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At least 1,225 records · Page 68Linked to original sources
PubMed1997

Motor depressant effects mediated by dopamine D2 and adenosine A2A receptors in the nucleus accumbens and the caudate-putamen.

We compared hypolocomotion and catalepsy mediated by striatal dopamine D2 and adenosine A2A receptors using microinfusions of the adenosine A2A receptor agonist 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS21680) and the dopamine D2 receptor antagonist raclopride into the nucleus accumbens and the caudate-putamen. The effective doses (ED25/50) of CGS21680 and raclopride which produced equivalent reductions of spontaneous locomotion after microinfusion into the nucleus accumbens were found to induce similar degrees of catalepsy after microinfusion into the caudate-putamen. This comparable, little separation of the effective doses of a dopamine D2 receptor antagonist and an adenosine A2A receptor agonist to produce locomotor inhibition and catalepsy support the idea that adenosine A2A receptor agonists as potential antipsychotic agents may have a similar therapeutic profile as dopamine D2 receptor antagonists.

Adenosine↗
PubMed1997

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant.

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT1A receptor agonist and 5-HT2 receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D2/D3 receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D2/D3 receptor-mediated transmission.

Animals↗
PubMed1997

Dopamine receptor antagonists block nerve growth factor-induced hyperactivity.

The role of dopamine receptors in mediating nerve growth factor (NGF)-induced locomotor stimulation was investigated by examining the effects of selective dopamine D1 and D2 receptor antagonists on the motor hyperactivity induced by NGF. A single intracerebroventricular administration of NGF (5.1 microg) increased locomotor activity immediately after injection in normal adult rats. This hyperactivity was partly blocked by the dopamine D1 receptor antagonist SCH23390 (R-(+)-7-chloro-2,3,4,5-tetrahydro-3-methyl-1-phenyl-1H-3-benzazepine-8- ol) and by the dopamine D2 antagonist raclopride ((S)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2-hydroxy-6-methoxy benzamide). Effective doses of raclopride did not alter spontaneous levels of activity in control rats. These results suggest that stimulation of both subtypes of dopamine receptors is necessary for eliciting NGF-induced hyperactivity in the rat. The role of the dopamine D2 receptor in mediating the behavioral actions of NGF appears to be more important than that of the dopamine D1 receptor.

Animals↗
PubMed1998

Interactions of ligands with active and inactive conformations of the dopamine D2 receptor.

The affinities of 19 pharmacologically diverse dopamine D2 receptor ligands were determined for the active and inactive conformations of cloned human dopamine D2 receptors expressed in Ltk cells. The agonist [3H]quinpirole was used to selectively label the guanine nucleotide-binding protein-coupled, active receptor conformation. The antagonist [3H]raclopride, in the presence of the non-hydrolysable GTP-analogue Gpp(NH)p and sodium ions and in the absence of magnesium ions, was used to label the free inactive receptor conformation. The intrinsic activities of the ligands were determined in a forskolin-stimulated cyclic AMP assay using the same cells. An excellent correlation was shown between the affinity ratios (KR/KRG) of the ligands for the two receptor conformations and their intrinsic activity (r=0.96). The ligands included eight structurally related and enantiopure 2-aminotetralin derivatives; the enantiomers of 5-hydroxy-2-(dipropylamino)tetralin, 5-methoxy-2-(dipropylamino)tetralin, 5-fluoro-2-(dipropylamino)tetralin and 2-(dipropylamino)tetralin. The (S)-enantiomers behaved as full agonists in the cyclic AMP assay and displayed a large KR/KRG ratio. The (R)-enantiomers were classified as partial agonists and had lower ratios. The structure-affinity relationships of these compounds at the active and the inactive receptor conformations were analysed separately, and used in conjunction with a homology based receptor model of the dopamine D2 receptor. This led to proposed binding modes for agonists, antagonists and partial agonists in the 2-aminotetralin series. The concepts used in this study should be of value in the design of ligands with predetermined affinity and intrinsic activity.

Cells, Cultured↗
PubMed1998

Similar pharmacological properties of 8-OH-DPAT and alnespirone (S 20499) at dopamine receptors: comparison with buspirone.

Alnespirone (S 20499) has previously been described as a potential anxiolytic drug that acts by stimulation of 5-HT1A receptors. Some data suggest that alnespirone might also be a weak dopamine D2 receptor agonist: it displays moderate affinity for dopamine D2 receptors in vitro and it inhibits prolactin release and induces yawning in rats. In order to test for possible interactions of alnespirone with dopamine receptors in vivo, we studied the changes of in vivo striatal [3H]SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benza zepine) and [3H]raclopride binding following the injection of a tracer dose of either tritiated ligand (4 microCi) in mice treated with increasing doses of alnespirone (5, 10, 20 and 40 mg/kg, i.p.) and, in the same animals, the changes in the levels of dopamine, 5-hydroxytryptamine (5-HT) and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). These changes were compared with those produced by increasing doses of the reference 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin, 0.25, 1 and 4 mg/kg, i.p.) or buspirone (5 and 20 mg/kg, i.p.). Decreased in vivo striatal [3H]SCH 23390 specific binding was observed in mice treated with 5, 10 and 40 mg/kg alnespirone. In contrast, increased in vivo striatal [3H]raclopride specific binding was observed in mice treated with 5 and 20 mg/kg alnespirone. In these animals, the striatal 5-HIAA/5-HT ratio was decreased by 5 to 40 mg/kg alnespirone, whereas the striatal HVA/DA ratio was unaffected at all tested doses of alnespirone. Similarly, 8-OH-DPAT decreased specific in vivo striatal [3H]SCH 23390 binding at 0.25, 1 and 4 mg/kg, and increased in vivo specific striatal [3H]raclopride binding at 1 and 4 mg/kg. In the same animals, all tested doses of 8-OH-DPAT decreased the striatal 5-HIAA/5-HT ratio but did not modify the striatal HVA/dopamine ratio. Buspirone (5 and 20 mg/kg) completely inhibited in vivo specific striatal [3H]raclopride binding and increased the striatal HVA/DA ratio but did not modify the striatal 5-HIAA/5-HT ratio, whereas apomorphine (3 mg/kg) decreased both in vivo specific striatal [3H]SCH 23390 and [3H]raclopride binding as well as the striatal HVA/DA and 5-HIAA/5-HT ratios. Finally, increasing doses of alnespirone or 8-OH-DPAT weakly increased sniffing induced by apomorphine (0.75 mg/kg, s.c.) in mice and decreased grooming induced by the dopamine D1 receptor agonist SK&F 39393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, 1.87 mg/kg, s.c.), whereas buspirone decreased both apomorphine-induced sniffing and SK&F 39393-induced grooming. These results indicate that alnespirone and 8-OH-DPAT have a similar profile and do not seem to interact directly with dopamine receptors. The results also suggest that the stimulation of 5-HT1A receptors by either alnespirone or 8-OH-DPAT modulates the availability of striatal [3H]SCH 23390 and [3H]raclopride binding sites and possibly the functioning of striatal dopamine D1 and D2 receptors in opposite directions.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

The cataleptogenic effects of the neuroleptic nemonapride are attenuated by its 5-HT1A receptor agonist properties.

The effects of the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cycloh exanecarboxamide (WAY 100635) on catalepsy induced by the dopamine D2-like receptor antagonist/5-HT1A receptor agonist nemonapride were examined and compared to its effects on catalepsy induced by neuroleptics that have low affinity for 5-HT1A receptors. Nemonapride induced catalepsy in both cross-legged position and bar tests at low, but not at high doses. Pretreatment with WAY 100635 (0.63 mg/kg) reinstated catalepsy at higher doses of nemonapride, indicating that the 5-HT1A receptor agonist properties of nemonapride are responsible for its inability to produce catalepsy at high doses. Additionally, WAY 100635 enhanced significantly the effects of low doses of nemonapride, and of the dopamine D2-like receptor antagonists raclopride and haloperidol. The present data indicate that the 5-HT1A receptor agonist properties of nemonapride attenuate its ability to induce catalepsy at higher doses, and suggest further that tonic 5-HT1A receptor activation may modulate neuroleptic-induced catalepsy.

Animals↗
PubMed1998

Autonomic mechanisms in the acute cardiovascular effects of cocaine in conscious rats.

We studied the differential involvement of central dopaminergic activation and autonomic nervous system regulatory mechanisms in the cardiovascular responses to cocaine in conscious rats. Sprague-Dawley rats, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were instrumented with catheters in the jugular vein and abdominal aorta at least 5 days before the experiment. Intravenous administration of cocaine (0.1-3.0 mg/kg) caused a dose-dependent increase in blood pressure that was biphasic, with a large and rapid increase peaking at 10 s, followed by a mild sustained pressor response. Pressor responses to cocaine were significantly greater in SHR when compared to WKY rats. However, pretreatment with dopamine D1 receptor antagonist SCH 23390 or the D2 receptor antagonist raclopride did not influence the effects of cocaine. Pretreatment with the alpha-adrenoceptor antagonist phentolamine or the ganglion blocker pentolinium blocked the peak response and reversed the more sustained response into a depressor effect. While pretreatment with propranolol alone did not alter the responses to cocaine, in rats pretreated with phentolamine and propranolol neither a pressor response nor a depressor response was observed. In conclusion, cocaine administration caused marked, but short lasting pressor responses that were mediated by sympathetic activation and alpha-adrenoceptor vasoconstriction with little involvement of central dopaminergic mechanisms. The rapid return of blood pressure towards baseline may be mediated by sympathoinhibition and beta-adrenoceptor-mediated vasodilatation, the latter of which being particularly prominent when alpha-adrenoceptor activation was prevented.

Acute-Phase Reaction↗
PubMed1999

The thyrotrophin-releasing hormone analogue MK771 induces tic-like behaviours: the effects of dopamine D1 and D2 receptor antagonists.

Thyrotrophin-releasing hormone (TRH) and its analogues induce tic-like behaviours in rodents such as blinking and forepaw licking. Changes in spontaneous blinking frequency are observed in several disease states with dopamine abnormalities and dopaminergic agents modulate blinking. We have therefore investigated the effects of dopamine D1 and D2 receptor antagonists on TRH analogue (1-pyro-2-aminoadipyl-L-histidyl-L-thiazolidine-4-carboxamide; MK771)-induced blinking and bouts of forepaw licking. MK771 (2.5 mg/kg)-induced blinking was not attenuated by the dopamine D1 receptor antagonists (+)-7-chloro-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro(1H)-3-benzazep ine maleate (SCH23390) (0.01, 1.0 and 5.0 mg/kg) and ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5- H-benz[2,1b]azepine (SCH39166; 1.0 and 5.0 mg/kg) or the dopamine D2 receptor antagonists raclopride (3.0 and 5.0 mg/kg) and sulpiride (5.0 and 10.0 mg/kg). D1 but not D2 receptor antagonists attenuated MK771-induced forepaw licking. MK771-induced blinking, therefore, appears not to involve dopamine D1 or D2 receptors and contrary to previously held belief dopamine does not appear to be pivotal in the control of blinking, while MK771-induced forepaw licking is modulated by dopamine D1 but not D2 receptors.

Animals↗
PubMed1999

Chronic haloperidol alters dopamine receptors: effects of cocaine exposure during the preweaning period.

The effect of cocaine exposure during the preweaning period on the function of the central dopaminergic systems was determined in adult rats. The present study investigated the alterations in dopamine receptors in 93-day-old male and female rats treated with cocaine (50 mg kg(-1) day(-1)), 1-[2-[bis(4-fluorophenyl)methoxyl]-4-[3-phenylpropyl]piperazine (GBR 12909) (50 mg kg(-1) every other day) or water during postnatal days 11-20. Haloperidol (2 mg kg(-1) day) or saline was injected during postnatal days 76-90 and the rats were killed on postnatal day 93. Quantitative receptor autoradiography with [3H]R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-b enzazepine ([3H]SCH 23390) for the dopamine D1 receptor and [3H]raclopride for the dopamine D2 receptor was carried out. The results show that haloperidol increased [3H]raclopride binding in many forebrain regions. Preweaning cocaine treatment in males increased the area showing this effect. Males generally were more responsive to haloperidol than females. However, in GBR 12909-treated females, raclopride binding showed widespread increases following haloperidol injection. For SCH 23390 binding, most regions showed a significant interaction between haloperidol, sex and preweaning treatment group. This was due primarily to the GBR 12909-treated males, which showed elevated basal dopamine D1 receptor binding levels and a haloperidol-induced reduction in dopamine D1 receptor binding in most regions evaluated. These data suggest that inhibition of the dopamine transporter during ontogeny produces long-term alterations in dopamine receptor regulation but that selective inhibitors of the dopamine transporter produced greater effects than cocaine on both raclopride and SCH 23390 binding following chronic haloperidol injection.

Animals↗
PubMed1999

Clozapine pre-treatment enhances raclopride catalepsy.

The clinical replacement of clozapine by another antipsychotic sometimes causes extrapyramidal signs, including dystonia, to appear suddenly. The present study was done, therefore, to test whether clozapine pre-treatment of rats could affect raclopride-induced catalepsy. Clozapine, at 5 mg/kg, given 2 h before a catalepsy-threshold dose of 0.1 mg/kg raclopride, markedly enhanced raclopride-induced catalepsy in the rats. The results are compatible with earlier in vitro data where pre-exposure of human cloned dopamine D2 receptors to clozapine resulted in an increased potency of raclopride in inhibiting the binding of [3H]clozapine to the receptors. The mechanism of clozapine potentiation of raclopride action may contribute to the clinically observed post-clozapine dystonia.

Animals↗
PubMed2001

Early signaling components in ultraviolet-B responses: distinct roles for different reactive oxygen species and nitric oxide.

The nature and origin of the reactive oxygen species (ROS) involved in the early part of Ultraviolet-B (UV-B)-induced signaling pathways were investigated in Arabidopsis thaliana using a range of enzyme inhibitors and free radical scavengers. The increase in PR-1 transcript and decrease in Lhcb transcript in response to UV-B exposure was shown to be mediated through pathways involving hydrogen peroxide (H(2)O(2)) derived from superoxide (O(2)(&z.rad;-)). In contrast, the up-regulation of PDF1.2 transcript was mediated through a pathway involving O(2)(&z.rad;-) directly. The origins of the ROS were also shown to be distinct and to involve NADPH oxidase and peroxidase(s). The up-regulation of Chs by UV-B was not affected by ROS scavengers, but was reduced by inhibitors of nitric oxide synthase (NOS) or NO scavengers. Together these results suggest that UV-B exposure leads to the generation of ROS, from multiple sources, and NO, through increased NOS activity, giving rise to parallel signaling pathways mediating responses of specific genes to UV-B radiation.

Acyltransferases↗
PubMed1997

Inhibition of the alternative oxidase stimulates H2O2 production in plant mitochondria.

The hypothesis that a non-coupled alternative oxidase of plant mitochondria operates as an antioxygen defence mechanism [Purvis, A.C. and Shewfelt, R.L., Physiol. Plant. 88 (1993) 712-718; Skulachev, V.P., Biochemistry (Moscow) 59 (1994) 1433-1434] has been confirmed in experiments on isolated soybean and pea cotyledon mitochondria. It is shown that inhibitors of the alternative oxidase, salicyl hydroxamate and propyl gallate strongly stimulate H2O2 production by these mitochondria oxidizing succinate. Effective concentrations of the inhibitors proved to be the same as those decreasing the cyanide-resistant respiration. The inhibitors proved to be ineffective in stimulating H2O2 formation in rat liver mitochondria lacking the alternative oxidase.

Animals↗
PubMed1990

Separation and determination of the ingredients of a cold medicine by micellar electrokinetic chromatography with bile salts.

The separation of fourteen active ingredients used in a cold medicine was investigated by micellar electrokinetic chromatography (EKC) employing bile salts. Basic drugs were also successfully separated by micellar EKC using bile salts with high theoretical plate numbers (2.0 x 10(5)-3.5 x 10(5)) within a relatively short time (ca. 20 min). The separation of these solutes by micellar EKC was not successful using sodium dodecyl sulphate. The effects of micellar concentration, pH and organic modifier content on migration times and selectivity were investigated. This technique was also applied to the determination of several active ingredients combined in commercial preparations by an internal standard method.

Acetaminophen↗