Biomedical subjects

W. Koek

Publications and source records attributed to W. Koek.

4 recordsLinked to original sources

PubMed1996

Behavioural specificity of chlordiazepoxide-produced StD.

Low doses of benzodiazepines produce state-dependence (StD) of food-rewarded lever pressing in rats, and it has been hypothesized that the changes of memory states that can thus be studied constitute the mechanism whereby benzodiazepines cause their characteristic psychopharmacological actions such as anxiolysis, apparent memory loss and dependence. Non-benzodiazepine CNS agents such as NMDA antagonists also produce StD in this procedure, suggesting that the StD hypothesis of psychopharmacological drug action can be expanded to include agents other than benzodiazepines. For this expansion to be possible, however, it must be shown that the StD mechanism operates in a specific manner. The present experiments examined whether varying the extent of food deprivation affects any of a number of quantitative features of chlordiazepoxide (CDP)-induced StD of food-rewarded lever pressing in rats. The data indicate that the CDP doses required to generate StD in both drug-to-saline and dose-to-dose transfer tests, are considerably lower in relatively sated as opposed to more deprived animals; little or no difference was found in tests assaying saline-to-drug transfer. The data add behavioural to available pharmacological evidence supporting the hypothesis that changes of memory state constitute the mechanism whereby CNS agents such as benzodiazepines and NMDA antagonists cause their characteristic psychopharmacological actions. Some directions for future research are identified to explore further the pharmacological and behavioural specificity of drug-produced StD.

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PubMed1995

Effects of the NMDA antagonist, dizocilpine, in various drug discriminations: characterization of intermediate levels of drug lever selection.

In each of different groups of rats trained to discriminate either 8-OH-DPAT, DOI, d-amphetamine, cocaine, chlordiazepoide or ethanol from saline, dizocilpine produced maximum percentages of drug lever (DL) selection that were intermediate between those produced by the training conditions. Dizocilpine also decreased DL selection produced by the training dose in each of the discriminations, except in ethanol-trained rats. In all discriminations, with the exception of ethanol-trained rats, the intermediate levels of DL, selection produced by dizocilpine were associated with increased FRF values (sum of the responses made on either lever before the first reinforcement occurred), increased lever selection latencies, and increased responding on the nonselected lever. At doses that, in general, had effects on response rate similar to those of dizocilpine, intermediate levels of DL selection were produced by BMY 7378 in 8-OH-DPAT-trained rats, by WY 50,324 in DOI-trained rats, by (-)-3-PPP in d-amphetamine- and in cocaine-trained rats, by alpidem in chlordiazepoxide-trained rats, and by PCP in ethanol-trained rats. The intermediate levels of DL selection produced by these latter drugs were not associated with simultaneous increases of FRF values, selection latencies, and responding on the nonselected lever. The results suggest that dizocilpine produces intermediate levels of drug-appropriate responding through the behavioral mechanism of partial generalization only in ethanol-trained rats; in all other discriminations examined here, the effects of dizocilpine appear to involve (1) pharmacological effects that differ from those of the training drug, and (2) behavioral mechanisms that are unrelated to stimulus generalization. The differentiation of partial generalization and other mechanisms whereby intermediate responding can occur in the drug discrimination paradigm requires analyses that are more detailed than those commonly used in drug discrimination research.

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PubMed1992

NMDA antagonists make learning and recall state-dependent.

Rats injected with either drug or saline were trained in a food-rewarded lever-pressing task until they could complete an FR10 requirement within the first 120s of the session, and were then tested for the retention of this response under various treatment conditions. In this procedure, state-dependency occurred with ketamine, phencyclidine, MK-801 and CGS 19755; rats trained with any of these NMDA antagonists failed to show response transfer when tested with saline. Also, in rats trained with saline the response failed to transfer in tests with any of these drugs. The doses at which the failure to transfer occurred in drug-to-saline tests, were approximately 3-fold lower than those at which the failure occurred in saline-to-drug tests. Even higher doses of these compounds were required to inhibit acquisition. The state-dependency which NMDA antagonists appear to produce in tests for saline-to-drug transfer, might constitute the mechanism whereby these compounds apparently disorganize the behavior of animals and, perhaps also, of humans. The data do not support the widely held notion that NMDA antagonists produce deficits in memory or retention; instead, at doses considerably lower than those impairing acquisition, NMDA antagonists produce a state upon which the recall of the newly learned response is dependent.

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PubMed1990

Comparative studies on the anti-punishment effects of chlordiazepoxide, buspirone and ritanserin in the pigeon, Geller-Seifter and Vogel conflict procedures.

The studies presented here compared the responsiveness to clinically effective anxiolytics of two major conflict procedures in rat (i.e. the Geller-Seifter and Vogel procedures) and of the newly introduced pigeon conflict procedure. The compounds studied were the prototypical benzodiazepine chlordiazepoxide and the non-benzodiazepine anxiolytics buspirone and ritanserin. Chlordiazepoxide produced reliable anti-punishment effects in all three procedures, but only the pigeon conflict procedure also revealed statistically significant effects on punished responding with buspirone and ritanserin. The data thus constitute the first confirmation of findings from another laboratory that these two non-benzodiazepine compounds exert robust disinhibitory effects on punished behavior in the pigeon. Further, the quantification of drug effects on punished and on unpunished responding in the pigeon. Further, the allowed the effects of the three compounds to be differentiated. The pigeon conflict procedure may be unique among available animal models of anxiety in combining the following two features. Firstly, the procedure allows the behavioral response to be highly defined and permits the experimenter to control rigidly the stimulus events which act in a conflicting manner to increase and decrease response frequency. Secondly, [??084] behavior in this procedure is responsive to benzodiazepines, but also to anxiolytic drugs the effects of which are not mediated by benzodiazepine receptors. It is proposed that the pigeon conflict procedure be used in extensive parametric studies, in an effort to examine the independent variables which may perhaps explain the widely varying and often paradoxical effects that drugs can produce in available animal models of anxiety.

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