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  • 1
    ISSN: 1432-2072
    Keywords: SKF 81297 ; SKF 82958 ; R(+)-6-Br-APB ; R-SKF 38393 ; SKF 75670 ; SCH 39166 ; (+)-PHNO ; Quinpirole ; Bromocriptine ; Cocaine ; d-Amphetamine ; GBR 12909 ; Observable behavior ; Partial agonist ; Efficacy ; Squirrel monkeys
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavioral effects of selective D1 and D2, nonselective, and indirectly acting dopamine agonists were compared in squirrel monkeys using continuous observation procedures. D1 agonists including SKF 81297, SKF 82958, andR(+)-6-Br-APB produced dose-dependent increases in the frequencies of stationary postures and head movements and had little or no effect on either huddling or scratching. In contrast, SKF 75670 andR-SKF 38393, which are considered to be D1 partial agonists, had effects comparable to those of the D1 antagonist SCH 39166. That is, the D1 partial agonists increased the duration of huddling without greatly altering the frequencies of stationary postures, head movements, or scratching. Unlike the D1 agonists, the D2 agonists (+)-PHNO, quinpirole, and bromocriptine increased the frequency of scratching, but did not consistently alter other observable behaviors. The indirect dopamine agonists cocaine, GBR 12909, andd-amphetamine and the nonselective D1/D2 agonist CY 208–243, but not (−)apomorphine, had effects comparable to those of D1 agonists such as SKF 81297. That is, each of these drugs increased the frequencies of stationary postures and head movements with little or no effect on scratching or huddling. Additionally, effects of the D1 agonist SKF 82958 and the indirect dopamine agonist cocaine were surmountably antagonized by the D1 antagonist SCH 39166. The present results show that: 1) behavioral effects of D1 and D2 agonists in monkeys are qualitatively different; 2) D1 agonists presumed to differ in intrinsic activity have dissimilar effects; and 3) effects of indirect dopamine agonists are comparable to those of D1 agonists with presumably high intrinsic activity.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-2072
    Keywords: Cocaine ; Dopamine ; Fixed-ratio ; (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine] ; Quinpirole ; Second-order ; Self-administration ; SKF 82958 [R,S-6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine] ; SKF 81297 [R,S-6-chloro-7, 8-dihydroxy-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine] ; SKF 77434 [R,S-7, 8-dihydroxy-3-allyl-1-phenyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine] ; Squirrel monkey ; D1 agonist ; D2 agonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Dopaminergic mechanisms are believed to play a prominent role in the self-administration of cocaine and other abused stimulants. The contribution of D2 receptors is now well established, but less is known about the role of D1 receptors in the reinforcing effects of these drugs. To help clarify the role of D1 mechanisms in stimulant self-administration, agonists differing in D1 receptor selectivity (SKF 81297〉SKF 82958〉SKF 77434) and efficacy (SKF 82958〉SKF 81297〉SKF 77434) were studied for their ability to maintain IV self-administration in squirrel monkeys previously trained to self-administer cocaine. Up to a 100-fold range of doses of each D1 agonist was studied under both a fixed-ratio (FR) and a second-order fixed-interval (FI) schedule of reinforcement. Parallel studies were conducted with the D2 receptor agonists, (+)-PHNO and quinpirole, under the second-order FI schedule. Of the three D1 agonists, only SKF 82958 maintained consistent self-administration under both the FR and second-order FI schedules and had dose-related effects that were qualitatively similar to those of (+)-PHNO and quinpirole under the latter condition. SKF 81297, which has high selectivity at D1 receptors and intermediate agonist efficacy, maintained self-administration in the majority of monkeys under the FR schedule, but did not maintain self-administration under the second-order FI schedule. SKF 77434, which has moderate selectivity at D1 receptors and low agonist efficacy, did not maintain self-administration under either schedule. The results suggest that the ability of D1 agonists to maintain IV self-administration in squirrel monkeys depends both on the type of schedule and on the pharmacological properties (i.e. selectivity and efficacy) of the particular drug. These results are also consistent with the view that D1, in addition to D2, receptor mechanisms play a role in the self-administration of abused stimulants.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Keywords: Lu 19-005 ; Stereoselectivity ; Monoamine uptake inhibitor ; Cocaine ; GBR 12909 ; Cocaine recognition site ; Operant behavior ; Radioreceptor assay ; Temperature dependence ; Indatraline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the monoamine uptake inhibitor Lu 19-005 ((±)-trans-3-(3,4-dichlorophenyl)-N-methyl-1-indanamine) and its (+) and (−) enantiomers, Lu 20-042 and Lu 20-043, were compared with those of cocaine and the selective dopamine uptake inhibitor GBR 12909 (1-{2-[bis-(4-fluorophenyl)methoxyl]ethyl}-4-(3-phenylpropyl)piperazin e) in behavioral and radioligand binding experiments. Behavioral experiments were conducted in groups of squirrel monkeys trained under fixed-interval schedules of reinforcement in which responding was maintained either by presentation of food or by termination of a visual stimulus associated with mild electric shock. Radioligand binding studies were conducted using [3H]CFT and [3H]GBR 12935 to label elements of the dopamine uptake system in caudate-putamen membranes of cynomolgus monkeys. All drugs produced dose-related increases in response rate under the fixed-interval schedules. Lu 19-005, Lu 20-042, and Lu 20-043 had relatively slow onsets (approximately 2 h) and relatively long durations of action, with effects persisting for two or more days following administration. Stereoselectivity was evident in the behavioral effects of the enantiomers of Lu 19-005, with Lu 20-042 being approximately 14 times more potent than Lu 20-043. In radioligand binding experiments, Lu 19-005 and its enantiomers were potent inhibitors of specifically bound [3H]CFT and [3H]GBR 12935. As in behavioral experiments, Lu 20-042 was more potent than Lu 20-043. The degree of stereoselectivity, however, varied with the temperature of the assay medium. At 37° C, Lu 20-043 was approximately 36 times more potent than Lu 20-043 in inhibiting the binding of [3H]CFT, whereas at 0–4° C, the difference in potency was only about 2-fold. The increased stereoselectivity at 37° C was due to a reduced potency for Lu 20-043. The results support the view that the behavioral effects of Lu 19-005 and its enantiomers are mediated at cocaine recognition sites associated with the dopamine uptake system. The results also show that incubation temperature can be a relevant factor in determining the relative potencies of drugs at [3H]CFT binding sites in vitro.
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  • 4
    ISSN: 1432-2072
    Keywords: Diazepam ; Pentobarbital ; Cocaine ; Substitution procedure ; Reinforcing properties ; Dependence potential ; Fixed-ratio schedules ; Rhesus monkeys
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Diazepam self-administration was studied in rhesus monkeys under several conditions of availability. Leverpress responding was maintained in twelve monkeys under a fixed-ratio 10 (FR 10) schedule of IV cocaine or pentobarbital delivery in daily sessions of 1–3 h duration. Each of several doses of diazepam (0.012–0.4 mg/kg/infusion) or vehicle was periodically substituted for 5–14 consecutive sessions. Between each substitution, responding was maintained by the baseline drug (cocaine or pentobarbital). Another procedure was to decrease the response requirement for drug delivery to a fixed-ratio one (FR 1). In three of eleven monkeys studied under conditions of a cocaine baseline and the FR 10 schedule, responding was maintained by diazepam and was inversely related to dose. In each of five monkeys tested in a similar manner but with a pentobarbital baseline, at least one dose of diazepam maintained responding above vehicle levels. Three of these monkeys had previously failed to self-administer diazepam under the cocaine baseline condition. Subsequently when two of these monkeys were returned to the cocaine baseline, diazepam was not self-administered above vehicle levels. Under FR 1 conditions of substitution, vehicle and pentobarbital intake increased in each monkey tested and cocaine intake increased in two of four monkeys. Diazepam self-administration also increased but did not exceed vehicle levels under the FR 1 schedule. However, in two monkeys the number of diazepam infusions was increased compared to the FR 10 substitution condition. These results emphasize the importance of testing drugs under several conditions to determine their relative dependence potential.
    Type of Medium: Electronic Resource
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