Overshadowing of nicotine discrimination in rats: a model for behavioural mechanisms of drug interactions?

Overshadowing can play an important role in conditioning with compound exteroceptive stimuli. Drug discrimination experiments have been carried out to examine overshadowing when mixtures of drugs serve as compound interoceptive stimuli. Three groups of rats were trained in a two-bar operant procedure with a tandem schedule of food reinforcement (n = 8). All rats were trained to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline, but in two groups of animals midazolam (0.1 or 0.2mg/kg s.c.) was co-administered with the nicotine to generate a compound stimulus. Dose-response curves were determined with nicotine and midazolam in each group. In rats trained with nicotine alone, there was a steep dose-response curve for the discriminative stimulus effect of nicotine. The presence of the smaller dose of midazolam in the training stimulus clearly attenuated, and the larger dose prevented, the appearance of the discriminative effect of nicotine, whereas there was a concomitant increase in the discriminative response to midazolam. These results suggest that midazolam overshadowed the response to nicotine in a dose-related manner. In rats trained with nicotine alone, the same doses of midazolam had no effect on the discriminative response established to the nicotine stimulus, indicating the absence of pharmacological antagonism. The results illustrate how conditioning factors may provide a behavioural mechanism for interactions between abused drugs.     

Discriminative stimulus effects of a nicotine-midazolam mixture in rats

Rats were trained to discriminate the effects of nicotine (0.4 mg/kg SC) plus midazolam (0.2 mg/kg SC) from those of saline in a two-bar operant conditioning procedure involving a tandem schedule of food reinforcement. After discrimination training, the component drugs of the mixture produced very considerable amounts of drug-appropriate responding when given separately. Mecamylamine and Ro 15-1788 only slightly attenuated the discriminative response to the mixture when given separately, but completely blocked the response when administered together. In different groups of rats trained to discriminate nicotine or midazolam separately from saline, neither drug appreciably altered the dose-response curve for the other, suggesting a minimal role for pharmacological interactions when effects of mixtures were assessed. The results suggest that the two components of a compound drug-produced stimulus can be perceived separately rather than being blended into a homogenous entity. Knowledge of the characteristics of compound drug-produced stimuli may aid interpretation of the discriminative effects of single drugs with wide spectra of action.     

Discrimination of agonist-antagonist mixtures: experiments with nicotine plus mecamylamine

Discrimination of a mixture of an agonist plus an antagonist has been analysed by training rats to discriminate (-)-nicotine (0.32mg/kg s.c.) from saline; in different groups of rats (n = 8), nicotine was administered either alone or in combination with the non-competitive nicotine antagonist mecamylamine (0.1-0.8mg/kg s.c.). Rats were trained in a two-bar operant conditioning procedure with a tandem schedule of food reinforcement. After 50 sessions, rats trained with nicotine alone had acquired the discrimination with an accuracy of about 85%. In combination, mecamylamine blocked accuracy during acquisition in a dose-related manner. In generalization tests, rats trained with nicotine alone yielded a typical dose-response curve for nicotine (ED(50) = 0.082mg/kg), without depression of response rate. In rats trained with nicotine plus 0.2mg/kg of mecamylamine, the ED(50) for the discriminative effect of nicotine was lowered (ED(50) = 0.036mg/kg), again without depression of response rate. In rats trained with nicotine plus 0.4-0.8mg/kg of mecamylamine, nicotine did not acquire stimulus control over behaviour (flat dose-response relationships), but in these animals, nicotine had a pronounced response rate-decreasing effect. These characteristics of discriminations based on nicotine plus mecamylamine differed substantially from those of previously described discriminations of nicotine plus midazolam, supporting the hypothesis that interactions between the latter drugs were based on a behavioural mechanism (overshadowing) rather than on interactions at the level of receptors.     

Nicotine trace discrimination in rats with midazolam as a mediating stimulus

It was shown previously that effects of drugs present prior to training sessions could serve as discriminative stimuli. Further experiments have aimed to determine whether a second drug can serve as a mediating stimulus that increases the strength of stimulus control by such pre-session drug effects. Rats were trained in a two-lever discrimination procedure with food reinforcers presented on a tandem variable-interval fixed-ratio (VI-FR) schedule. Injections of nicotine (0.6 mg/kg) or saline were followed after 5 min by administration of midazolam (0.2 mg/kg) as a putative mediating stimulus. The nicotine antagonist mecamylamine (1.0 mg/kg) was administered 5 min after midazolam, to block effects of nicotine during training sessions, as in previous work on pre-session drug effects. Stimulus control was acquired slowly and to an accuracy of only 75%. Midazolam did not facilitate the acquisition or magnitude of nicotine-induced stimulus control. However, extinction tests showed that the presence of midazolam was required for expression of stimulus control by pre-session effects of the training dose of nicotine. The response to nicotine (0.075-0.6 mg/kg) was dose-related, but the dose-response relationship was not dependent upon the presence of midazolam. In a group of rats trained with nicotine and midazolam as above, but without mecamylamine, stimulus control by nicotine was not dependent upon the presence of midazolam. In all cases, overall rates of responding were very low when tests were carried out without midazolam, suggesting the presence of state-dependent learning. The results imply that under appropriate conditions the discriminative stimulus effects of one drug (nicotine) can be mediated by the action of a second substance (midazolam). This finding can be conceptualized in terms of occasion setting, with nicotine serving as the feature and midazolam as the target stimulus. Furthermore, it appears that even when rates of responding show drug-state dependence, this is not necessarily the case for discriminative stimulus effects.     

Discriminative stimulus properties of the nicotinic agonist cytisine

Cytisine binds with high affinity and specificity to neuronal nicotinic receptors but its physiological and behavioural effects are complex and differ from those of nicotine. The present study explores the behavioural aspects further by comparing the discriminative stimulus effects of cytisine with those of nicotine. Two groups of rats were trained to discriminate cytisine (2 mg/kg SC) or nicotine (0.2 mg/kg SC) from saline in a two-lever operant conditioning procedure with food reinforcers presented on a tandem VI FR schedule. A third group of rats was trained to discriminate cytisine (3 mg/kg SC). Rats acquired these discriminations within 50 training sessions. The stimulus effects of both cytisine and nicotine appeared within 4 min of SC injection. In generalization tests, rats trained with either cytisine or nicotine showed steep dose-response curves (generalization gradients) for their respective training drug. However, rats trained with cytisine showed full dose-related, generalization to nicotine (93%), whereas rats trained with nicotine exhibited only partial generalization to cytisine (54%). Rats trained with either cytisine or nicotine exhibited similar, partial generalization (76–77%) to (+)-amphetamine. The nicotine antagonist mecamylamine blocked the discriminative stimulus effects of both cytisine and nicotine; it was confirmed that the block of nicotine (0.2 mg/kg) was complete, whereas the block of cytisine (2 and 3 mg/kg) was incomplete in two separate experiments. Overall, the results showed that cytisine, like nicotine, can serve as a robust discriminative stimulus but, in contrast to its relatively high affinity in binding experiments, cytisine was much less potent than nicotine in the behavioural studies. Although the stimulus effects of the two drugs were very similar, there were some subtle differences such as the asymmetrical cross-generalizations between them and possible small differences in susceptibility to antagonism by mecamyl-amine. These effects were interpreted either in terms of a putative partial agonist effect of cytisine, or by assuming that nicotine produces a compound stimulus. Such a stimulus would be mediated through two or more subtypes of nicotinic receptor, and cytisine would act at some, but not all, of these receptor subtypes. Received: 17 June 1996/Final version: 6 September 1996     

Drug discrimination and drug stimulus generalization with anxiolytics

Work with lorazepam in two-lever food-maintained drug discrimination procedures with baboons and rats found greater specificity in the generalization profile when this drug was used as a training drug compared to studies with other benzodiazepines (BZ). That is, animals trained to discriminate lorazepam have not reliably made the drug response in tests with barbiturates, although animals trained to discriminate diazepam, chlordiazepoxide, triazolam, oxazepam, and sometimes midazolam commonly have done so. Characterization of the discriminative stimulus effects of lorazepam has included manipulation of species, training dose, and route of administration; drug interaction studies; and tests with a variety of anxiolytics. The time course of the discriminative stimulus effects of lorazepam and other drugs also has been studied using a multiple session procedure in baboons. Some of these results have provided information relevant to the extent to which intermediate levels of the drug response in test sessions at doses that do not reduce response rates may meaningfully reflect threshold or partial drug stimulus effects.     

Selective antagonism of behavioural effects of nicotine by dihydro-β-erythroidine in rats

The influence of the nicotine antagonist dihydro-β-erythroidine (DHβE) was examined on various behavioural effects of nicotine in rats. Motor activity was recorded in photocell cages whereas discriminative stimulus effects were examined using two-lever drug discrimination procedures with a tandem schedule of food reinforcement (n?=?8 throughout). DHβE (0.1–3.2?mg/kg) failed to antagonise the decreases in motor activity that nicotine (0.4–0.6?mg/kg) produced in experimentally naive rats, whereas mecamylamine (1.5?mg/kg) completely blocked this effect of nicotine. DHβE (0.1–3.2?mg/kg) antagonised the increases in motor activity that nicotine (0.4?mg/kg) produced in rats with extensive previous exposure to both nicotine and the photocell apparatus. In rats trained to discriminate either 0.1 or 0.4?mg/kg nicotine from saline, DHβE (0.1–3.2?mg/kg) blocked the discriminative stimulus effect of nicotine. The block of the discriminative effect could be reversed by increasing the dose of nicotine; DHβE (1.6?mg/kg) shifted the dose-response curve for nicotine discrimination to the right by a factor of 9.4. In addition, nicotine in doses of 0.32–0.64?mg/kg decreased the overall rate of lever pressing but DHβE (1.6?mg/kg) did not influence the dose-response curve for this effect. Thus, DHβE potently blocked the locomotor activating and discriminative stimulus effects of nicotine at doses that did not antagonise its locomotor depressant and operant response rate-reducing effects. This selective blockade supports the involvement of different subtypes of nicotinic receptor in the mediation of diverse behavioural effects. Furthermore, the rightward shift of the dose-response curve for nicotine discrimination suggested a competitive mode of action for DHβE.     

Impact of training history on discrimination of a drug mixture by rats

The impact of training sequence on discrimination of a mixture of two drugs was investigated with five groups of rats (n = 10). In phase I, two groups were trained according to conventional two-lever, operant drug discrimination protocols with food reinforcement; one of these groups was trained with nicotine (0.4mg/kg) and the other group was trained with midazolam (0.15mg/kg). The three remaining groups served as controls and were subjected to 'sham' training in which administrations of saline, nicotine or midazolam were unrelated to contingencies of reinforcement. After completion of phase I (40 sessions), all five groups were trained to discriminate a mixture of nicotine (0.4mg/kg) plus midazolam (0.15mg/kg) from saline (phase II). Any differences between the groups in their performance during phase II could, therefore, be attributed to their different histories in phase I. During phase II, all groups discriminated the mixture from saline with similar accuracy (89-94% drug-appropriate responding after mixture as compared with 2-7% after saline). In the three groups of rats subjected to 'sham' training in phase I, there was partial generalization to both nicotine (45-53%) and midazolam (39-40%), each of which therefore contributed about equally to stimulus control by the mixture. In rats that were initially trained to discriminate nicotine, midazolam had acquired little stimulus control over behaviour (9%) and discrimination of the mixture was attributable largely to the nicotine (87%). Conversely, in rats that were initially trained to discriminate midazolam, nicotine contributed 3% and midazolam 76% to stimulus control by the mixture. These powerful, persistent effects of training sequence were interpreted as examples of associative blocking demonstrated with the interoceptive stimuli produced by psychoactive drugs.     

Antagonism of stimulus properties of nicotine by dihydro-β-erythroidine (DHβE) in rats

Rationale: Previous work has shown that a dose of DHβE, a competitive nicotinic receptor antagonist that blocked the discriminative stimulus properties of nicotine, was insufficient to block locomotor depression or operant rate-reducing effects of nicotine in rats. Examination of DHβE against other behavioural effects of nicotine may help in understanding its diverse actions. Objective: The present experiments examine the aversive stimulus properties of nicotine, a function implicated in the regulation of nicotine intake. Furthermore, to characterise the duration of pharmacological blockade produced by DHβE, the antagonist was examined in the drug discrimination (DD) procedure. Methods: Using the conditioned taste aversion (CTA) paradigm, male hooded rats were trained to avoid one of two distinctively flavoured solutions paired with nicotine (0.2 or 0.4 mg/kg) administration. In rats trained to discriminate 0.2 mg/kg SC nicotine in a two-lever procedure maintained under a tandem VI60”-FR10 schedule of food reinforcement, the offset of antagonism by DHβE was examined 5, 15 and 30 min following injection of nicotine (0.2 or 0.4 mg/kg SC) or vehicle. Results: Administration of DHβE (0.5, 1.6 and 5.0 mg/kg SC) 30 min before nicotine failed to block nicotine (0.4 mg/kg) CTA, while co-administration of DHβE (5.0 mg/kg SC) with nicotine (0.2 and 0.4 mg/kg SC) prevented the development of CTAs. This blockade complemented nicotine discrimination data in which DHβE blocked the discriminative stimulus effect of nicotine (0.2 or 0.4 mg/kg SC) for 45 min after its administration. Conclusions: These observations of DHβE’s short-lasting antagonism against the aversive and discriminative stimulus effects of nicotine support the involvement of the similar subtypes of nicotinic receptor in the mediation of these diverse behavioural effects. Received: 19 June 1999 / Final version: 11 November 1999     

Discrimination of a drug mixture in rats: role of training dose, and specificity

Many drugs produce compound discriminative stimuli with at least two elements; in contrast, the present study examines discrimination of a mixture of two drugs and tests the role of training dose in, and the specificity of, such a discrimination. Rats discriminated a mixture of nicotine (0.2mg/kg s.c.) and midazolam (0.1mg/kg s.c.) from saline in a two-bar operant conditioning procedure with accuracy of at least 80%. Stimulus control was analyzed by testing each drug separately. Initially, stimulus control was mainly attributable to the midazolam. The doses of drugs used to maintain the discrimination were then altered. As the training dose of nicotine increased and that of midazolam decreased, the magnitudes of responses to the separate drugs were progressively reversed, until stimulus control was mainly attributable to nicotine. Thus, responses to the components of the compound stimulus were systematically related to the amounts of drugs in the mixtures used to maintain the discrimination, and there was some evidence that a strong stimulus produced by one drug may have overshadowed a weaker stimulus produced by a different agent. To test specificity, generalization to other drugs was examined. There was no generalization to amphetamine, morphine or quipazine, up to doses that reduced overall rates of responding. It follows that cues produced by mixtures of drugs may be as specific as those produced by single agents.     

Antagonism of AND and AND-OR drug mixture discriminations in rats

It has been suggested that use of the AND-OR training method may be associated with an enhancement of the pharmacological specificity of discriminations based on mixture of drugs. Rats were trained to discriminate a mixture of nicotine (0.4 mg/kg s.c.) plus midazolam (0.2 mg/kg s.c.) from saline (AND-discrimination, n = 8) or to discriminate the mixture from either drug alone (AND-OR discrimination, n = 6). The studies used two-lever operant procedures with food reinforcers presented on a tandem schedule. After discriminations were acquired to 80% accuracy, the nicotine antagonist mecamylamine (0.03–1.0 mg/kg s.c.) and the benzodiazepine antagonist flumazenil (0.32–10 mg/kg i.p.) were tested on the response to the mixture of nicotine plus midazolam. The antagonist effects of either mecamylamine or flumazenil given alone were more marked in rats trained under the AND-OR procedure than in rats trained on the AND-discrimination. Similarly, the antagonist effects of mixtures of mecamylamine plus flumazenil were much more potent under the AND-OR than under the AND-discrimination procedure. The AND-OR method reduced the dose of the antagonist mixture needed to produce complete block by a factor of about 10, as compared with the AND-discrimination. These striking differences in sensitivity to antagonists support the view that AND-OR or related procedures may enhance the pharmacological specificity of complex drug discriminations.     

Combined discriminative stimulus effects of midazolam with other positive GABA<Subscript>A</Subscript> modulators and GABA<Subscript>A</Subscript> receptor agonists in rhesus monkeys

Rationale Interactions among compounds at GABA_A receptors might have important implications for the therapeutic and other effects of positive GABA_A modulators (e.g. benzodiazepines).Objectives This study examined whether a midazolam discriminative stimulus is modified by GABA_A agonists that act at sites other than benzodiazepine sites.Methods Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABA_A receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA_A receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam.Results When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1–3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32–1 mg/kg), gaboxadol (3.2–10 mg/kg) and progabide (10–32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive.Conclusions Direct-acting GABA_A receptor agonists are qualitatively different from positive GABA_A modulators in rhesus monkeys trained to discriminate midazolam. Although GABA_A receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA_A receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl^– flux at the GABA_A receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.     

The serotonin<Subscript>2C</Subscript> receptor agonist Ro-60-0175 attenuates effects of nicotine in the five-choice serial reaction time task and in drug discrimination

Rationale There is evidence that serotonin_2C (5-HT_2C) receptors can modulate some behavioural effects of nicotine, but the generality of this action is not known. Objective To analyse the influence of the 5-HT_2C agonist Ro-60-0175 on responses to nicotine in the five-choice serial reaction time task (5-CSRTT) and on its discriminative stimulus effect; these procedures constitute models for attention-enhancing and subjective effects of nicotine, respectively. Materials and methods In the 5-CSRTT, rats were trained to obtain food reinforcers by detecting light stimuli and then challenged with Ro-60-0175 (0.3–0.8 mg/kg) and nicotine (0.2 mg/kg). For drug discrimination studies, rats were trained to discriminate nicotine (0.2 mg/kg) from saline in a two-lever procedure using a tandem schedule of food reinforcement. Results In the 5-CSRTT, nicotine positively influenced most response indices, confirming previous results. Ro-60-0175 increased response latencies and omission errors and reduced anticipatory responding but had little effect on response accuracy; importantly, it counteracted the effects of nicotine on response speed and omission errors. Pentobarbitone (10–14 mg/kg) also slowed performance of the 5-CSRTT but did not weaken the nicotine-induced enhancement of performance. In the drug discrimination procedure, Ro-60-0175 was not generalised with nicotine but shifted the nicotine dose–response curve to the right in a dose-related manner. Conclusions The data suggest that selective occupancy of 5-HT_2C receptors can attenuate some effects of nicotine in the 5-CSRTT and weaken the nicotine discriminative stimulus; these effects cannot be explained by a sedative action of Ro-60-0175. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Drug mixtures and ethanol as compound internal stimuli.

Drug discrimination methods that entail training with mixtures of drugs may shed light on polydrug abuse and on the actions of single drugs that interact with more than one receptor. In AND-discrimination procedures (drug A + drug B vs. vehicle), mixtures are discriminated primarily on the basis of their component drugs: these discriminations may be useful for testing interactions between component drugs in mixtures. The role of training dose, overshadowing and associative blocking in AND-discriminations have been investigated. For example, after prior training with midazolam, it was possible to demonstrate associative blocking of the nicotine element of the mixture stimulus, and vice versa. Using the AND-OR discriminations (drug A + drug B vs. drug A or drug B) increased pharmacological specificity considerably, and these procedures may be valuable for determining whether the effects of a novel mixture are similar to the combined effects of the training drugs. Ethanol is an example of a single drug that may produce a compound cue; rats trained to discriminate ethanol from water generalize (asymmetrically) to GABA(A) enhancers such as chlordiazepoxide (CDP) or pentobarbitone, to NMDA antagonists such as dizocilpine (MK-801), and to some serotonin agonists, such as trifluoromethylphenylpiperazine (5-HT(1B/2C)). In addition, rats trained to discriminate mixtures of either CDP or pentobarbitone plus MK-801 generalize to ethanol. A previous history of training with MK-801 or CDP (prior to ethanol discrimination training) enhanced the MK-801-like and CDP-like effects of ethanol respectively, but associative blocking of proposed elements in the ethanol stimulus was not seen. These studies provide some support for the multielement concept of ethanol discrimination but also suggest that rules governing three-component stimuli (such as those putatively produced by ethanol) may differ from those for the two-component mixtures of drugs studied previously.     

Modulation of the discriminative stimulus produced by pentylenetetrazol by centrally administered drugs

Pentylenetetrazol is anxiogenic in humans and produces an interoceptive discriminative stimulus in rats which is mimicked by anxiogenic drugs and other treatments and antagonized by anxiolytic drugs. It was proposed that the discriminative stimulus of pentylenetetrazol originates centrally. This hypothesis was tested by injecting small amounts of anxiogenic or anxiolytic drugs into the brain and comparing their ability to mimic or block, respectively, the response to pentylenetetrazol, observed after systemic injection. Food-restricted rats were trained in a two-lever operant task to discriminate the interoceptive discriminative stimulus produced by pentylenetetrazol. Intraperitoneal or intracerebroventricular injection of Ro 5-3663 was substituted in a dose-dependent manner for the stimulus produced by systemically administered pentylenetetrazol. Diazepam injected systemically, blocked the pentylenetetrazol-like stimulus associated with Ro 5-3663 administered systemically or centrally. Midazolam injected intracerebroventricularly and in a dose-dependent manner, antagonized the discriminative stimulus produced by systemic injection of pentylenetetrazol. When injected into the amygdala, midazolam also antagonized in a dose-dependent manner the pentylenetetrazol-induced stimulus. Thus, these data suggest that there are sites in the CNS for both the initiation of a pentylenetetrazol-like stimulus by Ro 5-3663 and the antagonism of the stimulus produced by pentylenetetrazol by midazolam.     

Nicotine-like discriminative stimulus effects of bupropion in rats

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine; however, nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effects through a different mechanism than nicotine. Given bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission.     

Tolerance to the discriminative stimulus effects of midazolam: evidence for environmental modification and dose fading

The ability of behavioral variables to modify the development of tolerance to the discriminative stimulus effects of midazolam was evaluated. Rats were trained to discriminate 0.32mg/kg s.c. or 1.0mg/kg i.p. midazolam from no-drug, under a two-lever procedure, in daily experimental sessions consisting of multiple discrete 20-min trials: 15-min time-out, followed by 5-min under a fixed-ratio 15 schedule of food pellet delivery. Generalization testing was accomplished by administering progressively increasing doses of midazolam before each time-out period. During the chronic phases, twice daily injections of 10mg/kg midazolam or saline were given while discrimination training was either suspended or continued; generalization gradients for midazolam were determined weekly for 4 weeks. Chronic saline given when training was continued or suspended produced slight fluctuations in the midazolam minimal discriminable dose (MDD) (the first dose of midazolam in an individual generalization gradient to produce >/=90% drug-lever responding). Tolerance developed to the discriminative stimulus effects of midazolam when chronic midazolam was given while training was suspended: at Week 4, chronic midazolam produced 3-to 57-fold rightward shifts in the midazolam generalization gradient. In contrast, continued training during chronic midazolam produced no tolerance to the discriminative stimulus effects of midazolam: at Week 4 of chronic midazolam the MDD of midazolam was not different from pre-chronic and not different from either saline condition. The effects of chronic midazolam on stimulus effects and response rates were differentiated: despite tolerance to the stimulus effects of midazolam, there were no consistent changes in response rates during chronic midazolam administration.     

Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats

Rationale. Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear. Objective. The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine. Methods. One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline. Results. In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01–0.56 mg/kg) produced full, dose-related substitution; nornicotine (1–5.6 mg/kg) substituted only partially, and lobeline (2.71–15.34 mg/kg) and pilocarpine (0.26–2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1–5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2–26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48–0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine. Conclusions. Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine. Electronic Publication     

Midazolam cue in rats: Effects of Ro 15-1788 and picrotoxin

The discriminative stimulus effect of midazolam, a short-acting benzodiazepine, was used for testing the effects of drugs thought to act as antagonists at different sites in the proposed benzodiazepine receptor complex. Rats were trained in a standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. The benzodiazepine receptor antagonist Ro 15-1788 blocked the discriminative effect of midazolam but did not influence generalization to pentobarbitone (7.5 mg/kg). The indirect GABA antagonist picrotoxin attenuated both generalization to pentobarbitone and its response rate-reducing effect. Picrotoxin had no effect on the discriminative effect of midazolam at 0.4 mg/kg but it blocked the effect of 01 mg/kg. Even in doses which reduced overall response rates, nicotine did not block discrimination of midazolam (0.4 mg/kg). The results are consistent with models which postulate a GABA-linked ion channel which is a site of action for barbiturates and which is downstream of the benzodiazepine receptor itself.     

Nicotine and methamphetamine share discriminative stimulus effects

BACKGROUND: Nicotine and methamphetamine are both abused in similar settings, sometimes together. Because there are known interactions between central nicotinic acetylcholine receptors and dopamine receptors, it is of interest to characterize the nature of the interaction of these two compounds in vivo. METHODS: The purpose of this study was to characterize the extent to which these two compounds produce similar discriminative stimulus effects and to identify pharmacological mechanisms for their interaction. Male Sprague-Dawley rats were trained to discriminate methamphetamine or nicotine from saline. First, the ability of methamphetamine and nicotine to cross-substitute in rats trained to the other compound was tested. Subsequently, the ability of a dopamine antagonist (haloperidol) and a centrally acting nicotinic antagonist (mecamylamine) to block the discriminative stimulus effects of methamphetamine and nicotine were also tested. RESULTS: Nicotine fully substituted in methamphetamine-trained rats, but methamphetamine only partially substituted in nicotine-trained rats. In nicotine-trained rats, mecamylamine fully antagonized the discriminative stimulus effects of nicotine, but haloperidol had no effect. The partial substitution of methamphetamine was partially attenuated by haloperidol, but not altered by mecamylamine. In methamphetamine-trained rats, mecamylamine failed to antagonize the discriminative stimulus effects of methamphetamine, but haloperidol fully blocked the methamphetamine cue. Mecamylamine blocked the ability of nicotine to substitute for methamphetamine, but haloperidol had no effect. CONCLUSIONS: These results indicate that nicotine and methamphetamine share discriminative stimulus effects in some subjects and that the two compounds do not act at the same site, but produce their interaction indirectly. These findings suggest that these two compounds might be at least partially interchangeable in human users, and that there are potentially interesting pharmacological reasons for the commonly observed co-administration of nicotine and methamphetamine.