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Effects of different classes of partial benzodiazepine agonists on punished and unpunished responding in pigeons (1999)

Kleven, M. S. ; Koek, Wouter

Springer

Psychopharmacology 144 (1999), S. 405-410

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ISSN: 1432-2072

Keywords: Key words Conflict behavior ; Pigeon ; Anxiolytic ; Benzodiazepine partial allosteric agonist ; CGS 9896 ; ZK 95962 ; ZK 91296 ; Bretazenil ; Zolpidem ; Alpidem ; Imidazenil ; Abecarnil

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Rationale: Although all of the benzodiazepines in use for the treatment of anxiety are presumably full agonists, it is conceivable that partial benzodiazepine agonists may also be clinically effective on the basis of their effects in preclinical models of anxiety. Objectives: To compare the anxiolytic-like effects of different pharmacological/chemical classes of partial benzodiazepine agonists in the pigeon conflict procedure. Methods: Anticonflict effects in pigeons whose responding was maintained under a multiple FR30 food:FR30 food+shock schedule were characterized by 1) the magnitude of punished responding or 2) the percentage of pigeons (n=5–7/dose) showing significant increases in punished responding. Results: The partial allosteric modulators bretazenil and imidazenil produced anticonflict effects comparable with or superior to those observed following administration of the relatively full agonist midazolam. In contrast, neither the β-carbolines CGS 9896, ZK 95962 and ZK 91296, nor the imidazopyridines, alpidem and zolpidem, produced anticonflict effects comparable to either bretazenil and imidazenil or the relatively full benzodiazepine agonist, midazolam, at the doses examined in this study. Conclusions: Although the β-carboline ZK 95962 produced some anticonflict effects, none of the other compounds had anxiolytic-like effects like those observed with midazolam, bretazenil or imidazenil. However, because bretazenil and imidazenil produced robust anticonflict activity, the results indicate that partial allosteric modulators could have anxiolytic effects similar to those produced by higher efficacy compounds. Altogether, the results indicate that partial benzodiazepine agonists differ in their ability to produce robust anticonflict effects in the pigeon.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002130051024

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2

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Repeated administration of cocaethylene induces context-dependent sensitization to its locomotor effects (1996)

Prinssen, E. P. M. ; Kleven, M. S. ; Koek, W.

Springer

Psychopharmacology 124 (1996), S. 300-305

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ISSN: 1432-2072

Keywords: Cocaine ; Dopamine reuptake blockers ; Reverse tolerance ; Convulsions ; Context-dependency

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract The cocaine analog, cocaethylene, has recently been identified as an active metabolite in humans consuming ethanol and cocaine. Since this compound exhibits affinity for the dopamine transporter that is more selective than that of cocaine, it is conceivable that its behavioral properties may be distinguishable from those of cocaine (cf. Elsworth et al. 1993). To investigate further the behavioral effects of cocaethylene, its ability to induce sensitization to locomotor activity in C57BL/6 mice was determined and compared with that of cocaine. In the first part of the study, mice were treated repeatedly with cocaethylene in the test environment and were then challenged with several different doses of the same drug. Repeated administration of 10, 20 or 40 mg/kg cocaethylene (IP) for 3 consecutive days produced leftward and upward shifts of the cocaethylene (2.5–56.6 mg/kg, IP) doseeffect curve on day 4. In the second part of the study, mice were treated with 20 mg/kg cocaethylene for 3 days, but were immediately placed back in their home cage following the injection: repeated administration of cocaethylene for 3 consecutive days did not significantly affect the dose-effect curve of cocaethylene (2.5–40 mg/kg, IP) on day 4. In the same paradigm, repeated administration of 20 mg/kg cocaine for 3 consecutive days produced a significant leftward shift of the cocaine (2.5–56.6 mg/kg, IP) dose-effect curve on day 4. These results confirm that cocaethylene shares a number of properties with cocaine, but also suggest that the drugs are not identical.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02247434

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3

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Discriminative stimulus properties of cocaine: enhancement by ββ-adrenergic receptor antagonists (1997)

Kleven, M. S. ; Koek, Wouter

Springer

Psychopharmacology 131 (1997), S. 307-312

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ISSN: 1432-2072

Keywords: Key words β-Adrenergic receptors ; Tertatolol ; Cocaine ; Drug discrimination ; Dose versus dose discrimination ; ( ; )-Propranolol ; Nadolol ; ICI 118 ; 551 ; Betaxolol

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Although many of the behavioral effects of cocaine are widely believed to be mediated by blockade of dopamine transporters, recent studies suggest that norepinephrine (NE) may play a modulatory role. In this study, selective and nonselective β-adrenergic receptor antagonists were administered alone or in combination with cocaine (2.5 mg/kg, IP) to rats trained to discriminate a low dose (2.5 mg/kg) from a high dose of cocaine (10 mg/kg) in a two-lever, FR10 drug discrimination procedure. The central β2/β1-adrenergic antagonists (–)-propranolol and tertatolol, and the β2-adrenergic antagonist, ICI 118,551, produced high-dose appropriate responding in a dose-related manner when administered (IP) in combination with the low training dose of cocaine. In contrast, neither the peripheral β2/β1-adrenergic antagonist, nadolol, nor the central β1-adrenergic antagonist, betaxolol enhanced the behavioral effects of the low dose of cocaine in a manner comparable with that produced by compounds with central β2-adrenergic antagonist properties. Also in contrast to findings obtained using β-adrenergic antagonists, neither the α1-adrenergic agonist cirazoline, nor the α2-adrenergic ligands (±)-efaroxan and UK-14304 enhanced the behavioral effects of the low dose of cocaine. Overall, these results suggest that central β2-adrenergic receptors may play a modulatory role in the discriminative stimulus effects of cocaine.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002130050297

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Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys (1990)

Kleven, M. S. ; Woolverton, W. L.

Springer

Psychopharmacology 101 (1990), S. 208-213

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ISSN: 1432-2072

Keywords: Cocaine ; Bromocriptine ; Desmethylimipramine ; Rhesus monkey ; Self-administration

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract This experiment tested whether bromocriptine or desmethylimipramine (DMI), both agents used clinically to treat cocaine abuse, could specifically alter behavior maintained by cocaine injections. Rhesus monkeys were trained to press a lever in daily experimental sessions under a three-component multiple schedule of reinforcement. In the first and third components, food was available under a fixed-ratio (FR) 30 schedule. In the second component cocaine (0.025 or 0.050 mg/kg/injection, IV) was available under a FR 30 schedule. Monkeys received continuous (24 h/day) IV infusions of several doses of bromocriptine or DMI. Bromocriptine (0.8–6.4 mg/kg/day) was infused for at least the same number of sessions as was required for responding to decline to low levels when the monkeys were allowed to self-administer saline. DMI (0.8–12.8 mg/kg/day) was infused for a minimum of 3 weeks. In some instances, low doses of bromocriptine decreased responding maintained by cocaine without reducing food-maintained responding, while higher doses of bromocriptine decreased responding maintained by either food or cocaine. However, bromocriptine doses that reduced cocaine intake also caused overt stimulation of locomotor activity. In contrast, DMI, at doses as much as 10 times higher than those used clinically to treat cocaine abuse did not affect responding maintained by cocaine or food. These results indicate that bromocriptine can selectively reduce behavior maintained by cocaine, although apparently by a mechanism other than blockade of reinforcing effects. On the other hand, DMI did not alter the reinforcing effects of either cocaine or food under these conditions.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02244128

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5

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Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys (1996)

Rowlett, J. K. ; Woolverton, W. L. ; Massey, B. W. ; [et al.]

Springer

Psychopharmacology 125 (1996), S. 361-370

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ISSN: 1432-2072

Keywords: Self-administration ; Reinforcement ; Progressive-ratio ; Cocaine ; Rhesus monkey ; Reinforcing efficacy

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ratio (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or FR 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013–0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02246019

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6

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Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans (1999)

Kleven, M. S. ; Koek, Wouter

Springer

Psychopharmacology 141 (1999), S. 206-212

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ISSN: 1432-2072

Keywords: Key words Conflict behavior ; Pigeon ; Anxiolytic

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30food:FR30food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P〈0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002130050826

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Pharmacological characterization of the discriminative stimulus properties of the phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)-cyclohexyl]piperidine (1999)

Kleven, M. S. ; Kamenka, Jean-Marc ; Vignon, Jacques ; [et al.]

Springer

Psychopharmacology 145 (1999), S. 370-377

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ISSN: 1432-2072

Keywords: Key words BTCP ; Cocaine ; Prazosin ; Monoamine re-uptake blocker ; Norepinephrine ; Dopamine ; Drug discrimination

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Rationale: Although both cocaine and the phencyclidine analog, BTCP, have dopamine (DA) re-uptake blocking properties, under some conditions their behavioral effects can be differentiated. Therefore, we examined whether the discriminative stimulus (DS) effects of BTCP are different from those of cocaine. Objectives: To compare the effects of monoamine re-uptake blockers, varying in their in vitro potencies as inhibitors of DA, norepinephrine (NE), or serotonin re-uptake, in different groups of rats trained to discriminate either BTCP or cocaine from saline. Additionally, drugs from other pharmacological classes were tested in both groups. Methods: Rats were trained to discriminate either BTCP (5 mg/kg, i.p.) or cocaine (10 mg/kg, i.p.) from saline under a two-lever FR10 drug discrimination procedure. Results: BTCP and cocaine cross-substituted in BTCP- and cocaine-trained rats. The DA re-uptake blockers, mazindol, indatraline, methylphenidate, GBR12909, and GBR12935, occasioned dose-related drug-lever (DL) selection both in cocaine- and in BTCP-trained rats, with potencies that were significantly correlated. In contrast, the NE re-uptake blockers, nisoxetine, desipramine, and nortriptyline, produced higher levels of DL selection in BTCP-trained rats than in cocaine-trained rats, a profile like that reported in low-dose cocaine-trained rats. Drugs from other classes acted similarly in both discriminations. Further, the α1-adrenergic antagonist prazosin dose dependently blocked the DS effects of the training dose of BTCP, but not of cocaine. Conclusions: Theresults suggest that the DS effects of BTCP are similar to cocaine, and resemble those of a low training dose of cocaine.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002130051070

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