The diazepam stimulus complex: specificity in a rat model

doi:10.1016/0014-2999(82)90058-9

European Journal of Pharmacology

Volume 80, Issues 2–3, 21 May 1982, Pages 225-230

https://doi.org/10.1016/0014-2999(82)90058-9 Get rights and content

Abstract

Rats were trained to discriminate between one dose of diazepam (2.0 mg/kg) and saline in a two-lever operant chamber. When the group (n = 7) reached the training criterion, other drugs were introduced to test. Test drugs with supposed agonistic effects included drugs sharing one or more effects with diazepam, while drugs with supposed antagonistic effects were selected in relation to both reported effects and a supposed neurochemical substrate for the diazepam discriminative stimulus complex (DSC). It is concluded that a discriminative stimulus complex induced by a low dose of diazepam is highly specific and dependent on specific elements in the training procedure as well as in the testing procedure.

References (8)

F.C. Colpaert
Discriminative stimulus properties of benzodiazepines and barbiturates
F.C. Colpaert et al.
Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs: Relation to some intrinsic and anticonvulsant effects
European J. Pharmacol.
(1976)
H. Barry et al.
Similarities and differences in discriminative stimulus effects of chlordiazepoxide, pentobarbital, ethanol, and other sedatives
F.C. Colpaert et al.
Theoretical and methodological considerations on drug discrimination learning
Psychopharmacologia (Berlin)
(1976)

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Cited by (31)

Silexan, an essential oil from flowers of Lavandula angustifolia, is not recognized as benzodiazepine-like in rats trained to discriminate a diazepam cue
2013, Phytomedicine
Citation Excerpt :
Over a period of weeks the rats are trained to associate one lever with vehicle or placebo treatment, and the other level with drug administration. For example, benzodiazepine drug discrimination has been extensively studied and characterized using training drugs such as diazepam (e.g. Haug and Götestam 1982; Michelsen et al. 2007). Once successfully trained, tests of drug substitution can be conducted subsequently.
Recently, an essential oil of selected quality produced from the flowering tops of Lavandula angustifolia Mill. by steam distillation (Silexan) has been approved in Germany for the treatment of restlessness in case of anxious mood. Based on the observed clinical effects, it has been speculated that lavender oil may exert benzodiazepine-like action including the known dependence and abuse potential of this class of drugs. Although no evidence for such an activity was generated during the long-standing medicinal use of lavender oil, further preclinical investigations were now conducted to evaluate this potential side effect in more detail.
Twelve adult, male, Sprague-Dawley rats were trained to discriminate the benzodiazepine drug diazepam (2 mg/kg i.p.) from saline using a two-lever operant procedure. After approximately 40 training sessions the majority of rats learned the discrimination and pre-treatment with ascending doses of diazepam (0.3–2 mg/kg i.p.) produced a dose related generalization to the diazepam cue. In these same animals Silexan was administered to see if animals recognized the drug as “diazepam-like” i.e. generalized to diazepam or “saline-like”. Silexan tested at doses 3–30 mg/kg i.p. produced almost exclusively (>90%) saline-like responding. Also there was no effect of Silexan on response rate, i.e. rate of lever pressing, at any dose suggesting that the test article is well tolerated and does not exert a sedating effect.
In sum, Silexan has no diazepam-like interoceptive property in adult, male rats. This suggests that Silexan does not share the potential of benzodiazepines to induce the development of tolerance, dependence and addiction.
Pavlovian conditioning to a diazepam cue with yohimbine as the unconditional stimulus
1996, Neurobiology of Learning and Memory
On multiple occasions, rats were administered diazepam (2.0 mg/kg, ip) followed 30 min thereafter by yohimbine hydrochloride (2.5 or 5.0 mg/kg) or isotonic saline (forward conditioning groups). Three additional groups (backward conditioning controls) were given equivalent injections, but in reverse order. After eight such pairings, the effects of a single injection of diazepam on motor performance (balancing on a rotating drum) was assessed. Rats that had received either dose of yohimbine during forward conditioning trials maintained their balance longer than the saline controls. After four additional conditioning trials, the animals’ activity patterns in a plus-maze screening test for anxiolytics were examined. Placed into the maze after a single test injection of isotonic saline, the behavior of all groups was virtually identical: less than 16% of total entries into or time spent in the four arms of the maze was spent in the two “open” arms (unprotected by surrounding walls). When tested in the maze again, but 35 min after a single injection of diazepam, the groups that had received diazepam but not yohimbine during the conditioning phase exhibited the expected increase in open-arm activity, and equivalent increases were found in backward conditioning groups. However, the group previously conditioned with 2.5 mg/kg of yohimbine following diazepam also showed an increased open-arm activity when tested with diazepam alone, but it was significantly greater than that seen in the control group. In contrast, the group conditioned with 5.0 mg/kg yohimbine following diazepam exhibited no effect of diazepam upon their plus maze activity; consequently, these animals spent less time in the open arms than either of the other groups. Yohimbine alone normally decreases open-arm activity (a putative “anxiogenic” effect) in a linear dose-dependent fashion. The fact that it had a bidirectional conditional effect on the diazepam cue drug demonstrates that a conditional response in drug → drug conditioning cannot always be predicted on the basis of the behavioral response to the signaled drug. Consideration is given to possible reasons for these effects of diazepam → yohimbine pairings in terms of the known neuropharmacological properties of yohimbine.
Discriminated taste aversion with chlordiazepoxide
1991, Pharmacology, Biochemistry and Behavior
Discriminative stimulus effects have been studied extensively with the two-response, food-reinforced operant procedure and more recently also with discriminated taste aversion (DTA) procedures. DTA procedures have the advantage of a more rapid discrimination training. However, the test phase, i.e., drug substitution, of the DTA procedure is more time consuming (1 test per 4 days) than the test phase of the two-response procedure (2 tests per 5 days). The present study investigated whether a DTA procedure with 2 tests per 5 days could be implemented. In addition, the specificity of the DTA procedure was investigated. Rats were trained to discriminate chlordiazepoxide (CDP, 20 mg/kg, IP) from vehicle using a discriminated taste aversion procedure. Selective suppression of saccharin consumption after CDP injections was maximal after seven CDP-LiCl pairings. In subsequent substitution tests, with 2 tests per 5 days, CDP-mimicking effects were found only for another benzodiazepine, diazepam, and for a barbiturate, pentobarbital. The results indicate that rats can be rapidly trained to discriminate CDP from vehicle in the discriminated taste aversion procedure and that the CDP-cue so produced has the same specificity as in a two-response, food-reinforced operant procedure. However, the DTA procedure has a number of drawbacks that make its advantage over the two-response procedure questionable.
Drug discrimination in rats successively trained to discriminate diazepam and pentobarbital
1990, Pharmacology, Biochemistry and Behavior
In Phase 1, rats were trained to discriminate either diazepam or pentobarbital from the no-drug condition. Diazepam, pentobarbital, triazolam, meprobamate, and zopiclone occasioned 100% drug-lever responding in tests under both training conditions; but the generalization gradients determined under the pentobarbital training condition were shifted to the right of those determined under the diazepam training condition. In Phase 2, the training drugs were reversed for the two groups, as well as which lever was paired with drug or no drug, in an effort to produce greater specificity of the Phase 2 discrimination. In Phase 2 tests, the Phase 1 training drug occasioned responding on the Phase 2 drug lever in all rats, suggesting that retraining overrode the Phase 1 discrimination. There were indications, however, that Phase 1 training influenced Phase 2 responding: 1) Rats ceased responding partway through no-drug training sessions using the former drug lever, and criterion performance was somewhat more difficult to maintain in Phase 2. 2) In Phase 2, dose-effect curves determined under pentobarbital training were shifted even further to the right of those determined under diazepam training than in Phase 1.
Ethanol and chronic diazepam interactions on conflict behavior in rats
1989, Alcohol
Four groups of five rats each received training on the Geller-Seifter procedure and then received 0.5, 1.0 or 2.0 mg/kg diazepam (DZ) or vehicle, respectively, 15 min prior to the behavior sessions for 14 days. On Day 14 of DZ treatment rats also were administered 2.0 g/kg of ethanol (EtOH) 30 min prior to testing. Significant dose-related decreases in lever pressing occurred between groups over the 13 days of DZ treatment during the pre- and posttone periods. However, a significant effect attributable to days occurred only in the pretone period. During the tone period, the dose-related effects were greater but the variability also increased and specific contrasts between individual means were not significant. The largest increases in lever pressing associated with an anxiolytic effect occurred with 1.0 mg/kg of DZ at Day 6. On Day 14, all animals received 2.0 g/kg of EtOH and their performance was compared to performance on Day 13. During the pre- and posttone periods, the EtOH resulted in significantly less lever pressing in the control, 0.5 and 2.0 mg/kg DZ groups, indicating a sedative effect. Rats treated with 1.0 mg/kg of DZ did not exhibit this EtOH reduction in lever pressing. During the tone or conflict period, a significant dose-related increase in lever pressing due to the EtOH was observed. The increase in the control group was not significant. During repeated exposure to DZ there was a small but significant decrease in number of reinforcements which was enhanced by the EtOH at the 0.5 and 2.0 mg/kg DZ doses but not at 1.0 mg/kg DZ. There were no significant differences in number of reinforcements for the control group between Days 13 and 14. These results demonstrate a significant dose-dependent anxiolytic effect due to the combined treatment of EtOH and DZ which did not occur with either drug alone.
Ethanol and diazepam interactions on conflict behavior in rats
1988, Alcohol
Twenty-four adult male rats trained on the Geller-Seifter conflict procedure received: 1.0, 2.0, or 4.0 mg/kg diazepam at 15 min, 0.25, 0.5, 1.0, 2.0, or 4.0 g/kg of ethanol (EtOH) at 30 min prior to the test session, or combinations of the same diazepam doses and 0.5 g/kg of EtOH. Ethanol administration produced a significant (p<0.05) dose-related decrease in lever pressing during the periods prior to the introduction of the tone stimulus, compared to lever pressing during the corresponding control periods on the day prior to drug treatment. During the posttone periods 0.25 g/kg increased lever pressing (p<0.05), while doses of EtOH from 0.5 to 4.0 g/kg resulted in significantly lower levels of lever pressing in periods following the discontinuation of the tone. In the presence of the conflict evoking tone stimulus, rats treated with 2.0 g/kg of EtOH increased their rate of lever pressing, while animals receiving the other EtOH doses exhibited lever pressing comparable to that observed during the corresponding control periods. Administration of EtOH had no effect on the number of reinforcements received during the entire test session, except for a significant (p<0.05) reduction at the highest dose of 4.0 g/kg. Diazepam increased the number of reinforcements received during the entire test session as compared to those obtained during control sessions. Lever pressing was not affected by diazepam treatment during pretone or tone periods. During the posttone periods responses were significantly (p<0.05) increased in rats receiving the lowest dose of 1.0 mg/kg of diazepam but the other doses were without effect. Combined exposure to 0.5 g/kg of EtOH and either 1.0, 2.0 or 4.0 mg/kg of diazepam resulted in significant (p<0.05) reductions in lever pressing during the pretone periods compared to that observed with diazepam alone. The combination of EtOH with these doses of diazepam had no further effect on lever pressing during the posttone periods, or on the number of reinforcements received during the entire test session, compared to effects observed with diazepam alone. However, a significant (p<0.01) interactive effect of EtOH and diazepam was observed for lever pressing in the presence of the conflict evoking tone stimulus. Exposure to 4.0 mg/kg of diazepam and 0.5 g/kg EtOH resulted in a marked increase in lever pressing in the presence of the tone stimulus, whereas either of these drug doses alone, as well as combinations of other diazepam doses and EtOH, had no effect on lever pressing during the tone periods. These results support an anxiolytic action of EtOH, defined as an increase in punished responding; as well as a sedative action, defined as a decrease in unpunished responding. In addition, diazepam potentiates anxiolytic and sedative actions of EtOH.

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^☆: A preliminary version of this paper was presented at the 15th Conference of the Scandinavian Society for Biological Psychiatry, Sundvollen, 1980. This research was supported by the Norwegian Research Council for Science and the Humanities (Project No. C.35.65-2).

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The diazepam stimulus complex: specificity in a rat model☆

Abstract

European J. Pharmacol.

Similarities and differences in discriminative stimulus effects of chlordiazepoxide, pentobarbital, ethanol, and other sedatives

Theoretical and methodological considerations on drug discrimination learning

Psychopharmacologia (Berlin)