Partial generalization in pigeons trained to discriminate morphine from saline: Applications of receptor theory

Koek, Wouter; Woods, James H.

doi:10.1002/ddr.430160211

Cited by 24 publications

(9 citation statements)

References 12 publications

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“…Such disruptions occur also with other uncompetitive, ion channel-blocking NMDA antagonists, such as phencyclidine and ketamine (Koek et al, 1993). In morphinediscriminating pigeons, ketamine produced intermediate responding that did not markedly change when the training dose was varied, a finding that is consistent with a general disruption of discriminative responding (Koek and Woods, 1989). Here, ketamine also produced intermediate responding, but its effects changed as a function of training dose.…”

Section: Ghb Training Dose 415supporting

confidence: 73%

Discriminative Stimulus Effects of γ-Hydroxybutyrate: Role of Training Dose

Koek

Chen

Mercer

et al. 2005

J Pharmacol Exp Ther

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␥-Hydroxybutyrate (GHB) is a drug of abuse with actions at GHB and GABA receptors. This study examined whether the relative importance of GABA A , GABA B , and GHB receptors in the discriminative stimulus effects of GHB depends on the training dose. In comparison with a previous 100 mg/kg GHB-saline discrimination, pigeons were trained to discriminate either 178 or 56 mg/kg GHB from saline. Increasing the training dose shifted the GHB gradient to the right, and decreasing it shifted the gradient to the left. Similar shifts occurred with the GHB precursor ␥-butyrolactone, which substituted for GHB, and with the GABA B agonists baclofen and 3-aminopropyl(methyl)phosphinic acid hydrochloride (SKF97541) and the benzodiazepine diazepam, each of which produced at most 54 to 68% GHB-appropriate responding. The benzodiazepine antagonist flumazenil, the benzodiazepine inverse agonist ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-␣]-[1,4]-benzodiazepine-3-carboxylate (Ro 15-4513), and the GHB receptor antagonist (2E)-5-hydroxy-5,7,8,9-tetrahydro-6H-benzo[a] [7]annulen-6-ylidene ethanoic acid (NCS-382) produced a maximum of 66 to 97% GHB-appropriate responding in animals discriminating 56 or 100 mg/kg GHB and a maximum of 1 to 49% in animals discriminating 178 mg/kg. NCS-382 did not attenuate the effects of GHB. The GABA B antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348) blocked GHB at all training doses. The results suggest that increasing the training dose of GHB increases the pharmacological selectivity of its discriminative stimulus effects. At a high training dose, diazepaminsensitive GABA A receptors, for which flumazenil and Ro 15-4513 have affinity, may no longer be involved. Diazepam-sensitive GABA A receptors and GABA B receptors appear to play a similar role at all training doses. There was no evidence for GHB receptor involvement.

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Section: Ghb Training Dose 415supporting

confidence: 73%

Discriminative Stimulus Effects of γ-Hydroxybutyrate: Role of Training Dose

Koek

Chen

Mercer

et al. 2005

J Pharmacol Exp Ther

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“…In contrast to cyclazocine, intermediate responding observed with the PCP-like NMDA antagonists did not appear to be mediated by low efficacy actions at opioid receptors (Koek and Woods 1989;Koek et al 1993). Further, dizocilpine produced intermediate responding not only in opioid-trained animals, but also in several pharmacologically unrelated drug discriminations (Koek et al 1995).…”

Section: Experimental Findingsmentioning

confidence: 98%

Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABA A -ergic ligands

Bergman

Holtzman

Katz³

et al. 2000

Psychopharmacology

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Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.

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“…In the opioid system, for example, receptor-selective partial agonists are more likely to produce drug-appropriate responding to a small dose of a full agonist than to a large dose of a full agonist (Shannon and Holtzman, 1979;Koek and Woods, 1989;Picker et al, 1992Picker et al, , 1994Grabus et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Patterns of Nicotinic Receptor Antagonism: Nicotine Discrimination Studies

Jutkiewicz¹,

Brooks²,

Kynaston³

et al. 2011

J Pharmacol Exp Ther

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Evaluation of the discriminative stimulus effects of drugs is a useful procedure for identification of receptor mediation of in vivo drug effects. This assay can be enhanced when the stimulus effects of different doses of agonist are evaluated. In the present study, rats were trained to discriminate small or large doses of nicotine from saline, and interactions of these effects with nicotinic receptor antagonists and partial agonists were determined. The insurmountable nicotine antagonist mecamylamine blocked both the discriminative stimulus and response rate-reducing effects of nicotine but was less effective against the large dose of nicotine. The ␣4␤2*-selective, competitive antagonist dihydro-␤-erythrodine (DH␤E) antagonized the discriminative stimulus effects of both doses but was less effective against the larger training dose of nicotine. Schild analyses of DH␤E suggested that different nicotinic receptor populations may be mediating the stimulus effects of large and small doses of nicotine. This suggestion was supported by observations that the discriminative stimulus effects of the partial agonist cytisine were more like those of the large dose than of the small dose of nicotine and that cytisine antagonized the effects of only the small nicotine dose. Varenicline produced nicotine-like effects in both training dose groups but reduced the discriminative stimulus effects of intermediate doses of nicotine in the group trained to the small dose of nicotine. Overall, these results suggest that small doses of nicotine produce their stimulus effects via ␣4␤2* nicotine receptors, whereas larger doses of nicotine recruit additional nicotine receptor subtypes, as revealed by drug discrimination assays in rats.

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Partial generalization in pigeons trained to discriminate morphine from saline: Applications of receptor theory

Cited by 24 publications

References 12 publications

Discriminative Stimulus Effects of γ-Hydroxybutyrate: Role of Training Dose

Discriminative Stimulus Effects of γ-Hydroxybutyrate: Role of Training Dose

Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABA A -ergic ligands

Patterns of Nicotinic Receptor Antagonism: Nicotine Discrimination Studies

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