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J De Vry

Publications and source records attributed to J De Vry.

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Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat.

Six groups of rats (N = 8), trained to discriminate chlordiazepoxide (5 or 20 mg/kg), pentobarbital (5 or 15 mg/kg) or ethanol (750 or 1500 mg/kg) from saline in a two-lever food-reinforced procedure, were tested for stimulus generalization with the three drugs. Training drug, but not training dose, affected the extent of generalization to a test drug; symmetrical generalization between chlordiazepoxide and pentobarbital and asymmetrical generalization between chlordiazepoxide and ethanol and between pentobarbital and ethanol was observed. Training dose level affected slope and ED50 of the generalization gradients of training drugs and substitution drugs, discriminative performance, response bias and threshold dose for response suppression. Indices of lever selection and percentage drug-appropriate lever responses yielded similar generalization maxima, slopes and ED50S. The potency of chlordiazepoxide relative to the potency of pentobarbital to induce drug stimulus generalization varied across the experimental groups. The results indicate differences between the discriminative effects of chlordiazepoxide, pentobarbital and ethanol. It is suggested that the discriminative effects of chlordiazepoxide, pentobarbital and ethanol are not based on their response rate modulating effects and that training dose is not a determinant for the extent of cross-generalization between these compounds.

Animals↗

Effects of chlordiazepoxide training dose on the mixed agonist-antagonist properties of benzodiazepine receptor antagonist Ro 15-1788, in a drug discrimination procedure.

In experiment 1, rats (n = 12) were trained to discriminate the benzodiazepine (BDZ) compound chlordiazepoxide (CDP, 20 mg/kg, IP) from saline in a two-lever food-reinforced procedure, and subsequently were tested for stimulus control with different doses of CDP, Ro 15-1788 (a proposed BDZ receptor antagonist) and Ro 15-1788 plus 20 mg/kg CDP. Ro 15-1788 (0.63-40 mg/kg) dose-dependently antagonized CDP, and induced predominantly saline appropriate responding when administered alone. Thereafter, the same rats were retrained by progressively decreasing the training dose, to discriminate 2.5 mg/kg CDP from saline, and were tested again with the same compounds. Ro 15-1788 (0.16-40 mg/kg) now failed to antagonize CDP (2.5 mg/kg) and increased the percentage of drug-appropriate responding in a dose-related manner when administered alone. In experiment 2, separate groups of rats (n = 10) were similarly trained to discriminate either 15 or 3 mg/kg CDP from saline. Tests with CDP, Ro 15-1788 and Ro 15-1788 plus CDP (either 15 or 3 mg/kg) yielded similar results to experiment 1, suggesting that the training dose effects on generalization and antagonism of Ro 15-1788 were not affected by the manner in which the lower CDP dose acquired drug stimulus control. It is concluded that mixed agonist-antagonist properties are apparent after variations of the BDZ training dose in a drug discrimination procedure.

Animals↗

Differential interactions between chlordiazepoxide, pentobarbital and benzodiazepine antagonists Ro 15-1788 and CGS 8216 in a drug discrimination procedure.

Rats were trained to discriminate either chlordiazepoxide (CDP, 4 mg/kg, IP, N = 8) or pentobarbital (PB, 10 mg/kg, IP, N = 8) from saline in a two-lever food-reinforced procedure. CDP and PB dose-dependently substituted for each other (greater than or equal to 90% drug lever responses); indicating that their discriminative stimulus properties were closely similar. However, discriminative stimulus control induced by CDP and PB differentially was affected by the proposed benzodiazepine (BDZ) antagonists Ro 15-1788 (0.08-20 mg/kg, IP) and CGS 8216 (2.5-20 mg/kg, IP) in each experimental group; suggesting that the discriminative stimulus properties of CDP and PB are mediated by different mechanisms of action. When administered alone, Ro 15-1788 (5 and 20 mg/kg), but not CGS 8216, induced CDP like discriminative effects, suggesting that Ro 15-1788 may have partial (BDZ like) agonist properties, not shown by CGS 8216. Additional evidence for a behavioral difference between Ro 15-1788 and CGS 8216 is suggested by differential effects of both compounds on response rate. The results may reflect differential interactions of the compounds with the BDZ receptor-GABA receptor-Cl- ionophore complex.

Animals↗

The Ro 15-1788 cue: evidence for benzodiazepine agonist and inverse agonist properties.

Rats discriminating Ro 15-1788 (10 mg/kg, i.p.) from vehicle completely generalized this cue to typical benzodiazepines, and partially generalized it to barbiturates, pentylenetetrazol, CGS 8216, beta-CCM and PK 8165. CL 218872, Ro 5-4864, phenytoine, progabide, propranolol, yohimbine and various CNS stimulants predominantly induced vehicle-appropriate responding. Chlordiazepoxide, pentobarbital, CL 218 872, PK 8165, pentylenetetrazol, CGS 8216 and beta-CCM failed to block the Ro 15-1788 cue. Generalization to both anxiolytics/anticonvulsants and anxiogenics/(pro) convulsants suggests that Ro 15-1788 has benzodiazepine agonist and inverse agonist properties.

Animals↗

Stimulus control induced by benzodiazepine antagonist Ro 15-1788 in the rat.

The imidazodiazepine Ro 15-1788 is a proposed benzodiazepine receptor antagonist. Recently however, behavioural effects of Ro 15-1788 have been demonstrated. In the present study, rats (n = 12) were trained to discriminate Ro 15-1788 (10 mg/kg, IP, t = 15 min) from vehicle in a two-lever food-reinforced procedure. All rats showed a reliable discrimination (mean injection-appropriate lever responding greater than 85%) after about 60 daily training sessions. Drug stimulus control was evidenced by an orderly generalization gradient obtained with 0.01-30 mg/kg Ro 15-1788 (ED50 for stimulus generalization: 0.12 mg/kg). Since even low doses of Ro 15-1788 have discriminative effects in the rat, it is concluded that Ro 15-1788 may have potent behavioural activity.

Animals↗

Effects of drug-induced differences in reinforcement frequency on discriminative stimulus properties of fentanyl.

Rats were trained to discriminate between fentanyl (0.04 mg/kg) and saline in a two-lever procedure. Using a FR 10 schedule of food reinforcement, drug-induced differences between the number of reinforcers obtained under fentanyl and saline conditions were observed. The effect of eliminating these differences on the outcome of generalization tests was investigated by different manipulations. In one group (N = 10), the FR 10 schedule used during saline sessions was changed to FR 6 during drug sessions. In a second group (N = 12), saline sessions ended after the number of reinforcers obtained was equal to the number obtained during the preceding drug session. A control group (N = 10) was trained using a FR 10 schedule under both conditions. Elimination of differences in reinforcement frequency accelerated the acquisition of the discrimination, diminished response bias, flattened the slope and reduced the ED50 value of generalization gradients of fentanyl, morphine and sufentanil and increased the ED50 value of naloxone in antagonizing 0.04 mg/kg fentanyl. It is concluded that the unconditioned effects of 0.04 mg/kg fentanyl on response rate in a FR 10 procedure lead to differences between saline and drug sessions which contribute to the apparent discriminative stimulus properties of fentanyl.

Animals↗

Effects of nimodipine and other calcium channel antagonists in alcohol-preferring AA rats.

Several lines of evidence suggest that L-type calcium (CA2+) channels play a role in excessive ethanol (EtOH) intake. In accordance with this, a considerable amount of antagonists for these ion channels has been found to suppress EtOH intake and preference in various animal models of alcoholism. The aim of the present study was to examine antialcohol effects of L-type Ca2+ channel antagonists in alcohol-preferring AA rats. These rats, a Wistar line selectively bred for a high 10% v/v EtOH preference in a free-choice situation, have thus far not been subjected to systematic investigations with Ca2+ channel antagonists. Therefore, effects on EtOH preference and intake, as well as on food and total fluid intake, were evaluated for the 1,4-dihydropyridine (DHP) derivatives nimodipine, felodipine, isradipine, nicardipine, nifedipine, and nitrendipine, as well as for the phenylalkylamine verapamil and the benzothiazepine diltiazem, utilizing a limited access, free-choice procedure. All DHPs were found to be highly effective in reducing both EtOH intake and preference, without affecting total fluid intake. Irrespective of route of application (IP or PO), the effective dose ranges were found to be very similar across compounds (10-30 mg/kg). Nevertheless, because food intake was also reduced, the effects were not completely selective. For nimodipine, the (-)-enantiomer seemed to be more effective as its (+)-enantiomer, possibly reflecting stereoselectivity at central binding sites. Compared to the DHPs, verapamil produced a similar profile of activity, but diltiazem was found to be ineffective. These results confirm and extend previous findings with L-type Ca2+ channel antagonists obtained in other models of alcoholism and suggest that this class of compounds offers an interesting approach for the pharmacotherapy of alcoholism.

Alcohol Drinking↗

[The presynaptic metabolic modulation of the impulse-dependent release of 3H-serotonin from rat brain slices by ipsapirone (TVX Q 7821) and other serotonin agonists].

The experiments with thin slices of the cortex and dorsal raphe nucleus of rat midbrain which were incubated with [3H]-hydroxytryptamine ([3H-]HT) have established that serotonin and its agonists inhibit 3H-HT release from the electrically stimulated slices. The serotonin agonists ipsapirone (TVX Q 7821), buspirone, gepirone, and 8-OH-DPAT which mainly stimulate the Type 1A serotonin receptors of somatodendritic synapses inhibit the release of [3H]-HT from the dorsal raphe nucleus slices to a greater extent rather from those of the cortex. On the contrary, the serotonin agonists TFMPP, mCPP, and Ru 24969 which predominantly affect 1B-HT receptors largely inhibit [3H]-HT release from the electrically stimulated cortical slices. Ipsapirone-induced inhibition of the impulse-dependent release of [3H]-HT has been found to be associated with changes in intracellular cAMP levels and protein kinase activity. The nature of serotonin agonist-induced modulation of the impulse-dependent release of [3H]-HT from serotoninergic neurons is discussed in the paper.

Animals↗