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At least 919 records · Page 51Linked to original sources

PubMed1999

A selective dopamine D4 receptor antagonist, NRA0160: a preclinical neuropharmacological profile.

NRA0160, 5 - [2- ( 4- ( 3 - fluorobenzylidene) piperidin-1-yl) ethyl] - 4 -(4-fluorophenyl) thiazole-2-carboxamide, has a high affinity for human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 0.5, 0.9 and 2.7 nM, respectively. NRA0160 is over 20,000fold more potent at the dopamine D4.2 receptor compared with the human cloned dopamine D2L receptor. NRA0160 has negligible affinity for the human cloned dopamine D3 receptor (Ki=39 nM), rat serotonin (5-HT)2A receptors (Ki=180 nM) and rat alpha1 adrenoceptor (Ki=237 nM). NRA0160 and clozapine antagonized locomotor hyperactivity induced by methamphetamine (MAP) in mice. NRA0160 and clozapine antagonized MAP-induced stereotyped behavior in mice, although their effects did not exceed 50% inhibition, even at the highest dose given. NRA0160 and clozapine significantly induced catalepsy in rats, although their effects did not exceed 50% induction even at the highest dose given. NRA0160 and clozapine significantly reversed the disruption of prepulse inhibition (PPI) in rats produced by apomorphine. NRA0160 and clozapine significantly shortened the phencyclidine (PCP)-induced prolonged swimming latency in rats in a water maze task. These findings suggest that NRA0160 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.

Animals↗

PubMed1996

Remacemide hydrochloride and ARL 15896AR lack abuse potential: additional differences from other uncompetitive NMDA antagonists.

This study was designed to determine the possible abuse liability and phencyclidine-like effects of the low-affinity uncompetitive N-methyl-D-aspartate (NMDA) antagonists remacemide hydrochloride [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamine hydrochloride] and ARL 15896AR [(+)-alpha-phenyl-2-pyridine-ethanamine dihydrochloride]. For the abuse-liability studies, in rats trained to self-administer cocaine intravenously (0.1 mg/kg/injection), doses of remacemide HCl, ARL 15896AR, phencyclidine, and saline were made available, and the number of injections self-administered was recorded. In different sets of rats, we assessed the ability of these drugs to induce phencyclidine-like stereotyped behavior. Doses of the compounds were expressed as multiples of the 50% effective dose (ED50), as determined from the maximal electroshock (MES) test by using either oral or intravenous administration. None of the remacemide hydrochloride or ARL 15896AR doses was self-administered at a level higher than that of the saline vehicle, unlike cocaine and phencyclidine, which were self-administered at high and moderate levels, respectively. Unlike that with remacemide hydrochloride and ARL 15896AR, oral administration of the high-affinity uncompetitive NMDA receptor-antagonists phencyclidine, ARL 16247 [N-(3-ethylphenyl)-N-methyl-N'-naphthylguanidine] and MK-801 engendered phencyclidine-like stereotypy at doses near their MES ED50 values. These data confirm the unusual safety of remacemide hydrochloride and ARL 15896AR and demonstrate that they do not possess reinforcing properties. As such, they are unlikely to present a drug-abuse problem in human beings.

Acetamides↗

PubMed1997

Striatal synaptophysin levels are not indicative of dopaminergic supersensitivity.

Recent evidence suggests that behavioral supersensitivity to dopamine (DA) agonists observed in chronic neuroleptic-treated animals might be related to changes in synaptic morphology and density. The aim of this study was to test this hypothesis using Western blotting to determine the striatal synaptophysin levels in rats chronically treated with haloperidol followed by sub-acute administration of a DA agonist. Chronic haloperidol treatment (1 mg/kg/day for 21 days) produced an 88% increase in striatal synaptophysin levels and a 73% increase in apomorphine-induced stereotypes. Sub-acute administration of the DA D-1 receptor agonist SKF38393 (10 mg/kg/day for 5 days) or the DA D-2 receptor agonist quinpirole (1 mg/kg/day for 5 days) did not modify the haloperidol-induced increase in striatal synaptophysin levels. However, sub-acute administration of SKF38393 attenuated (62%) haloperidol-induced stereotypies. We conclude that there is no direct relationship between stereotyped behavior and synaptophysin levels indicating that striatal synaptophysin levels are not a good marker of dopaminergic supersensitivity.

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

PubMed2000

Super-stereotypy I: enhancement of a complex movement sequence by systemic dopamine D1 agonists.

Peripheral administration of D1 dopamine agonists elicits grooming behavior from rodents. The present study examined grooming behavior and the relative probability and stereotypy of a natural sequence of grooming movements (called a syntactic grooming chain) that follows a predictable fixed pattern of serial order. We compared the amount of grooming behavior vs. the stereotypy of sequential patterns after peripheral administration of either a partial D1 agonist (SKF 38393; 2.5, 5.0, 10, 20 mg/kg), a full D1 agonist (SKF 82958; 0.1, 0.2, 0.5, 1.0 mg/kg; i.p.), a D2 agonist (quinpirole; 5.0, 10 mg/kg), or ACTH (2.0, 5.0 mg/kg). There was a dissociation between the elicited grooming amount, the pattern frequency, and the pattern completion or sequential stereotypy after these drugs. Quinpirole and ACTH both reduced the likelihood that the sequential pattern would be completed in the normal pattern (and reduced the overall amount of grooming). Administration of either SKF 38393 or SKF 82958 increased the tendency to engage in complex stereotyped sequential patterns of grooming (even though only the partial D1 agonist increased the total amount of grooming). In addition, SKF 38393 increased the sequential stereotypy of the already-stereotyped pattern itself (as measured by the probability of completing the stereotyped sequence once it began). Thus, dopamine D1 receptor activation appears to contribute to a kind of sequential super-stereotypy in which a complex, stereotyped behavioral sequence is initiated more frequently and more often goes to completion.

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

PubMed1996

Nitric oxide synthase inhibitor L-NAME prevents amphetamine-induced prodynorphin gene expression in the rat.

1. The effect of nitric oxide synthase inhibitor on amphetamine-induced behavioral changes and prodynorphin gene expression in the nucleus accumbens and striatum of the rat has been studied. 2. L-NAME attenuated behavioral stereotypic activity evoked by amphetamine administration. 3. Acute amphetamine administration (5mg/kg i.p.) increased the prodynorphin mRNA level in the nucleus accumbens and striatum after 3 hr. 4. A nitric oxide synthase inhibitor L-nitro-arginine methyl ester (L-NAME, 10, 50 mg/kg i.p.) had no effect on the level of prodynorphin mRNA, but prevented dose-dependently the amphetamine-induced increase in prodynorphin gene expression in both the nucleus accumbens and the striatum. 5. These data indicate that inhibition of the nitric oxide pathway attenuates biochemical and behavioral effects of amphetamine.

Amphetamine↗

PubMedDate not supplied

Action of fibrinopeptides A and B on the central dopaminergic system of rats pretreated with indomethacin.

Fibrinopeptides A and B (FAB) stimulate central dopamine neurons. Inhibition of prostaglandin synthesis by administration of indomethacin potentiated the stimulatory action of FAB on apomorphine stereotypy, while induced inhibitory action of FAB on amphetamine stereotypy. Results of studies on the level and turnover of dopamine do not explain the changes in the stereotyped behavior. The data suggest that prostaglandins may to some extent participate in the mechanism of the central action of FAB.

Amphetamine↗

PubMed1994

[An ontogenic study of behavioral sensitization to cocaine in the rat].

The present study examined ontogeny of behavioral effect of acute cocaine administration and behavioral sensitization to a challenge dose of cocaine in rats previously treated with chronic cocaine. Acute stimulating effects of cocaine in behaviors were observed in as early as 7-postnatal-day (PND) rat. However, they needed higher dose of cocaine than adult rats. Adult pattern of response to acute doses of cocaine was seen in stereotypy and locomotion at 21 PND, and in rearing at 28 PND. Rats at ages of 7, 14, 21 or 28 PNDs received repeated injections of either saline or cocaine 15 mg/kg twice a day for five consecutive days. After an abstinent period of three weeks, sensitization to a challenge dose of cocaine (15 mg/kg) was assessed. Cocaine-induced stereotyped behaviors were significantly enhanced only when cocaine-pretreatment was initiated at PND 21 and 28, but not at the earlier ages of PND 7 or 14. These results suggest that cocaine-induced behavioral sensitization occurs only when subchronic cocaine administration was commenced after PND 21.

Animals↗

PubMed1987

Psychotropic agents: synthesis and antipsychotic activity of substituted beta-carbolines.

A series of novel substituted beta-carbolines was synthesized and tested for potential antipsychotic activity. Several compounds displayed moderate antipsychotic activity in vitro and in vivo as determined by relevant receptor binding assays and behavioral tests. The effect of substituents on antipsychotic activity was examined. The beta-carbolines 10 and 19 containing 2-(2-pyridinyl)ethyl and 2-(2-quinolinyl)ethyl side chains were the most potent analogues, blocking discrete trial conditioned avoidance responding in rats with AB50's of 23 and 10 mg/kg, respectively. Both showed moderate activity at the D2 receptor sites, but they lacked oral activity. In contrast, the beta-carboline 13 containing the 4-(4-pyridinyl)butyl side chain exhibited oral activity in the discrete trial conditioned avoidance screen with an AB50 of 31 mg/kg. Most compounds did not antagonize apomorphine-induced stereotyped behavior, which is indicative of low potential for extrapyramidal side effect (EPS) liability.

Animals↗

PubMed1980

An automated method for studying stereotyped gnawing.

Stereotyped behavior in rats, consisting of compulsive, repetitive sniffing and gnawing, caused by high doses of amphetamine-like psychostimulants, may serve as an animal model for psychosis. Previous methods for measuring behavioral stereotypies of this kind have required continuous observation and rating of the behaviors or semiquantitative techniques that fail to produce a continuous record of the behaviors. The present paper describes a simple automated method that provides a continuous quantitative record of the specific gnawing behavior induced in rats by methylphenidate, an amphetamine-like psychostimulant. The apparatus described and the test procedures developed are compatible with a wide variety of common counters and recorders.

Animals↗

PubMed1975

Studies on dopamine kinetics in rat brain tissue under the influence of morphine.

The effects of several drugs on the kinetics of 14C-dopamine were studied in slices of rat striata in vitro. While morphine (35 muM) did not affect the uptake of 14C-dopamine into the slices, d-amphetamine (50muM) and imipramine (100 muM) strongly inhibited it. Morphine significantly slowed the K+ -induced release of the labelled dopamine; imipramine almost completely blocked it, while amphetamine h had no clear effect. The effect of morphine was dose-dependent and could be inhibited by the narcotic antagonist naloxone. The results demonstrate that each of the drug had a characteristic pattern of effects in our system studied. The inhibitory action of morphine on the dopamine release in vitro probably reflects in vivo symptoms of a central dopamine deficiency in rats (catalepsy, akinesia, muscular rigidity) after morphine application. In further series of experiments, it was studied if the sensitivity of brain dopamine receptors increased after repeated applications of morphine, which induced clear signs of physical dependence. Since chronic morphine treatment did not increase the potency of apomorphine (which directly stimulates dopamine receptors) in inducing stereotyped behavior, it is concluded that an increased sensitivity of dopamine receptors is not necessarily involved in morphine tolerance and dependence.

Animals↗

PubMed1982

Chronic benztropine and haloperidol administration induce behaviorally equivalent pharmacological hypersensitivities separately but not in combination.

This study reports the pharmacologic induction of behavioral pharmacologic hypersensitivity in an animal model of tardive dyskinesia. Four groups of rats received IP injections twice daily of 2.5 mg/kg haloperidol (H), 10 mg/kg benztropine (B), 2.5 mg/kg H plus 10 mg/kg benztropine (H + B), or saline for 4 weeks. Drug-induced catalepsy and spontaneous oral activity were measured daily during treatment. At 1 and 2 weeks after withdrawal of treatment, all groups were tested with apomorphine (AP) for the induction of stereotyped behavior. At 6 weeks after withdrawal of treatment, all animals were tested for catalepsy after receiving 2.5 mg/kg H. During the chronic treatment phase, H inhibited and B enhanced spontaneous oral activity. Also, H induced profound catalepsy during week 1, with partial tolerance to this effect observed during weeks 2-4. At 2 weeks after withdrawal, equivalent enhancement of AP stereotypy was seen in the H and B groups, but H + B (and saline) did not cause enhancement. At 6 weeks after withdrawal, enhancement of catalepsy was observed in the H and B groups, while H + B and control groups did not differ. Both H and B administered chronically can produce hypersensitivity when given alone, but this effect is attenuated when H and B are given in combination. While preservation of the dopamine-(DA)-acetylcholine balance during treatment appears to protect against hypersensitivity, the blockade of DA reuptake by benztropine, rather than its anticholinergic properties, may explain both the failure of combined treatment to induce hypersensitivity and the ability of B alone to induce hypersensitivity.

Animals↗

PubMed2002

Repeated cocaine administration differentially affects NMDA receptor subunit (NR1, NR2A-C) mRNAs in rat brain.

We investigated the effects of intermittent intraperitoneal (i.p.) injections of cocaine (20 mg/kg) on subunit mRNAs of N-methyl-D-aspartate (NMDA) receptors (NR1/NR2A-2C) in the rat brain by in situ hybridization using phosphor screen analysis. The level of NR1 subunit mRNA significantly increased in hippocampal complexes 1 h after a single i.p. injection of cocaine. After repeated cocaine injection, the mean scores of stereotyped behavior were increased with the number of injections. The level of NR1 subunit mRNA was obviously decreased in the striatum and cortices 24 h (early withdrawal) after a final injection following 14 days of subchronic administration. During the early withdrawal period, the amount of the NR1 subunit decreased in the nucleus accumbens, globus pallidus, and subiculum. In the dentate gyrus, the NR1 mRNA level significantly increased during early withdrawal in rats subchronically treated with cocaine. Levels of NR2B subunit mRNA were reduced in the cortices and striatum. During late withdrawal from cocaine, the level of NR2C subunit mRNA in the cerebellum was also reduced. These findings suggest that the disruption of NR1, NR2B, and NR2C subunits in the discrete brain regions occurs under the cocaine-related behavioral abnormalities and would be closely implicated in the initiation and expression of behavioral sensitization induced by repeated cocaine administration. Further studies on the changes in non-NMDA receptors are required to elucidate the biological significance of glutamate receptors for the mechanisms underlying the development of behavioral sensitization.

Anesthetics, Local↗

PubMed2000

Inhibition of nitric oxide synthase in the ventral tegmental area attenuates cocaine sensitization in rats.

1. Male Sprague-Dawley rats were pretreated via bilateral infusion of the VTA with the selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (0, 8, or 40 ng/hemisphere), prior to each of 7 daily systemic cocaine (30 mg/kg, i.p.) or saline (1 ml/kg) treatments. 2. After a 7-day treatment withdrawal period, rats received a final systemic challenge with either cocaine (30 mg/kg, i.p.) or saline (1 ml/kg). 3. Locomotor and stereotypic activity were measured following the first and last treatments. 4. Daily cocaine treatment led to the development of sensitization to its stereotypic effects as revealed upon drug challenge. 5. The development of sensitization of cocaine-induced stereotypy was completely blocked by daily intra-VTA pretreatment with 7-nitroindazole. 6. In addition, attenuation of the locomotor effects of cocaine challenge was also observed in animals that received daily intra-VTA 7-nitroindazole (40 ng/hemisphere) infusions. 7. The results indicate that VTA nitric oxide is necessary for the development of sensitization of cocaine-induced stereotypic behavior, and that its repeated inhibition may produce lasting effects on the locomotor response to the drug.

Animals↗

PubMed2006

Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetamines.

Acute sodium deficiency sensitizes adult rats to psychomotor effects of amphetamine. This study determined whether prenatal and early life manipulation of dietary sodium sensitized adult offspring to psychomotor effects of amphetamine (1 or 3 mg/kg ip) in two strains of rats. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) dams were fed chow containing low NaCl (0.12%; LN), normal NaCl (1%; NN), or high NaCl (4%; HN) throughout breeding, gestation, and lactation. Male offspring were maintained on the test diet for an additional 3 wk postweaning and then fed standard chow thereafter until testing began. Overall, blood pressure (BP), total fluid intake, salt preference, and adrenal gland weight were greater in SHR than in WKY. WKY LN offspring had greater water intake and adrenal gland weight than did WKY NN and HN offspring, whereas WKY HN offspring had increased BP, salt intake, and salt preference compared with other WKY offspring. SHR HN offspring also had increased BP compared with other SHR offspring; all other measures were similar for SHR offspring. The low-dose amphetamine increased locomotor and stereotypical behavior compared with baseline and saline injection in both WKY and SHR offspring. Dietary sodium history affected the rats' psychomotor response to the higher dose of amphetamine. Injections of 3 mg/kg amphetamine in both strains produced significantly more behavioral activity in the LN offspring than in NN and HN offspring. These results show that early life experience with low-sodium diets produce long-term changes in adult rats' behavioral responses to amphetamine.

Age Factors↗

PubMed1982

Effects of chronic lithium treatment on dopamine receptors in the rat corpus striatum. I. Locomotor activity and behavioral supersensitivity.

Spontaneous locomotor activity and dopaminergic responsivity were assessed after long-term dietary treatment with the anti-manic drug lithium. Chronic dietary Li administration was not accompanied by the toxicities often reported with other modes of administration. In addition, the diet reliably yields serum and brain Li levels in the prophylactic range for manic-depressive illness. After 4 weeks exposure to Li, spontaneous locomotor activity was reduced as compared to subjects on the control diet whether or not food intake was restricted. The depression of locomotor activity following an injection of the dopamine agonist, apomorphine, was less severe in animals that ingested Li compared to those with free access to the control diet. Finally, in confirmation of the findings of Pert et al., chronic Li administration led to a partial attenuation of apomorphine-evoked stereotyped behaviors in subjects rendered supersensitive to the drug by daily injections of haloperidol (HAL) for 3 weeks. The findings suggest that the commonly reported suppressant action of Li on spontaneous behavior is not attributable to overt toxicity or to diminished growth rate. Similarly, these health factors do not account for the ability of chronic Li treatment to suppress the behavioral manifestation of dopaminergic supersensitivity associated with long-term HAL exposure.

Animals↗

PubMed1983

Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies.

Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.

Adenylyl Cyclases↗

PubMed2006

The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats.

It has repeatedly been shown that uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can mimic certain aspects of positive and negative symptoms of schizophrenia in human volunteers and laboratory animals. The purpose of the present study was to expand these findings and to determine whether the selective metabotropic glutamate receptor subtype 5 (mGluR5) antagonist, MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine), could induce similar effects in Wistar rats. First, MTEP (1.0-10.0 mg/kg; intraperitoneally) after acute and subchronic (daily for 5 days) administration as well as the uncompetitive antagonists of the NMDA receptor of either high affinity, phencyclidine (0.5-4.0 mg/kg; subcutaneously (s.c.)) and (+)-MK-801 (0.03-0.25 mg/kg; s.c.), or low-moderate affinity, ketamine (2.0-16.0 mg/kg; s.c.) and memantine (0.15-20.0 mg/kg; s.c.), following daily administration for 3 days were tested in the social interaction test to determine their ability to reproduce the negative and positive symptoms measured by social isolation and stereotyped behavior, respectively. Second, the compounds were tested in the motility test following acute administration to determine their ability to induce locomotor hyperactivity reflecting the positive symptoms. In line with previous findings, all examined NMDA receptor antagonists produced social interaction deficits, locomotor hyperactivity, and stereotypy except memantine. Notably, this study found that MTEP following both acute and subchronic administration dose-dependently induced social isolation, but did not cause either locomotor hyperactivity or stereotypy. These data demonstrate that social behavior deficits in rats can be caused by both the blockade of the NMDA receptor and the inhibition of mGluR5, whereas mGluR5 antagonists may not independently be able to mimic the positive symptoms.

Analysis of Variance↗

PubMed1995

Ontogeny of behavioral sensitization to cocaine.

The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56-60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21-25 or 28-32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later.

Animals↗