a adenosine receptors in baroreflex function, we compared full baroreflex stimulus-response curves for HR, RSNA, and pre-ASNA (intravenous nitroprusside/phenylephrine) before and after bilateral NTS microinjections of selective adenosine A2a receptor agonist (CGS-21680; 2.0, 20 pmol/50 nl), selective A2a receptor antagonist (ZM-241385; 40 pmol/100 nl), and nonselective A1 + A2a receptor antagonist (8-SPT; 1 nmol/100 nl) in urethane/α-chloralose anesthetized rats. Activation of A2a receptors decreased the range, upper plateau, and gain of baroreflex-response curves for RSNA, whereas these parameters all increased for pre-ASNA, consistent with direct effects of the agonist on regional sympathetic activity. However, no resetting of baroreflex-response curves along the MAP axis occurred despite the marked decreases in baseline MAP. The antagonists had no marked effects on baseline variables or baroreflex-response functions. We conclude that the activation of NTS A2a adenosine receptors differentially alters baroreflex control of HR, RSNA, and pre-ASNA mostly via non-baroreflex mechanism(s), and these receptors have virtually no tonic action on baroreflex control of these sympathetic outputs.

New Findings on the Sensitivity of Free-Operant Timing Behaviour to 5-Hydroxytryptamine Receptor Stimulation

2014 ◽  
Vol 2 (2) ◽  
pp. 210-232 ◽  
Author(s):  
S. Body ◽  
T. H. C. Cheung ◽  
G. Bezzina ◽  
C. L. Hampson ◽  
K. C. F. Fone ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Weber Fraction ◽  
Receptor Stimulation ◽  
Mediated Effects ◽  
Free Operant ◽  
New Findings ◽  
Way 100635 ◽  
Timing Behaviour ◽  
Sb 242084

Timing performance maintained under the free-operant psychophysical procedure (FOPP) is sensitive to 5-hydroxytryptamine (5-HT)1A and 5-HT2A receptor stimulation. Agonists of these receptors displace the psychometric function towards shorter durations, reducing , the index of central tendency of timing. Here we report the effects of Ro-600175, a selective 5-HT2C receptor agonist, and mCPP, a 5-HT receptor agonist with high affinity for 5-HT2C receptors and lower affinity for 5-HT1A, 5-HT1B and 5-HT2A receptors, on timing behaviour. Rats were trained under the FOPP to press two levers (A and B) in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychometric curves were fitted to the data from each rat under each treatment condition for derivation of timing indices [ (time corresponding to %B = 50%), Weber fraction]. The rats received systemic treatment with Ro-600175, mCPP, and mCPP in combination with antagonists of 5-HT1A (WAY-100635), 5-HT1B (isamoltane), 5-HT2A (MDL-100907) or 5-HT2C (SB-242084) receptors. mCPP (2.5 mg kg−1 i.p.), but not Ro-600175 (1, 2, 4 mg kg−1 i.p.), reduced . SB-242084 (0.6 mg kg−1 i.p.) potentiated mCPP’s effect on . mCPP’s effect on was not altered by isamoltane (8.0 mg kg−1 i.p.), but was attenuated by MDL-100907 (1.0 mg kg−1 i.p.) and WAY-100635 (0.1 mg kg−1 s.c.). The results suggest that mCPP’s effect on timing is mediated by an agonistic action at 5-HT1A and 5-HT2A, but not 5-HT1B, receptors. The role of 5-HT2C receptors is unclear, in view of SB-242084’s ability to potentiate the effect of mCPP, while Ro-600175 had no effect on . The possibility is considered that 5-HT2C receptors may counteract 5-HT1A and/or 5-HT2A receptor-mediated effects on timing performance.

scholarly journals Endothelin-B Receptors in Cerebral Resistance Arterioles and their Functional Significance after Focal Cerebral Ischemia in Cats

1997 ◽  
Vol 17 (11) ◽  
pp. 1157-1165 ◽  
Author(s):  
Omar Touzani ◽  
Samuel Galbraith ◽  
Peter Siegl ◽  
James McCulloch
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Focal Cerebral Ischemia ◽  
Receptor Activation ◽  
Induced Response ◽  
Brain Vessels ◽  
Pial Arterioles ◽  
Cerebral Arterioles ◽  
Endothelin B

In the cerebral circulation, endothelin-A receptor activation mediates marked prolonged vasoconstriction whereas endothelin-B (ETB) receptor activation effects dilation. In contrast to some peripheral vascular beds, ETB receptor–induced vasoconstriction has not yet been demonstrated in brain vessels. In this study in chloralose-anesthetized cats, with perivascular microapplications of ETB selective agonist (BQ-3020) and antagonist (BQ-788), we investigated whether ETB receptor–mediated constriction could be uncovered in cortical arterioles in vivo. In addition, we examined whether normal dilator response to ETB receptor activation is preserved in postishemic cerebral arterioles. The first microapplication of the selective ETB receptor agonist BQ-3020 (1 μmol/L) onto a pial cortical arteriole elicited marked dilation (caliber increased by 26.3 ± 15.1% from preinjection baseline). A second application of BQ-3020 (10-minute interval) onto the same vessel failed to evoke any significant vasomotor response. Subsequent (third and fourth) adventitial microapplication of the ETB receptor agonist on the same arteriolar site effected a significant constriction of cerebral arterioles (−15.3 ± 12.7% and −9.7 ± 6.3% from preinjection baseline, respectively, at 20 and 30 minutes after the first application). The pial arterioles did not display tachyphylaxis to repeated applications of potassium (10 mmol/L). The perivascular application of the ETB receptor antagonist BQ-788 (0.001 to 1 μmol/L) had no effect on arteriolar caliber per se but blocked both BQ-3020–induced dilation (inhibitory concentration ∼ 5 nmol/L) and vasoconstriction elicited by repeated activation of ETB receptors. After middle cerebral artery occlusion, most of the arterioles examined displayed a sustained dilation. The microapplication of BQ-3020 into the perivascular space surrounding postischemic dilated arterioles elicited a constriction of a similar magnitude to that induced by application of CSF (−17 ± 7% and −17 ± 7% from preinjection baseline, respectively). The adventitial microapplication of the ETB receptor antagonist (BQ-788, 0.1 μmol/L) on postocclusion dilated pial arterioles effected no change in the arteriolar caliber when compared with preinjection baseline. This BQ-788–induced response was significantly different from that induced by perivascular microinjection of CSF ( P < 0.001, analysis of variance). These investigations indicate that (1) repeated activation of ETB receptors displays tachyphylaxis of the vasodilator response but also uncovers significant constriction of cerebral arterioles in vivo; (2) the ability of BQ-3020 to elicit dilation is lost within 30 minutes of induced focal ischemia; and (3) ETB-mediated contractile tone contributes in a small but significant manner in limiting postischemia dilation of cortical pial arterioles.

scholarly journals Adrenergic α1 receptor activation is sufficient, but not necessary for phrenic long-term facilitation

2014 ◽  
Vol 116 (11) ◽  
pp. 1345-1352 ◽  
Author(s):  
A. G. Huxtable ◽  
P. M. MacFarlane ◽  
S. Vinit ◽  
N. L. Nichols ◽  
E. A. Dale ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Receptor Antagonist ◽  
Adrenergic Receptors ◽  
Intermittent Hypoxia ◽  
Receptor Agonist ◽  
Receptor Activation ◽  
Motor Nucleus ◽  
Long Term Facilitation ◽  
Dose Dependent

Acute intermittent hypoxia (AIH; three 5-min hypoxic episodes) causes a form of phrenic motor facilitation (pMF) known as phrenic long-term facilitation (pLTF); pLTF is initiated by spinal activation of Gq protein-coupled 5-HT2 receptors. Because α1 adrenergic receptors are expressed in the phrenic motor nucleus and are also Gq protein-coupled, we hypothesized that α1 receptors are sufficient, but not necessary for AIH-induced pLTF. In anesthetized, paralyzed, and ventilated rats, episodic spinal application of the α1 receptor agonist phenylephrine (PE) elicited dose-dependent pMF (10 and 100 μM, P < 0.05; but not 1 μM). PE-induced pMF was blocked by the α1 receptor antagonist prazosin (1 mM; −20 ± 20% at 60 min, −5 ± 21% at 90 min; n = 6). Although α1 receptor activation is sufficient to induce pMF, it was not necessary for AIH-induced pLTF because intrathecal prazosin (1 mM) did not alter AIH-induced pLTF (56 ± 9% at 60 min, 78 ± 12% at 90 min; n = 9). Intravenous (iv) prazosin (150 μg/kg) appeared to reduce pLTF (21 ± 9% at 60 min, 26 ± 8% at 90 min), but this effect was not significant. Hypoglossal long-term facilitation was unaffected by intrathecal prazosin, but was blocked by iv prazosin (−4 ± 14% at 60 min, −13 ± 18% at 90 min), suggesting different LTF mechanisms in different motor neuron pools. In conclusion, Gq protein-coupled α1 adrenergic receptors evoke pMF, but they are not necessary for AIH-induced pLTF.

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