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1.
Joanna Listos Sylwia Talarek Sylwia Fidecka 《Pharmacology, biochemistry, and behavior》2010,94(4):510-515
In the present study the effect of adenosinergic system on the development of diazepam tolerance to motor disturbances in mice was investigated. Diazepam tolerance was obtained by administration of diazepam at a dose of 5.0 mg/kg, s.c. for ten consecutive days. On the 1st and the 10th day of the experiment motor impairments were measured in two behavioural tests: rota-rod and chimney test. We showed that acute diazepam injection produced significant motor impairments in mice and that effect was decreased by repeated diazepam treatment, confirming the development of tolerance to the motor impairing effect of diazepam. We demonstrated that adenosine A1 and/or A2A receptor agonists: CPA (0.025 and 0.05 mg/kg, i.p.), CGS 21680 (0.1 and 0.2 mg/kg, i.p.), NECA (0.005 and 0.01 mg/kg, i.p.) pretreatment with diazepam were able to attenuate the development of diazepam tolerance and adenosine receptor antagonists: DPCPX (1.0 and 3.0 mg/kg, i.p.), DMPX (3.0 and 6.0 mg/kg, i.p.) and caffeine (10.0 and 20.0 mg/kg, i.p.) induced the opposite effect. The most apparent effects were obtained by non-selective agonist (NECA) and antagonist (caffeine) of adenosine receptors. We conclude that adenosinergic system plays an important role in mechanisms underlying the development of benzodiazepine tolerance. 相似文献
2.
Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the control of motor activity. However, there are few studies investigating this interaction in other brain regions and its role in additional functions. In the present study, we evaluated whether reserpine-treated rats (1.0 mg/kg, i.p.) exhibit altered social recognition memory abilities. The effects of acute administration of the dopamine receptor agonists 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine (SKF 38393, dopamine D(1) receptor agonist) and quinpirole (dopamine D(2) receptor agonist), together with the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A(1) receptor antagonist) and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A(2A) receptor antagonist), were also investigated. Twenty-four hours after treatment, reserpine-treated rats exhibited a significant disruption in the ability to recognize a juvenile rat after a short period of time. These animals did not show any motor deficit. The social recognition disruption induced by reserpine was reversed by acute treatment with quinpirole (0.05-0.1 mg/kg, i.p.), caffeine (10.0-30.0 mg/kg, i.p.) or ZM241385 (0.5-1.0 mg/kg, i.p.), but not with SKF 38393 (0.5-3.0 mg/kg, i.p.) or DPCPX (0.5-3.0 mg/kg, i.p.). Moreover, a synergistic response was observed following the co-administration of 'non-effective' doses of ZM241385 (0.1 mg/kg, i.p.) and quinpirole (0.01 mg/kg, i.p.). These results reinforce and extend the notion of antagonistic interactions between adenosine and dopamine receptors, and demonstrate, for the first time, that the blockade of adenosine A(2A) receptors and the activation of dopamine D(2) receptors can reverse the social recognition deficits induced by reserpine in rats. 相似文献
3.
The anxiolytic property of ethanol is generally accepted to be an important motivational factor for its consumption and the development of alcohol dependence. Recent studies suggest that adenosine receptors mediate important actions of ethanol, such as motor incoordination and hypnotic effects. In addition, several lines of evidence support the involvement of adenosine in anxiety. The aim of the present study was to evaluate the role of adenosine receptors in the anxiolytic-like effect of ethanol in mice. The effects of acute administration of the adenosine receptor antagonists caffeine (nonselective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A1 receptor antagonist) and 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A(2A) receptor antagonist), together with the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), and their interaction with ethanol in the elevated plus-maze test in mice were studied. The highest doses of caffeine (30.0 mg/kg, i.p.) and DPCPX (6.0 mg/kg, i.p.) produced an anxiogenic-like effect, while CCPA administration (0.25 mg/kg, i.p.) showed an anxiolytic-like activity. The prior administration of "non-anxiogenic" doses of caffeine (10.0 mg/kg, i.p.) and DPCPX (3.0 mg/kg, i.p.), but not ZM241385 (1.0 mg/kg, i.p.), significantly reduced the anxiolytic-like effect of ethanol (1.2 g/kg, i.p.). Moreover, anxiolytic-like response was observed by the co-administration of "non-anxiolytic" doses of CCPA (0.125 mg/kg) and ethanol (0.6 g/kg). These results reinforce the involvement of adenosine in anxiety and suggest that the activation of adenosine A1 receptors, but not adenosine A(2A) receptors, mediate the anxiolytic-like effect induced by ethanol in mice. 相似文献
4.
Carina R. Boeck Caroline Martinello Adalberto A. de Castro Morgana Moretti Tiago dos Santos Casagrande Remo Guerrini Girolamo Calo’ Elaine C. Gavioli 《Naunyn-Schmiedeberg's archives of pharmacology》2010,381(2):153-160
Neuropeptide S (NPS) is the endogenous ligand of a G-protein-coupled receptor named as NPSR. Behavioral effects have been recently attributed to NPS, i.e. hyperlocomotion, anxiolysis, and wakefulness. However, little is known about the mechanisms by which NPS evokes such biological actions. The present study aimed to investigate the role played by the adenosine A2A and A1 receptors in hyperlocomotion induced by NPS. Spontaneous locomotion was assessed in an activity cage for 30 min in mice acutely treated with caffeine (a nonselective adenosine receptor antagonist), ZM241385 (a selective A2A receptor antagonist), or CPT (a selective A1 receptor antagonist) before NPS challenge (0.1 nmol, i.c.v.), which induce hyperlocomotion in mice. The pretreatment with caffeine (3 mg/kg, i.p.), in an inactive dose per se, prevented the increase in locomotion evoked by NPS. The co-administration of NPS (0.1 nmol, i.c.v.) and ZM241385 (0.1 pmol, i.c.v.) counteracted hyperlocomotion evoked by NPS. The co-administration of NPS and CPT (0.1 pmol, i.c.v.) slightly facilitated the increase in locomotion evoked by NPS alone. In summary, the pharmacological blockade of A2A receptors significantly attenuated the stimulatory effects of NPS. By contrast, the antagonism of A1 receptors facilitated NPS-induced hyperlocomotion in mice, but we cannot rule out a merely additive effect of two stimulatory systems in the brain. Altogether, this is the first evidence of a putative role played by A2A and A1 receptors in modulating hyperlocomotion induced by NPS. 相似文献
5.
Previous work revealed that adenosine antagonists as theophylline reversed neuroleptic-induced catalepsy and potentiated anticataleptic effects of dopamine agonists reflecting specific adenosine-dopamine receptor interactions in the central nervous system. We tested whether similar functional interactions exist between adenosine receptors and glutamate receptors of the N-methyl-D-asparte (NMDA) subtype. The present study demonstrates that the anticataleptic effects of the competitive NMDA receptor antagonist CGP37849 and the non-competitive NMDA receptor antagonist dizocilpine can be potentiated by coadministration of a threshold dose of the adenosine receptor antagonist theophylline (2.5 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.)-pretreated rats. This potentiation was elicited only with higher doses of CGP37849 (4 and 8 mg/kg, i.p.) or dizocilpine (0.16 mg/kg, i.p.) in haloperidol (0.5 mg/kg, i.p.), but not in reserpine (5 mg/kg, i.p.) plus -methyl-ptyrosine (100 mg/kg, i.p.)-pretreated animals. Therefore, these synergistic interactions seem to be brought about by indirect monoamine-dependent mechanisms rather than direct functional interrelationships between NMDA and adenosine A2a receptors. 相似文献
6.
Allison M. Mott Eric J. Nunes Lyndsey E. Collins Russell G. Port Kelly S. Sink Jörg Hockemeyer Christa E. Müller John D. Salamone 《Psychopharmacology》2009,204(1):103-112
Rationale Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related
processes. Research involving choice tasks has shown that rats with impaired DA transmission reallocate their instrumental
behavior away from food-reinforced tasks with high response requirements and instead select less effortful food-seeking behaviors.
Objective Previous work showed that adenosine A2A antagonism can reverse the effects of the DA antagonist haloperidol in an operant task that assesses effort-related choice.
The present work used a T-maze choice procedure to assess the effects of adenosine A2A and A1 antagonism.
Materials and methods With this task, the two arms of the maze have different reinforcement densities (four vs. two food pellets), and a vertical
44 cm barrier is positioned in the arm with the higher density, presenting the animal with an effort-related challenge. Untreated
rats strongly prefer the arm with the high density of food reward and climb the barrier in order to obtain the food.
Results Haloperidol produced a dose-related (0.05–0.15 mg/kg i.p.) reduction in the number of trials in which the rats chose the high-barrier
arm. Co-administration of the adenosine A2A receptor antagonist MSX-3 (0.75, 1.5, and 3.0 mg/kg i.p.), but not the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.75, 1.5, and 3.0 mg/kg i.p.), reversed the effects of haloperidol on effort-related
choice and latency.
Conclusions Adenosine A2A and D2 receptors interact to regulate effort-related decision making, which may have implications for the treatment of psychiatric
symptoms such as psychomotor slowing or anergia that can be observed in depression, parkinsonism, and other disorders. 相似文献
7.
Some adenosine modulators can modify stress- and ethanol-induced ulcers. However, little is known about their effects on NSAID-induced
gastric ulcers. Our studies show that cyclopentyladenosine (CPA), an A1 selective receptor agonist, produced exacerbation of the NSAID-induced gastric lesion (100% at 10 mg/kg p.o.). CPA administered
alone also demonstrated ulcerogenic capacity. PD-125944 (DPMA) and CGS 21680, A2a selective agonists, protected gastric mucosa from NSAID-induced damage with ED50 of 4.4 and 1.2 mg/kg p.o. respectively. The effect of DPMA was reversed by 8-(3-chlorostyryl) caffeine (CSC), an A2A antagonist, with an ID50 of 9 mg/kg i.p. The adenosine uptake blocker S-(4-nitrobenzyl)-6-thioinosine (NBTT; 1 mg/kg i.p.) reversed the damage with
maximum inhibition of 50-60%. This response was reversed by CSC (10 mg/kg i.p.) but not by 8-cyclopentyl-l,3-dipropylxanthine
(5 mg/kg i.p.), an A1 receptor antagonist. These data suggest that selective activation of A2 adenosine receptors completely prevents indomethacin-induced gastric ulcers. However, selective stimulation of A1 receptors causes both direct gastric damage and enhances that induced by NSAIDs. Therefore, an increase in endogenous adenosine
produces partial inhibition of the injury, suggesting a predominant role for A2 receptors in the regulation of gastric mucosa integrity. 相似文献
8.
S. M. POUCHER J. R. KEDDIE R. BROOKS G. R. SHAW D. MCKILLOP 《The Journal of pharmacy and pharmacology》1996,48(6):601-606
4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1–10 mg kg?1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg?1 min?1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg?1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6–10 mg kg?1, i.v.) by 94% after 10 mg kg?1 (p.o.) and by up to 74% after 0.3 mg kg?1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg?1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1–10 mg kg?1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg?1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg?1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A2a receptors in the action of adenosine in-vivo. 相似文献
9.
Stella L De Novellis V Vitelli MR Capuano A Mazzeo F Berrino L Rossi F Filippelli A 《Naunyn-Schmiedeberg's archives of pharmacology》2003,368(2):113-118
Adenosine reduces opioid withdrawal symptoms by activating A1 adenosine receptors, probably by inhibiting excitatory amino acid release. Since blockade of A2A adenosine receptors seems to enhance dopaminergic striatopallidal transmission, we evaluated the role of the purinergic system in the opiate withdrawal syndrome by using two A1 receptor agonists [N6-cyclohexyladenosine, CHA and 2-chloro-N6-cyclopentyladenosine, CCPA], and two A2A receptor antagonists (SCH 58261 and 8-(3-chlorostyryl)caffeine, CSC).Male adult rats received increasing doses of morphine sulphate suspended in 5 ml/kg of a sustained release preparation (40–100 mg/kg s.c.) daily for 4 days and 20 h after the last administration, the withdrawal syndrome was evoked by naloxone (5 mg/kg i.p.). Animals were observed for 30 min for signs of opiate withdrawal. Other groups of rats were implanted with concentric probes for microdialysis and dopamine levels were measured in the nucleus accumbens. CHA and CCPA (0.05, 0.1 or 0.5 mg/kg i.p.) significantly reduced "wet-dog" shakes, diarrhoea, teeth chattering, jumping and writhing. SCH 58261 and CSC (0.1, 0.5 or 1 mg/kg i.p.), given 10 min before naloxone, also reduced signs of opiate withdrawal. CHA plus SCH 58261 and CCPA plus CSC greatly enhanced the reduction of withdrawal signs observed with CHA and CCPA or CSC and SCH 58261 alone. In vivo microdialysis showed that naloxone significantly decreased DA release; this effect was prevented by pretreatment with systemic SCH 58261 and CSC, but not with CHA and CCPA. Our results demonstrate that A1 and A2A adenosine receptors mediate the effect induced by adenosine in opiate withdrawal syndrome and suggest that adenosine A1 agonists and adenosine A2A antagonists may be beneficial in the treatment of this syndrome.L. Stella and V. de Novellis share first authorship 相似文献
10.
El Yacoubi M Ledent C Parmentier M Costentin J Vaugeois J 《European journal of pharmacology》2000,401(1):63-77
The acute motor effects elicited by drugs acting upon adenosine A(2A) receptors, namely the highly selective agonist CGS 21680 or the antagonists SCH 58261 and ZM 241385, were investigated in mice. CGS 21680 dose-dependently (0.1-2.5 mg/kg i.p.) decreased horizontal and vertical motor activities. The depressant effect of CGS 21680 (0. 5 mg/kg i.p.) was maintained in mice pretreated by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline (10-30 mg/kg i.p. ), which poorly penetrates the blood-brain barrier, but was completely lost in adenosine A(2A) receptor knockout mice. Thus, the adenosine A(2A) receptor is critically involved in motor activity. SCH 58261 (1-10 mg/kg i.p.) increased locomotion and rearing with a quick onset, but for a shorter period in mice habituated to the environment than in mice unfamiliar to it. ZM 241385 (7.5-60 mg/kg i. p.) stimulated horizontal and vertical activities with a slow onset at the two highest tested doses, similarly in naive and in habituated mice. The increase in locomotion elicited by ZM 241385 (15-30 mg/kg i.p. and 10-20 nM i.c.v.) was retained in mice treated by CGS 21680 (0.5 mg/kg i.p.) but that elicited by SCH 58261 (1-3-10 mg/kg i.p. and 10-20 nM i.c.v.) partially subsided. In conclusion, both 'striatal-like'/'SCH 58261-sensitive' adenosine A(2A) receptors and 'ZM 241385-sensitive'/'atypical' CGS 21680 binding sites may mediate CGS 21680-induced motor effects. Moreover, our results suggest that 'atypical' CGS 21680 binding sites could be adenosine A(2A) receptors with a peculiar pharmacological profile. 相似文献
11.
Rationale: The elevated plus-maze and the light/dark box are two established anxiety tests in rodents, which are useful to screen putative
anxiogenic effects of drugs. Objective: Caffeine is well known to promote anxious behaviour in humans and animal models, but the precise site of action of the drug
is still a matter of debate. The present study investigated whether the anxiogenic effects of caffeine observed in mice depend
on the blockade of A2A receptor. First, the effects induced by the non-selective drug caffeine were compared with those elicited by two selective
A2A receptor antagonists over a wide range of doses in the same experimental conditions. The effects of A2A or A1 adenosine receptor agonists and of a selective A1 adenosine receptor antagonist were also investigated. Second, wild-type and A2A receptor knockout mice offered another approach to delineate the role played by A2A receptor in caffeine’s anxiogenic effects. Methods: Mice were exposed to the elevated plus-maze or to the light/dark box for 5 min after acute or chronic administration of tested
drugs. Results: Caffeine acutely administered (50 or 100 mg/kg IP) induced anxiety-like effects in both procedures. Its chronic administration
(50 mg/kg IP twice daily) for 1 week or consumption in the drinking water (0.3 g/l) for 8 days or 2 months were also anxiogenic
in the plus-maze test. The A2A receptor antagonists ZM241385 (up to 60 mg/kg IP) and SCH58261 (up to 10 mg/kg IP) were devoid of acute effects in both tests.
One week administration of ZM241385 (30 mg/kg IP) or SCH58261 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist
(DPCPX) and an agonist (CPA) at A1 receptors had no acute effects on anxiety-related indices, whereas an A2A receptor agonist (CGS 21680) displayed non-specific motor effects in the plus-maze test. Acute administration of caffeine
(50 mg/kg IP) induced no clear-cut anxiety-like effects in the plus-maze test in A2A receptor knockout mice that exhibited higher basal anxiety levels than wild-type mice. Chronic administration (50 mg/kg IP
twice daily) for 1 week elicited less anxiety-like behaviour in A2A receptor knockout than in wild-type mice. Conclusions: Adaptative mechanisms following mutation in A2A receptors or their long-term blockade after chronic ingestion of caffeine may be responsible for increase proneness to anxiety.
However, the short-term anxiety-like effect of caffeine in mice might not be related solely to the blockade of adenosine A2A receptors, since it is not shared by A2A selective antagonists.
Received: 21 March 1999 / Final version: 24 June 1999 相似文献
12.
Rationale Our previous findings have shown rapid cross-tolerance between ethanol and Δ9-tetrahydrocannabinol and that intraperitoneal (i.p.) injection of cannabinoid receptor type 1 (CB1R) antagonist SR141716
(SR) does not interfere with tolerance to either of these drugs in mice.
Objectives This study investigates the effects of SR, alone or in combination with the CB receptor agonist WIN 55,212-2 (WIN), on the
development of acute and rapid tolerance to the incoordinating effect of ethanol in rats.
Materials and methods Male Wistar rats received SR, through i.p. (0.5–2.0 mg/kg) or intracerebroventricular (i.c.v.) injections (0.5–4.0 μg), alone
or together with WIN (1.0 μg, i.c.v.), in combination with ethanol (2.7 g/kg, i.p.). Another group received WIN (1.0 μg, i.c.v.)
in combination with ethanol (2.3 g/kg), and the rats were tested for motor coordination. Rapid tolerance was assessed 24 h
later by administering ethanol to all animals and retesting them under the same dose regimen. Acute tolerance was evaluated
for 75 min after ethanol (3.0 g/kg, i.p.) in animals treated with SR or WIN (i.c.v.).
Results The reduced motor impairment on day 2 (i.e., rapid tolerance) was blocked by SR (i.p. and i.c.v.). WIN (1.0 μg, i.c.v.) facilitated
rapid tolerance and also prevented the blockade of rapid tolerance by SR (1.0 μg, i.c.v.). In the acute tolerance procedure,
SR did not affect the motor incoordination induced by ethanol.
Conclusions The results suggest that the endocannabinoid system may contribute to the development of rapid tolerance to ethanol. 相似文献
13.
Angelo A. Izzo Nicola Mascolo Francesca Borrelli F. Capasso 《Naunyn-Schmiedeberg's archives of pharmacology》1999,359(1):65-70
We have studied the effect of SR141716A (0.1–5 mg/kg, i.p.), a cannabinoid CB1 receptor antagonist, and WIN (0.1–5 mg/kg, i.p.), a cannabinoid receptor agonist, on acute defaecation and gastrointestinal
transit in mice and on intraluminal fluid accumulation in the rat small intestine. SR141716A increased while WIN 55,212-2
decreased defaecation, gastrointestinal transit and fluid accumulation. A per se non-effective dose of SR141716A (0.3 mg/kg)
counteracted the inhibitory effect of WIN 55,212-2 (1 mg/kg) on gastrointestinal functions studied. The effect of SR141716
on both intestinal fluid accumulation in rats and gastrointestinal transit in mice was inhibited by atropine (1 mg/kg, i.p.),
but not by hexamethonium (1 mg/kg, s.c.), SR140333 (20 μg/kg, i.p.) or SR48968 (20 μg/kg, i.p.), antagonists of NK1 and NK2 receptors, respectively. These results suggest that intestinal fluid accumulation and motility are inhibited by endogenous
cannabinoid(s) acting at the cannabinoid CB1 receptors. This effect may be mediated by mechanisms involving muscarinic cholinoceptors.
Received: 13 July 1998 / Accepted: 25 September 1998 相似文献
14.
Rationale We previously reported that the head-twitch responses induced by the 5-HT2 receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) (DOI-HTRs) were decreased in streptozotocin-induced diabetic mice.Objectives We examined the involvement of γ-aminobutyric acid (GABA)/benzodiazepine system on the suppression of DOI-HTRs in diabetic mice.Results The benzodiazepine receptor antagonist flumazenil (0.1–1 mg/kg, i.v.) dose-dependently and significantly increased DOI-HTRs in diabetic mice to the same levels as in nondiabetic mice. However, flumazenil (0.1–1 mg/kg, i.v.) did not affect DOI-HTRs in nondiabetic mice. The benzodiazepine receptor agonist diazepam (0.1–1 mg/kg, i.p.) had no effect on DOI-HTRs in either nondiabetic or diabetic mice. The GABAA receptor antagonist bicuculline (0.1–1 mg/kg, i.p.) and the benzodiazepine receptor partial inverse agonist Ro 15-4513 (0.1–1 mg/kg, i.v.) dose-dependently and significantly suppressed DOI-HTRs in nondiabetic mice to the same levels as in diabetic mice. Ro 15-4513-induced reduction of DOI-HTRs in nondiabetic mice was completely antagonized by flumazenil (1 mg/kg, i.v.), but not diazepam (0.3 mg/kg, i.p.).Conclusions We suggest that the abnormal diazepam-insensitive benzodiazepine receptor function partly underlies the suppression of DOI-HTRs in diabetic mice. 相似文献
15.
Pelin Tanyeri Oguz Mutlu Güner Ulak Füruzan Yildiz Akar Ipek Komsuoglu Celikyurt Bekir Faruk Erden 《Drug development research》2013,74(4):242-251
Preclinical Research |
16.
The influence of the selective adenosine A(2A) receptor antagonist ZM 241385 on exogenous l-DOPA-derived dopamine (DA) release in intact and dopamine-denervated rats was studied using an in vivo microdialysis in freely moving animals. Local infusion of l-DOPA (2.5 microM) produced a marked increase in striatal extracellular DA level in intact and malonate-lesioned rats. Intrastriatal perfusion of ZM 241385 (50-100 microM) had no effect on basal extracellular DA level, but enhanced dose-dependently the l-DOPA-induced DA release in intact and malonate-lesioned animals. A non-selective adenosine A(2A) receptor antagonist DMPX (100 microM), similarly to ZM 241385, accelerated conversion of l-DOPA in intact and malonate-denervated rats. This effect was not produced by the adenosine A(1) receptor antagonist, CPX (10-50 microM). However, ZM 241385 did not affect the l-DOPA-induced DA release in rats pretreated with reserpine (5 mg/kg i.p.) and alpha-methyl-p-tyrosine (AMPT, 300 mg/kg i.p.). Obtained results indicate that blockade of striatal adenosine A(2A) receptors increases the l-DOPA-derived DA release possibly by indirect mechanism exerted on DA terminals, an effect dependent on striatal tyrosine hydroxylase activity. Selective antagonists of adenosine A(2A) receptors may exert a beneficial effect at early stages of Parkinson's disease by enhancing the therapeutic efficacy of l-DOPA applied exogenously. 相似文献
17.
Yukihiro Ohno Junta Imaki Yukari Mae Tsuyoshi Takahashi Ayaka Tatara 《Neuropharmacology》2011,60(2-3):201-208
Previous studies showed that 5-HT1A and 5-HT2 receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT3~5-HT7 subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25–100 mg/kg, i.p.) dose-dependently enhanced HAL (0.3 mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50 mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT2 antagonist, 0.3-3 mg/kg, i.p.), ondansetron (5-HT3 antagonist, 0.1–1 mg/kg, i.p.), or SB-258585 (5-HT6 antagonist, 1–10 mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT1A antagonist, 1–10 mg/kg, i.p.), GR-125487 (5-HT4 antagonist, 1–10 mg/kg, i.p.), SB-699551 (5-HT5A antagonist, 1–10 mg/kg, i.p.) nor SB-269970 (5-HT7 antagonist, 1–10 mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1–1 mg/kg, i.p.) and SB-258585 (3 and 10 mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5 mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5 μg (13.7 nmol) per side) or SB-258585 (5 μg (8.92 nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT3 and 5-HT6 receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS. 相似文献
18.
Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP 总被引:7,自引:0,他引:7
Rationale: Current treatment of Parkinson’s disease (PD) is based on dopamine replacement therapy, but this leads to long term complications,
including dyskinesia. Adenosine A2A receptors are particularly abundant in the striatum and would be a target for an alternative approach to the treatment of
PD. Objectives: The purpose of this study is to examine the efficacy and potency of the novel selective adenosine A2A receptor antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dhydro-1H-purine-2,6-dione (KW-6002) in ameliorating
the motor deficits in various mouse models of Parkinson’s disease. Methods: We evaluated the efficacy and potency of KW-6002 and other reference compounds in the selective adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5’-N-ethylcarboxamidoadenosine (CGS 21680)-, haloperidol- or reserpine-induced catalepsy models. The effect of KW-6002 on reserpine
or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride(MPTP)-induced hypolocomotion was also examined. Results: The ED50s of KW-6002 in the reversal of CGS21680-induced and reserpine-induced catalepsy were 0.05 mg/kg, PO and 0.26 mg/kg, PO, respectively.
Compared to the ED50 of other adenosine antagonists and dopamine agonist drugs, KW-6002 is over 10 times as potent in these models. KW-6002 also
ameliorated the hypolocomotion (minimum effective dose; 0.16 mg/kg) induced by nigral dopaminergic dysfunction with MPTP or
reserpine treatment. Combined administrations of subthreshold doses of KW-6002 and l-dopa (50 mg/kg, PO) exerted prominent effects on haloperidol-induced and reserpine-induced catalepsy, suggesting that there
may be a synergism between the adenosine A2A receptor antagonist KW-6002 and dopaminergic agents. Conclusions: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson’s disease, and may offer a new therapeutic approach to the treatment
of Parkinson’s disease.
Received: 22 March 1999 / Final version: 25 May 1999 相似文献
19.
Rationale: Previous studies have suggested that the α2-adrenergic receptor antagonist yohimbine produced antinociceptive effects in the formalin test in rats. However, yohimbine
is also an agonist at serotonin (5-HT)1A receptors, suggesting the possibility that the antinociceptive effects of yohimbine might be mediated via these receptors. Objective: The purpose of the present studies was to evaluate the potential role of 5-HT1A receptors in mediating the antinociceptive effects of yohimbine. Methods: The antinociceptive effects of yohimbine were evaluated using the formalin test in rats. Results: Yohimbine (2.5–10 mg/kg s.c.) produced dose-related antinociception during both phase I and phase II of the formalin test,
and was approximately equipotent and equiefficacious to morphine. The selective 5-HT1A receptor antagonist WAY 100,635 (0.03–3.0 mg/kg s.c.) produced a partial reversal of yohimbine. In comparison, the selective
5-HT1A receptor agonist (±)8-hydroxy- dipropylaminotetralin HBr (8OH-DPAT; 1.0 mg/kg s.c.) also produced a dose-related antinociception
in the formalin test, although 8OH-DPAT was completely reversed by WAY 100,635 (3.0 mg/kg s.c.). The antinociceptive effects
of yohimbine were not antagonized by the 5-HT1B/1D antagonist GR 127935 (1.0 mg/kg and 3.0 mg/kg s.c.), the 5-HT2 antagonist LY53857 (1.0 mg/kg s.c.), or the 5-HT3 antagonist zatosetron (3.0 mg/kg s.c.). Conclusions: The present results demonstrate that yohimbine produces a dose-related antinociception in the formalin test in rats which
is mediated in part by the agonistic actions at 5-HT1A receptors.
Received: 10 September 1999 / Final version: 5 November 1999 相似文献
20.
Rationale An endocannabinoid signaling system has not been identified in hamsters.
Objective We examined the existence of an endocannabinoid signaling system in Syrian hamsters using neuroanatomical, biochemical, and
behavioral pharmacological approaches.
Materials and methods The distribution of cannabinoid receptors was mapped, and membrane fatty-acid amide hydrolase (FAAH) activity and levels of
fatty-acid amides were measured in hamster brain. The impact of cannabinoid CB1 receptor blockade and inhibition of FAAH was evaluated in the elevated plus maze, rota-rod test, and models of unconditioned
and conditioned social defeat.
Results A characteristic heterogeneous distribution of cannabinoid receptors was detected in hamster brain using [3H]CP55,940 binding and autoradiography. The FAAH inhibitor URB597 inhibited FAAH activity (IC50 = 12.8 nM) and elevated levels of fatty-acid amides (N-palmitoyl ethanolamine and N-oleoyl ethanolamine) in hamster brain. Anandamide levels were not reliably altered. The cannabinoid agonist WIN55,212-2 (1–
10 mg/kg i.p.) induced CB1-mediated motor ataxia. Blockade of CB1 with rimonabant (5 mg/kg i.p.) induced anxiogenic-like behavior in the elevated plus maze. URB597 (0.1–0.3 mg/kg i.p.) induced
CB1-mediated anxiolytic-like effects in the elevated plus maze, similar to the benzodiazepine diazepam (2 mg/kg i.p.). Diazepam
(2–6 mg/kg i.p.) suppressed the expression, but not the acquisition, of conditioned defeat. By contrast, neither URB597 (0.3–3.0 mg/kg
i.p.) nor rimonabant (5 mg/kg i.p.) altered unconditioned or conditioned social defeat or rota-rod performance.
Conclusions Endocannabinoids engage functional CB1 receptors in hamster brain to suppress anxiety-like behavior and undergo enzymatic hydrolysis catalyzed by FAAH. Our results
further suggest that neither unconditioned nor conditioned social defeat in the Syrian hamster is dependent upon cannabinoid
CB1 receptor activation. 相似文献