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F C Colpaert

Publications and source records attributed to F C Colpaert.

At least 73 records · Page 4Linked to original sources
PubMed1996

Pharmacology of cloned human 5-HT1D receptor-mediated functional responses in stably transfected rat C6-glial cell lines: further evidence differentiating human 5-HT1D and 5-HT1B receptors.

This study was undertaken to investigate the pharmacology of human serotonin (5-HT)1D receptor sites by measuring two functional cellular responses, inhibition of forskolin-stimulated cAMP formation and promotion of cell growth, using transfected rat C6-glial cell lines and a broad series of 5-HT receptor agonists. Stable and separate transfection of a pcDNA3 or pRcRSV plasmid, each containing a cloned human 5-HT1D receptor gene, in rat C6-glial cells was confirmed with RT-PCR of 5-HT1D receptor mRNA and radioligand binding with [3H] 5-carboxamidotryptamine (5-CT) and [3H] sumatriptan. The 5-HT1D receptor density was 350 and 1050 fmol/mg protein for the C6-glial/pcDNA3/5-HT1D and C6-glial/pRcRSV/5-HT1D cell line, and forskolin (100 microM)-induced cAMP formation was inhibited by 45 and 78% in the presence of 1 microM 5-HT, respectively. A comparison of the intrinsic agonist activities for sixteen 5-HT receptor ligands with their corresponding binding affinities for the human 5-HT1D receptor site showed similar results for both cell lines with the exception of the partial agonist m-trifluoro-phenyl-piperazine (TFMPP). Three classes of compounds were observed: 1) efficacious agonists, such as 5-CT, 5-methoxytryptamine, 5-HT, sumatriptan, bufotenine, 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole (RU 24,969), tryptamine and 8-hydroxy-2(di-n-propilamino)tetralin (8-OH-DPAT), with agonist potency close to their binding affinity; 2) the partial agonists metergoline, 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrolo-(1,2-a) quinoxaline (CGS 12066B), 1-naphthylpiperazine and 2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide (GR 127,935) with marked intrinsic agonist activity but at concentrations higher than their binding affinity; and 3) the silent antagonists ritanserin, ketanserin and methiothepin, apparently free of intrinsic agonist activity, with antagonist potency close to their binding affinity. The cAMP data were further supported by the observed promotion of cell growth by stimulation of both transfected cell lines with sumatriptan under serum-free conditions; half-maximal stimulation was obtained at 4.4 nM (C6-glial/pcDNA3/5-HT1D) fully in agreement with its EC50-value (5.7 nM) for inhibition of cAMP formation. This growth promoting effect was antagonised by 1 microM methiothepin and not observed in pcDNA3-plasmid-transfected and non-transfected C6-glial cells. A comparative study with a C6-glial/pcDNA3/5-HT1B cell line expressing a similar amount of cloned human 5-HT1B receptors (Bmax: 360 fmol/mg protein) showed almost no intrinsic agonist activity for metergoline, 1-naphtylpiperazine and GR 127,935. Together with the 5-HT1D receptor binding selectivity and antagonist activity of ketanserin and ritanserin, the findings define important pharmacological differences between cloned human 5-HT1D and 5-HT1B receptor sites.

Animals↗
PubMed1996

Promotion of cell growth by stimulation of cloned human 5-HT1D receptor sites in transfected C6-glial cells is highly sensitive to intrinsic activity at 5-HT1D receptors.

5-Hydroxytryptamine (serotonin, 5-HT), essentially known as a neurotransmitter and vasoactive agent, also functions as a mitogen in various cell types through several different second messenger systems. Stimulation of cloned human 5-HT1D receptor sites by sumatriptan in stably transfected rat C6-glial/5-HT1D cells promotes cell growth (Pauwels et al. (1996) Naunyn-Schmiedeberg's Arch Pharmacol 353:144-156). In the present study, the pharmacology of this growth response was investigated using a broad series of 5-HT receptor ligands. The data were compared with the responses obtained by measuring inhibition of forskolin-stimulated cAMP formation. 5-HT (EC50: 25 nM) promoted cell growth of C6-glial/5HT1D cells, and this in contrast to the absence of any measurable effect in pcDNA3-plasmid transfected and non-transfected C6-glial cells. The 5-HT effect could be mimicked by the following compounds (EC50 in nM): zolmitriptan (0.41), 2'-methyl-4'-(-methyl[1,2,4] oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amid (GR 127,935;0.86), naratriptan (0.92), metergoline (1.9), sumatriptan (2.9), (N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl] ethylamine (MK-462; 3.0), and R(+)-8-(hydroxy-2-(di-n-propylamino)tetralin (R(+)-8-OH-DPAT; 30.7). These EC50 -values correspond to the compounds binding affinities at the human 5-HT1D receptor site and, with the exception of GR 127,935 and metergoline also to the EC50-values found by measuring over 5 min inhibition of forskolin (100 microM)-stimulated cAMP formation. Prolonged exposure of GR 127,935(3 h) and metergoline (30 min) to cells yielded EC50 values in the cAMP assay more close to those measured in the mitogenic response. The growth response to sumatriptan, 5-HT, GR 127,935 and metergoline was blocked by the apparently silent antagonist methiothepin, ritanserin and ketanserin with potencies similar to blockade of inhibition of stimulated cAMP formation. The 8-OH-DPAT effect also is likely mediated by 5-HT1D receptors; stereoselectivity was found with its enantiomers at this receptor site and the effect was blocked by ketanserin (1 microM) but not by spiperone (1 microM). Micromolar concentrations of the 5-HT1B receptor agonist 3-(1,2,5,6-tetrahydro)-4-pyridil-5-pyrrolo[3,2-b]pyril-5-one (CP 93,129) and of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl_-2-aminopropane (DOI) induced cell growth with a potency that accorded with the affinity of these compounds for the human 5-HT1D receptor site. These effects were sensitive to ketanserin (1 microM) antagonism, but not to blockade by beta-adrenergic blockers and the 5-HT2 receptor antagonist 2-anilino-N-[2-(3-chlorophenoxy)-propyl] acetamidine hydroiodide (BW 501-C-67). The findings suggest that 5-HT1A, 5-HT1B and 5-HT2 receptors are not implicated in 5-HT-stimulated C6-glial/5-HT1D cell growth. In conclusion, human 5-HT1D receptors are involved in the growth of C6-glial/5-HT1D cells. This cellular response is highly sensitive to the intrinsic activity of compounds at 5-HT1D receptors.

Animals↗
PubMed1996

Stimulation of cloned human serotonin 5-HT1D beta receptor sites in stably transfected C6 glial cells promotes cell growth.

The involvement of serotonin 5-HT1D beta receptor sites was investigated in the growth of rat C6 glial cells permanently transfected with a gene encoding a human 5-HT1D beta receptor. The 5-HT receptor identity of control and transfected C6 glial/5-HT1D beta cells was determined by reverse transcription-polymerase chain reaction using primers specific for rat 5-HT1A, rat 5-HT1B, rat 5-HT1D alpha, human 5-HT1D beta, and rat 5-HT2A receptor genes. Constitutive mRNA for 5-HT2A receptors was present in control and transfected C6 glial/5-HT1D beta cells, whereas mRNA for 5-HT1D beta receptor sites was only present in the transfected C6 glial/5-HT1D beta cell line. 5-HT inhibited forskolin-stimulated cyclic AMP formation and promoted cell growth, in contrast to the absence of any measurable effect in pcDNA3 plasmid-transfected and nontransfected C6 glial cells. The 5-HT effects could be mimicked by sumatriptan (EC50 = 44-76 nM) and were totally and partially blocked by methiothepin (IC50 = 9 nM) and GR 127,935 (2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide; IC50 = 97 pM), respectively. No effect on cell growth was measured with the 5-HT2 receptor agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; 10 microM], suggesting that 5-HT2A receptors are not involved in the 5-HT-stimulated C6 glial/5-HT1D beta cell growth. Dibutyryl-cyclic AMP (0.3 mM)-treated cultures did not show sumatriptan-promoted cell growth, indicating an inhibitory role for cyclic AMP in the cell growth mediated by 5-HT1D beta receptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1995

Differentiation between partial and silent 5-HT1D beta receptor antagonists using rat C6-glial and Chinese hamster ovary cell lines permanently transfected with a cloned human 5-HT1D beta receptor gene.

Intrinsic activities of serotonin (5-HT) receptor ligands at cloned human 5-HT1D beta receptor sites were determined by measuring cAMP responses in two permanently transfected cell types: rat C6-glial and Chinese hamster ovary (CHO)-K1 cells. Both transfected cell lines expressed a similar 5-HT1D beta receptor density (361 to 448 fmol/mg protein) and displayed a number of similar cAMP responses: marked inhibition of forskolin-stimulated cAMP formation by 5-HT; a similar agonist potency and efficacy with 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine, bufotenine, sumatriptan, 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrolo-(1,2-a)quinoxal ine (CGS 12066B), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole (RU 24,969), and tryptamine, their maximal effect being comparable to that of 5-HT; less agonist efficacy with m-trifluoro-phenyl-piperazine (TFMPP) (it inhibited at most 63% of stimulated cAMP formation); and antagonist activity against the 5-CT-mediated agonist response with methiothepin, 2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127,935), and ritanserin. Metergoline and 1-naphtylpiperazine showed different intrinsic activities. In contrast to their pronounced antagonist activity in the transfected CHO-K1 cell line, the antagonist effect was only partial and absent for metergoline and 1-naphtylpiperazine in the transfected C6-glial cell line, respectively. In conclusion, these cell lines are useful as a tool to measure with high sensitivity differences in intrinsic activities of 5-HT receptor ligands and, therefore, discriminate between silent antagonists (no intrinsic activity) and antagonists with intrinsic activity (i.e. partial agonists), even though this intrinsic activity may be relatively weak.

Animals↗
PubMed1995

Can the DRL 72s schedule selectively reveal antidepressant drug activity?

The effects of three antidepressants, desipramine (2.5-20 mg/kg) tranylcypromine (0.63-2.5 mg/kg) mianserin (1.25-10 mg/kg) and three non-antidepressants, chlordiazepoxide (CDP; 1.25-10 mg/kg) haloperidol (0.02-0.16 mg/kg) d-amphetamine (0.31-1.25 mg/kg) were evaluated in rats responding for water reinforcement under a DRL 72s schedule. The antidepressants all produced dose-related decreases in overall response rates, but no significant changes in reinforcement frequency. In contrast, the anxiolytic CDP did increase the number of reinforcers obtained. Haloperidol decreased both reinforcers and responses whilst d-amphetamine stimulated responding, thereby decreasing reinforcement frequency. An analysis of the modes of inter-response times (IRTs) revealed no significant shifts in the peaks of the IRT distributions for most of the drugs tested. Amphetamine, however, (0.31 and 0.63 mg/kg) decreased the modal values in correspondence with the shift to the left of the peak of responding caused by this compound. These results are discussed in the context of the use of the DRL 72s procedure as a screening test for antidepressant drugs.

Animals↗
PubMed1995

Empirical evidence that the state dependence and drug discrimination paradigms can generate different outcomes.

The study compared the outcomes generated by the State Dependence and Drug Discrimination paradigms with ethanol in the rat. Food-deprived rats learned to complete a fixed-ratio 10 schedule of bar presses for food within 120 s while treated with 320- to 1250-mg/kg doses of ethanol. Subsequent tests of recall of this response with saline failed to generate any evidence that transfer was hampered following the drug-to-saline state change. In contrast, each of 14 rats learned to discriminate 1250 mg/kg ethanol from saline in a Drug Discrimination procedure that also required the animals to press one of two levers for food according to a fixed- ratio 10 schedule. The results offer the first empirical evidence to demonstrate directly that the State Dependence and Drug Discrimination paradigms can generate different outcomes in otherwise identical experimental conditions.

Animals↗
PubMed1995

The 5-HT1D receptor antagonist GR 127,935 is an agonist at cloned human 5-HT1D alpha receptor sites.

The cAMP response of the 5-HT1D receptor antagonist GR 127,935 was compared with 5-CT and ketanserin at cloned human 5-HT1D alpha receptor sites in transfected C6-glial cells. GR 127,935 showed marked agonist activity (EC50-value: 141 nM), its maximal effect being comparable to that of the agonist 5-CT (EC50-value: 0.91 nM), unlike the apparently silent antagonist ketanserin (KB-value: 34 nM).

Animals↗
PubMed1995

Ketanserin inhibits the transient outward current in rabbit ventricular myocytes.

The effects of ketanserin on the calcium-independent component of the transient outward potassium current (Ito) was investigated in isolated rabbit ventricular myocytes using the whole-cell patch-clamp technique. Ketanserin concentration-dependently (0.1-100 microM) reduced Ito (IC50 2.25 +/- 2.2 microM; Hill coefficient, nH 0.91), and decreased both the fast and slow Ito inactivation time constants so that the decay of the peak outward current was significantly accelerated. Our results indicate that, in addition to its antagonist activity on 5HT2A/C receptors, ketanserin reduces the calcium-independent component of Ito. Blockade of Ito could explain the proarrhythmic properties of ketanserin in vivo.

Animals↗
PubMed1995

Investigation of the mechanism by which ketanserin prolongs the duration of the cardiac action potential.

Action potential duration (APD) lengthening is believed to underlie the cardiac arrhythmogenicity of ketanserin, a serotonin (5-HT)2A/2C receptor antagonist. We wished to determine (a) whether this activity involves blockade of 5-HT2A/2C receptors and (b) the precise mechanism of ketanserin-induced APD prolongation. APs were recorded in guinea pig isolated papillary muscles by conventional "floating" microelectrodes, and potassium currents in guinea pig isolated myocytes were recorded in the whole-cell configuration. Ketanserin (1-10 microM) increased APD (EC50 value for enhancing APD at 90% repolarization (APD90) 3.1 +/- 2.7 microM, n = 24), without affecting resting potential, maximum upstroke velocity (Vmax) or AP amplitude (APA). Pirenperone (10 microM), a ketanserin congener, similarly increased APD90 from 204 +/- 3 to 241 +/- 7 ms (p < 0.001, n = 6). No increase in APD was observed, however, with ritanserin or ICI 170809, even at high concentrations (10 microM, n = 6, respectively), two 5-HT2A/2C receptor antagonists chemically distinct from ketanserin, thereby excluding the involvement of 5-HT2A/2C receptors in mediating APD lengthening. That APD prolongation was mediated specifically by the benzolyl-piperidine moiety of ketanserin and pirenperone was confirmed by 1-propyl-4(4-fluorobenzoyl)piperidine (PFBP), which evoked APD lengthening effects remarkably similar to those produced by ketanserin and pirenperone (EC50 3.73 +/- 2.6 microM, n = 12). In isolated cardiomyocytes, ketanserin (1-32 microM) selectively and concentration-dependently reduced the IKr component of the delayed outward current (IK) without affecting the inward rectifier current, IK1. Thus, ketanserin (32 microM) significantly reduced IK at a potential value of -20 mV from 813 +/- 65 to 569 +/- 55 pA (p < 0.001, n = 6), whereas at a potential value of -110 mV, IK1 was not significantly affected (730 +/- 103 vs. 603 +/- 143 pA, respectively; n=6). The results demonstrate that APD is prolonged by ketanserin and congeners but not be chemically different 5-HT2A/2C receptor antagonists. The benzoyl-piperidine moiety appears to mediate the APD-prolonging effects of ketanserin and pirenperone specifically. Furthermore, ketanserin-induced APD lengthening does not appear to involve 5-HT2A/2C receptors but is consecutive to direct blockade of myocardial potassium channels.

Action Potentials↗
PubMed1995

Intrinsic activity of the non-prostanoid thromboxane A2 receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in the rat vasculature in vivo.

1. We evaluated the effects of daltroban on (i) human platelet shape change and aggregation in vitro, and (ii) mean systemic and pulmonary arterial pressures (MAP and MPAP, respectively) as well as haematocrit, in anaesthetized, open-chest Sprague-Dawley rats, compared with those of a chemically distinct prostanoid thromboxane A2 (TxA2) receptor antagonist, SQ 29,548, and agonist, U-46619. 2. In human platelets in vitro, daltroban (10 nM-100 microM; n = 6 per group) concentration-dependently induced shape change, attaining at 50 microM, a maximum amplitude of 0.83 +/- 0.09 mV representing 46.4 +/- 4.8% of that evoked by U-46619 (1.78 +/- 0.20 mV at 0.2 microM; n = 9); and inhibited U-46619-induced platelet aggregation with an IC50 of 77 (41-161)nM. SQ 29,548 (10 nM-100 microM; n = 6 per group) failed to evoke any platelet shape change, but potently inhibited U-46619-induced platelet aggregation with an IC50 < 10 nM. 3. In anaesthetized rats in vivo, daltroban (10-2500 micrograms kg-1, i.v. infused over 2 min; n = 4-8 per group) produced a bell-shaped dose-response curve for MPAP and haematocrit, and evoked maximal increases of 12.7 +/- 2.1 mmHg and 5.8 +/- 1.5% at 80 micrograms kg-1 (n = 6) and 630 micrograms kg-1 (n = 8), respectively (both P < 0.05) with ED50s of 20 (16-29) and 217 (129-331) micrograms kg-1, respectively. By comparison, U-46619(0.16-20 microg kg-1, i.v.), induced dose-dependent increases in MPAP and haematocrit (25.4 +/- 1.0 mmHg and 16.1 +/- 2.9% at the highest dose; n = 12, both P<0.01), with ED50s of 1.8 (1.3-2.5) and 3.9(3.5- 5.4) microg kg- 1, respectively. Daltroban dose-dependently increased MAP with a maximum amplitude of 42.2 +/- 4.4 mmHg at a dose of 80 microg kg-1 [ED50 = 94 (64-125) microg kg-1], similar to that induced by U-46619 (41.3 +/- 9.6 mmHg) at a dose of 0.63 microg kg-1 [ED50= 0.22 (0.13-0.24) microg kg-1]. SQ 29,548(10-2500 microg kg-1, i.v.; n =4 per group) failed to modify significantly any of these parameters.4. Our results clearly demonstrate that daltroban, in a similar manner to the TxA2 analogue, U-46619,but unlike the TxA2 receptor antagonist, SQ 29,548, exhibits significant intrinsic activity in human platelets in vitro and in the rat vasculature in vivo, possibly through TxA2 receptor activation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Use of the pithed rat model to determine the relative potencies of 5-HT2A/2C receptor antagonists following acute intravenous and oral administration.

We investigated the usefulness of the pithed rat model to determine the relative potencies of 5-HT2A/2C receptor antagonists following acute intravenous and oral administration in inhibiting 5-HT-induced pressor responses. The 5-HT2A/2C receptor antagonists, pirenperone, ketanserin, and ritanserin, all dose-dependently inhibited 5-HT-induced pressor responses when administered either intravenously 5 min prior to commencing 5-HT injections or acutely via the oral route 30 min before pithing. All three compounds were found to be of comparable potency in inhibiting 5-HT-induced pressor responses when given i.v. (range of ID50s 3.7-27.5 micrograms/kg), whereas substantial differences became apparent after oral administration (range of ID50s 13.0-214.0 micrograms/kg), as reflected also by the p.o./i.v. ID50 ratios for the drugs. In conclusion, inhibition of 5-HT-induced pressor responses in the pithed rat preparation provides a reproducible and robust procedure in which comparisons can be made of relative potencies of 5-HT2A/2C receptor antagonists, not only by the intravenous route, but also following acute oral administration.

Administration, Oral↗
PubMed1993

Inhibition of methylphenidate-induced behaviors in rats: differences among neuroleptics.

Methylphenidate (MPD) increased in rats the incidence of sniffing, rearing and locomotion, and this along dose-response curves that had an inverted U-shape; at 40 mg/kg, MPD exclusively induced stereotyped gnawing, which was inhibited by neuroleptics. However, as gnawing induced by 40 mg/kg MPD was inhibited in a dose-dependent manner, other responses (i.e., sniffing, rearing and locomotion) appeared. Higher doses of neuroleptics also inhibited these latter responses, so that the behavior of the MPD-treated animals became similar to that of normal controls. Only some nonsedative neuroleptics appeared able to normalize the behavior of MPD-treated rats at doses that induced neither complete behavioral suppression nor adverse effects. The neuroleptics differed markedly, however, in terms of the relative doses at which they 1) inhibited gnawing, 2) inhibited the other effects of MPD and 3) induced complete behavioral suppression and/or adverse effects. This variation among neuroleptics, which appears to represent a novel aspect of their ability to antagonize behavioral effects of central nervous system stimulants, may be based on differences in the extent to which they exert agonist activity at dopamine receptors. Assuming that MPD-induced behaviors model the positive symptoms of schizophrenia, it may be hypothesized that the differences among the neuroleptics observed here provide an indication of their efficacy to reduce positive symptoms in schizophrenics.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Effects of phencyclidine-type drugs in rats discriminating fentanyl from saline: pharmacological and behavioral characterization of intermediate levels of drug lever selection.

In rats trained to discriminate 0.04 mg/kg fentanyl from saline, phencyclidine (PCP) and the PCP-type drugs ketamine and (+/- )-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine produced effects that are usually referred to as partial generalization. Partial generalization could conceivably result from low efficacy actions at the receptor mediating the discriminative stimulus effects of the training drug. The PCP-type drugs produced maximum percentages of drug lever (DL) selection intermediate between those produced by the training conditions, but their curves relating dose to percentage of DL selection were not shallower than that of fentanyl. The PCP-type drugs decreased DL selection produced by the training dose of fentanyl, but there was no relationship between these antagonist effects and the DL selection produced by the PCP-type drugs when given alone. Naltrexone antagonized DL selection produced by fentanyl, but not that produced by the PCP-type drugs. The potency order of the PCP-type drugs to produce DL selection was in agreement with their relative affinities for PCP receptors, but not with those for morphine receptors. The intermediate levels of DL selection produced by the PCP-type drugs were associated with increased lever selection latencies and increased responding on the nonselected lever; this pattern of effects resembled the behavior of animals that had not yet acquired the discrimination. The results suggest that PCP-type drugs produce intermediate levels of drug-appropriate responding in fentanyl-trained rats through mechanisms involving not opioid receptors and partial generalization, but involving PCP receptors and performance deficits conceivably resulting from state dependency. Thus, the results stress the importance of a pharmacological and behavioral analysis of intermediate responding in drug discrimination to examine its validity as a measure of efficacy and of stimulus similarity.

Animals↗
PubMed1992

Suppression of nigrostriatal and mesolimbic dopamine release in vivo following noradrenaline depletion by DSP-4: a microdialysis study.

Pretreatment of rats with the noradrenergic neurotoxin DSP-4 selectively reduced regional levels of noradrenaline in the brain by more than 75%, and decreased the concentration of endogenous DA in microdialysates of the caudate nucleus and nucleus accumbens by 52% and 28%, respectively. Results support the hypothesis that central noradrenergic mechanisms facilitate nigrostriatal and mesolimbic dopamine transmission in vivo.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Behavioral pharmacology of antagonists at 5-HT2/5-HT1C receptors.

The possible implication of 5-HT2 receptors in CNS disorders such as schizophrenia, anxiety and depression suggests that 5-HT2 antagonists may be useful in the treatment of these disorders. The present review examines behavioral procedures used to characterize 5-HT2 antagonist properties of compounds and behavioral models of clinical activity in which 5-HT2 antagonists have been reported to be active. The pharmacological profile of 5-HT2 receptors in part resembles that of 5-HT1C receptors. Responses that have been proposed to involve the activation of 5-HT1C receptors are examined for their usefulness to detect 5-HT1C antagonist properties of compounds; these responses would help to differentiate 5-HT2 from 5-HT1C antagonist activity.

Animals↗
PubMed1991

Differential modulation of (+)-amphetamine-induced rotation in unilateral substantia nigra-lesioned rats by alpha 1 as compared to alpha 2 agonists and antagonists.

In rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra (SN), the indirect dopaminergic agonist, (+)-amphetamine (AMPH), dose-dependently induced robust, ipsilateral rotation: this could be dose-dependently abolished by the dopamine (D2/D1) antagonist, haloperidol. The selective alpha 1 antagonist, prazosin, dose-dependently attenuated the action of AMPH though rotation was not completely abolished. In the presence of a constant dose of prazosin, the dose-response curve for induction of rotation by AMPH was shifted to the right. The action of prazosin was mimicked by a further alpha 1 antagonist, corynanthine. In contrast, the selective alpha 1 agonist, ST 587, potentiated the rotation evoked by AMPH. The selective alpha 2 antagonist, idazoxan, dose-dependently potentiated the action of AMPH and, in the presence of a constant dose of idazoxan, the dose-response curve for AMPH was shifted to the left. This effect of idazoxan was mimicked by a further alpha 2 antagonist, yohimbine. In distinction, the selective alpha 2 agonist, UK 14,304, dose-dependently attenuated the action of AMPH, an action mimicked by the alpha 2 partial agonist, clonidine. Upon administration alone, the above mentioned drugs did not induce rotation. The data indicate that activation and antagonism of alpha 1 receptors enhance and inhibit rotation, respectively, whereas activation and antagonism of alpha 2 receptors inhibit and enhance rotation, respectively. These findings demonstrate an opposite alpha 1 and alpha 2 receptor-mediated control of rotation in this model. They suggest that an increase and decrease in noradrenergic tone, respectively, facilitate and inhibit locomotor activity controlled via the nigro-striatal dopaminergic pathway. The possible relevance of these findings to Parkinson's disease is discussed.

Adrenergic alpha-Agonists↗