Effects of (R)-8-OH-DPAT and the enantiomers of UH-301 on motor activities in the rat: antagonism of (R)-8-OH-DPAT-induced effects

Björk, Lena; Fredriksson, Anders; Hacksell, Uli; Lewander, Tommy

doi:10.1016/0924-977x(92)90024-3

Cited by 22 publications

(9 citation statements)

References 16 publications

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“…the effect may be baseline-dependent. This is confirmed by the findings of Bjork et al (1992) who tested rats either unhabituated or habituated in cages similar to the home cages. In this study (R)-8-OH-DPAT increased locomotor activity, and this increase was antagonized by (S)-UH-301.…”

Section: 'Y~vsupporting

confidence: 76%

The effect of 5‐HT_1A receptor agonists on locomotor activity in the guinea‐pig

Evenden

1994

British J Pharmacology

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1 The present study examined the effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), flesinoxan, ipsapirone and buspirone, all agonists at the 5-HTIA receptor, on the locomotor activity of guinea-pigs. The effects of these drugs were contrasted with those of the non-selective 5-HT agonist, 5-methoxy-N,N-dimethyl tryptamine (5-MeO-DMT) and the dopamine D2 antagonist, raclopride. 2 8-OH-DPAT, flesinoxan and 5-MeO-DMT markedly increased the locomotor activity of naive, unhabituated guinea-pigs in a dose-dependent manner. Buspirone also did so, although to a lesser extent and for a shorter time. The doses at which this effect was seen were higher than those normally employed in rats. Ipsapirone and raclopride had no significant effects on locomotor activity. 3 The locomotor activity increasing effect of 1.0 mg kg-' 8-OH-DPAT was blocked by the selective 5-HTA antagonist (S)-UH-301 (3.0 and 10.0mg kg-'), but not by (-)-alprenolol (15.0mg kg-'). Ipsapirone (30.0mgkg-') and raclopride (3.0mgkg-') antagonized 8-OH-DPAT-induced locomotor activity but only to a small extent. The 5-HT reuptake inhibitor, zimelidine (10.0 mg kg-') had no effect.4 The effect of the 5-HTIA agonists in the guinea-pig contrasts with the effects of 8-OH-DPAT on the locomotor activity of unhabituated rats and mice tested in the same apparatus, but are similar to the effects of 8-OH-DPAT on habituated rats, which show a low baseline of activity. 5These results support the suggestion that 5-HTIA agonists may have an intrinsic activating effect which may be masked by other effects of the drug (e.g. hypothermia, 5-HT syndrome). The rank ordering of the 5-HTIA agonists also suggests that the degree to which the drugs increase locomotor activity is related to their agonist efficacy at the postsynaptic 5-HTIA receptor.

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Section: 'Y~vsupporting

confidence: 76%

The effect of 5‐HT_1A receptor agonists on locomotor activity in the guinea‐pig

Evenden

1994

British J Pharmacology

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“…Together this provides the picture of a stereotyped forward locomotion along the walls of the arena. This pattern of activity is strongly supported by a topographical analysis of the distribution of activity within the open-field (Estival & Hillegaart, unpublished results), and provides a good explanation for the different effects on motor activity in normal rats reported for 8-OH-DPAT, depending on experimental conditions (Mittman & Geyer 1989;Bjork et al 1992;Kalkman & Soar 1990;Evenden & Angeby-Moller 1990). The effects on spontaneous motor activity produced by 8-OH-DPAT can be blocked by (-)pindolo1 (Johansson & Ahlenius 1989), and are at least partially mediated via forebrain (postsynaptic) ~-H T , A receptors (Hillegaart et a!.…”

Section: Discussionsupporting

confidence: 55%

Antagonism of Reserpine‐Induced Suppression of Spontaneous Motor Activity by Stimulation of 5‐HT_1A Receptors in Rats

Ahlénius¹,

Salmi²

1995

Pharmacology & Toxicology

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The 5-HT1A and the DA D2 receptor agonists 8-OH-DPAT (0.05-3.2 mg kg-1 subcutaneously, -20 min.) and quinpirole (0.08-1.25 mg kg-1 subcutaneously, -20 min.), respectively, both partially antagonized reserpine-induced (5 mg kg-1 subcutaneously, -16 hr) suppression of spontaneous motor activity in the rat. Four different aspects of the spontaneous motor activity were recorded in a photocell-equipped open-field (8 x 8 photocells, 90 mm apart, defining two horizontal planes): locomotor activity (all photocell counts at the lower level); rearing (all photocell counts at the upper level); forward locomotion (the proportion movements across the arena); peripheral activity (the proportion locomotor activity as picked up by the photocell beam closest to the wall, i.e. 25 mm). As defined by these variables, the pattern of activity produced by 8-OH-DPAT or quinpirole were indistinguishable. The effects produced by 8-OH-DPAT were fully antagonized by the 5-HT1 antagonist (-) pindolol (4 mg kg-1 subcutaneously, -30 min.), but not by the DA D2 receptor antagonist raclopride (2 mg kg-1 subcutaneously, -30 min.) nor by the 5-HT2 receptor antagonist ritanserin (2 mg kg-1 subcutaneously, -30 min.), whereas effects produced by quinpirole were fully antagonized by raclopride (2 mg kg-1 subcutaneously, -30 min.). Effects produced by quinpirole, but not 8-OH-DPAT, were potentiated by administration of the DA D1 agonist SKF-38,393 (3 mg kg-1 subcutaneously, -20 min.). It is concluded that effects by 8-OH-DPAT on spontaneous motor activity in the reserpine treated rat primarily are due to stimulation of postsynaptic 5-HT1A receptors.

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“…To further substantiate the protective role of 5-HT1A receptor stimulation against NMDA-induced caspase-3 activation, we used the recently available UH-301 enantiomers; the R-UH-301 enantiomer acts as a 5-HT1A agonist and the S-UH-301 isomer is a 5-HT1A antagonist (Bjork et al, 1992). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

Madhavan

Freed

Anantharam

et al. 2002

J Pharmacol Exp Ther

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Apoptosis and glutamate-mediated excitotoxicity may play a role in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we investigated whether stimulation of the 5-hydroxytryptamine 1A (5-HT1A) receptor attenuates N-methyl-D-aspartate-(NMDA) and 1-methyl-4-phenylpyridinium (MPP ϩ )-induced apoptotic cell death in cell culture models. A brief exposure (20 min) of M213-2O striatal cells to NMDA and glutamate produced a delayed increase in caspase-3 activity and DNA fragmentation in a dose-and time-dependent manner. NMDA-induced caspase-3 activity and DNA fragmentation were almost completely blocked by the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and (R)-5-fluoro-8 hydroxy-2-(dipropylamino)-tetralin (R-UH-301). Additionally, the protective effects of 8-OH-DPAT and R-UH-301 on NMDA-induced caspase-3 activation and apoptosis were reversed by pretreatment with the 5-HT1A antagonists N- [2-[4-(2-methoxyphenyl(WAY 100635) and S-UH-301, respectively. Similarly, doseand time-dependent increases in caspase-3 activity and DNA fragmentation were observed in rat primary mesencephalic neurons after a brief exposure to NMDA and glutamate. Caspase-3 activation and DNA fragmentation in primary mesencephalic neurons were almost completely inhibited by 8-OH-DPAT. This neuroprotective effect of 8-OH-DPAT was reversed by WAY 100635. Additionally, 8-OH-DPAT blocked tyrosine hydroxylase (TH)-positive cell death after NMDA exposure and also almost completely attenuated the NMDA-induced Ca 2ϩ influx in primary mesencephalic cultures. Furthermore, 8-OH-DPAT and R-UH-301 blocked apoptotic cell death in the primary mesencephalic neurons that were exposed to the Parkinsonian toxin MPP ϩ . Together, these results suggest that 5-HT1A receptor stimulation may be a promising pharmacological approach in the development of neuroprotective agents for PD.Parkinson's disease (PD) is a major neurodegenerative disorder with a lifetime incidence of 1 to 2%. The drug L-DOPA has been the gold standard PD treatment for more than three decades now and can bring considerable relief from the debilitating symptoms of the disease. However, its long-term use has several limitations, including severe fluctuations in effectiveness and drug-induced involuntary movements (Fahn, 1999;Carlsson, 2002). Importantly, L-DOPA simply compensates for the dopamine deficiency in Parkinson's patients and fails to attenuate the progression of the disease. Hence, novel neuroprotective agents designed to interfere with the basic pathogenic mechanism of cell death in PD are clearly needed.Excitotoxic mechanisms may contribute to the nigrostriatal degeneration in PD (Greenamyre, 1993;Olanow and Tatton, 1999). Glutamate binds to a variety of excitatory amino acid receptors, especially the NMDA receptor, leading to prolonged and excessive depolarization and neuronal activation resulting in the death of target neurons (Choi, 1988;

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Effects of (R)-8-OH-DPAT and the enantiomers of UH-301 on motor activities in the rat: antagonism of (R)-8-OH-DPAT-induced effects

Cited by 22 publications

References 16 publications

The effect of 5‐HT_1A receptor agonists on locomotor activity in the guinea‐pig

The effect of 5‐HT_1A receptor agonists on locomotor activity in the guinea‐pig

Antagonism of Reserpine‐Induced Suppression of Spontaneous Motor Activity by Stimulation of 5‐HT_1A Receptors in Rats

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

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Effects of (R)-8-OH-DPAT and the enantiomers of UH-301 on motor activities in the rat: antagonism of (R)-8-OH-DPAT-induced effects

Cited by 22 publications

References 16 publications

The effect of 5‐HT1A receptor agonists on locomotor activity in the guinea‐pig

The effect of 5‐HT1A receptor agonists on locomotor activity in the guinea‐pig

Antagonism of Reserpine‐Induced Suppression of Spontaneous Motor Activity by Stimulation of 5‐HT1A Receptors in Rats

5-Hydroxytryptamine 1A Receptor Activation Protects againstN-Methyl-d-aspartate-Induced Apoptotic Cell Death in Striatal and Mesencephalic Cultures

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The effect of 5‐HT_1A receptor agonists on locomotor activity in the guinea‐pig

The effect of 5‐HT_1A receptor agonists on locomotor activity in the guinea‐pig

Antagonism of Reserpine‐Induced Suppression of Spontaneous Motor Activity by Stimulation of 5‐HT_1A Receptors in Rats